ESMO Congress 2018

MUNICH – Men with metastatic hormone-naive prostate cancer may benefit from treatment with the combination of abiraterone (Zytiga), prednisolone, and androgen deprivation regardless of risk group or disease volume, STAMPEDE trialists contend.

Results of the STAMPEDE and LATITUDE trials, published in 2017 in the New England Journal of Medicine, showed significant improvements in overall survival with abiraterone, androgen deprivation therapy (ADT) and either prednisone (in LATITUDE) or prednisolone (in STAMPEDE) compared with ADT alone.

Data from the LATITUDE trial were used to support approval by both the Food and Drug Administration and European Medicines Agency of abiraterone in combination with ADT and a glucocorticoid for the new indication of treatment of men with metastatic high-risk castration-sensitive prostate cancer.

“So where we stand, at the minute, in terms of guidance: the EAU [European Urology Association] and the NCCN [National Comprehensive Cancer Network] have suggested that we consider treatment for men with hormone-naive metastatic prostatic cancer, but in 2018 the FDA and EMA licensed the drug for high-risk disease, so there’s therefore an evolving uncertainty about what we should be doing in low-risk disease,” Alex Hoyle, MBChB, of Christie NHS Foundation Trust, Manchester, England, said on behalf of colleagues in the STAMPEDE trial group.

The problem is that there is no international consensus on what constitutes low-risk disease, Dr. Hoyle said at the European Society for Medical Oncology Congress.

For example, in the CHAARTED trial, risk was defined by volume, with high-risk patients defined as those with visceral metastases and/or four or more bone metastases with one or more outside the vertebral column or pelvis. In contrast, the LATITUDE investigators defined high-risk patients as those with two or more high-risk features, including three or more bone metastases, visceral metastases, and/or a Gleason score of 8 or more.

To determine whether men with low-risk disease could also benefit from the combination, Dr. Hoyle and colleagues performed a retrospective analysis of the STAMPEDE trial, using staging scans to stratify patients with M1 disease into either high- or low-risk categories according to the LATITUDE risk criteria. The reviewers were blinded to the treatment arm for each patient. They also performed a secondary differential analysis by tumor volume according to the CHAARTED criteria.

The investigators then retrospectively reviewed outcomes for 901 evaluable patients, median age 67 years, with a median PSA of 96 ng/mL, followed for a median of 42 months. The sample included 428 patients determined to have low-risk disease, and 473 determined to have high-risk disease.

Overall survival (OS), the primary endpoint, was significantly better for patients treated with the combination vs. ADT alone in both high- and low-risk groups. The 3-year OS in high-risk patients treated with the abiraterone/prednisolone/ADT was 64.7% compared with 45% for patients treated with AD alone, an absolute difference of 19.7% that translated into a hazard ratio (HR) for death of 0.54 (P less than .001).

For patients in the low-risk group, 3-year OS was 82.4% with the combination vs. 78% with ADT alone, an absolute difference of 4.4%, translating into an HR of 0.66 (P = .041).

Three-year prostate cancer-specific survival, a secondary endpoint, was better with abiraterone in the high-risk (67% vs. 47.9%, HR 0.57, P less than .001) and low-risk (88.7% vs. 81.6%, HR 0.51, P = .008) populations.

The results were even more pronounced in favor of the abiraterone combination for the secondary endpoint of failure-free survival (FFS) in both groups, with 45.1% of high-risk patients on abiraterone having no biochemical failure at 3 years vs. 12.2% for those treated with ADT alone (HR 0.48, P less than .001). The respective FFS rates in the low-risk group were 80.8% vs. 56.4% (HR 0.66, P = .041).

ADT was superior in analyses of skeletal related event-free survival (HR 0.48 for high risk and 0.31 for low risk, P less than .001 for both comparisons), and metastasis progression-free survival (HR 0.54, P less than .001 for high risk, HR 0.66, P = .041 for low risk).

An exploratory analysis using the CHAARTED risk criteria showed similar results, with the combination significantly better in every category except prostate cancer–specific survival in patients with low-volume disease, although here, too, there was a clear trend favoring abiraterone.

“Abiraterone plus prednisolone in addition to ADT improves survival endpoints in metastatic hormone-naive prostate cancer,” Dr. Hoyle said.

Invited discussant Karim Fizazi, MD, PhD, of Gustave Roussy Cancer Institute at the University of Paris-Sud, France, said that the study, despite some limitations, was very important.

“For patients with high-risk de novo disease, until today we’ve had two standards of care: castration plus abiraterone or castration plus docetaxel. For patients with low risk, that was strongly debated – either castration alone or castration plus docetaxel. After this publication, I think it’s fair to say that for patients with high-risk disease the role of abiraterone is being strengthened, while for patients with low-risk disease, ADT plus abiraterone probably is going to become the new standard,” he said.

The STAMPEDE trial is supported by the Medical Research Council of the United Kingdom, the Salford Royal and the Christie NHS Foundation trusts, and Manchester Cancer Research Centre. Dr. Hoyle reported having no conflicts of interest. Dr. Fizazi reported advisory board participation and/or honoraria from Amgen, Astellas, AstraZeneca, Bayer, Clovis, CureVac, Essa, Genentech, Janssen, MSD, Orion, and Sanofi.

SOURCE: Hoyle AP et al. ESMO 2018. Abstract LBA4.

MUNICH – Men with metastatic hormone-naive prostate cancer may benefit from treatment with the combination of abiraterone (Zytiga), prednisolone, and androgen deprivation regardless of risk group or disease volume, STAMPEDE trialists contend.

Results of the STAMPEDE and LATITUDE trials, published in 2017 in the New England Journal of Medicine, showed significant improvements in overall survival with abiraterone, androgen deprivation therapy (ADT) and either prednisone (in LATITUDE) or prednisolone (in STAMPEDE) compared with ADT alone.

Data from the LATITUDE trial were used to support approval by both the Food and Drug Administration and European Medicines Agency of abiraterone in combination with ADT and a glucocorticoid for the new indication of treatment of men with metastatic high-risk castration-sensitive prostate cancer.

“So where we stand, at the minute, in terms of guidance: the EAU [European Urology Association] and the NCCN [National Comprehensive Cancer Network] have suggested that we consider treatment for men with hormone-naive metastatic prostatic cancer, but in 2018 the FDA and EMA licensed the drug for high-risk disease, so there’s therefore an evolving uncertainty about what we should be doing in low-risk disease,” Alex Hoyle, MBChB, of Christie NHS Foundation Trust, Manchester, England, said on behalf of colleagues in the STAMPEDE trial group.

The problem is that there is no international consensus on what constitutes low-risk disease, Dr. Hoyle said at the European Society for Medical Oncology Congress.

For example, in the CHAARTED trial, risk was defined by volume, with high-risk patients defined as those with visceral metastases and/or four or more bone metastases with one or more outside the vertebral column or pelvis. In contrast, the LATITUDE investigators defined high-risk patients as those with two or more high-risk features, including three or more bone metastases, visceral metastases, and/or a Gleason score of 8 or more.

To determine whether men with low-risk disease could also benefit from the combination, Dr. Hoyle and colleagues performed a retrospective analysis of the STAMPEDE trial, using staging scans to stratify patients with M1 disease into either high- or low-risk categories according to the LATITUDE risk criteria. The reviewers were blinded to the treatment arm for each patient. They also performed a secondary differential analysis by tumor volume according to the CHAARTED criteria.

The investigators then retrospectively reviewed outcomes for 901 evaluable patients, median age 67 years, with a median PSA of 96 ng/mL, followed for a median of 42 months. The sample included 428 patients determined to have low-risk disease, and 473 determined to have high-risk disease.

Overall survival (OS), the primary endpoint, was significantly better for patients treated with the combination vs. ADT alone in both high- and low-risk groups. The 3-year OS in high-risk patients treated with the abiraterone/prednisolone/ADT was 64.7% compared with 45% for patients treated with AD alone, an absolute difference of 19.7% that translated into a hazard ratio (HR) for death of 0.54 (P less than .001).

For patients in the low-risk group, 3-year OS was 82.4% with the combination vs. 78% with ADT alone, an absolute difference of 4.4%, translating into an HR of 0.66 (P = .041).

Three-year prostate cancer-specific survival, a secondary endpoint, was better with abiraterone in the high-risk (67% vs. 47.9%, HR 0.57, P less than .001) and low-risk (88.7% vs. 81.6%, HR 0.51, P = .008) populations.

The results were even more pronounced in favor of the abiraterone combination for the secondary endpoint of failure-free survival (FFS) in both groups, with 45.1% of high-risk patients on abiraterone having no biochemical failure at 3 years vs. 12.2% for those treated with ADT alone (HR 0.48, P less than .001). The respective FFS rates in the low-risk group were 80.8% vs. 56.4% (HR 0.66, P = .041).

ADT was superior in analyses of skeletal related event-free survival (HR 0.48 for high risk and 0.31 for low risk, P less than .001 for both comparisons), and metastasis progression-free survival (HR 0.54, P less than .001 for high risk, HR 0.66, P = .041 for low risk).

An exploratory analysis using the CHAARTED risk criteria showed similar results, with the combination significantly better in every category except prostate cancer–specific survival in patients with low-volume disease, although here, too, there was a clear trend favoring abiraterone.

“Abiraterone plus prednisolone in addition to ADT improves survival endpoints in metastatic hormone-naive prostate cancer,” Dr. Hoyle said.

Invited discussant Karim Fizazi, MD, PhD, of Gustave Roussy Cancer Institute at the University of Paris-Sud, France, said that the study, despite some limitations, was very important.

“For patients with high-risk de novo disease, until today we’ve had two standards of care: castration plus abiraterone or castration plus docetaxel. For patients with low risk, that was strongly debated – either castration alone or castration plus docetaxel. After this publication, I think it’s fair to say that for patients with high-risk disease the role of abiraterone is being strengthened, while for patients with low-risk disease, ADT plus abiraterone probably is going to become the new standard,” he said.

The STAMPEDE trial is supported by the Medical Research Council of the United Kingdom, the Salford Royal and the Christie NHS Foundation trusts, and Manchester Cancer Research Centre. Dr. Hoyle reported having no conflicts of interest. Dr. Fizazi reported advisory board participation and/or honoraria from Amgen, Astellas, AstraZeneca, Bayer, Clovis, CureVac, Essa, Genentech, Janssen, MSD, Orion, and Sanofi.

SOURCE: Hoyle AP et al. ESMO 2018. Abstract LBA4.

MUNICH – Men with metastatic hormone-naive prostate cancer may benefit from treatment with the combination of abiraterone (Zytiga), prednisolone, and androgen deprivation regardless of risk group or disease volume, STAMPEDE trialists contend.

Results of the STAMPEDE and LATITUDE trials, published in 2017 in the New England Journal of Medicine, showed significant improvements in overall survival with abiraterone, androgen deprivation therapy (ADT) and either prednisone (in LATITUDE) or prednisolone (in STAMPEDE) compared with ADT alone.

Data from the LATITUDE trial were used to support approval by both the Food and Drug Administration and European Medicines Agency of abiraterone in combination with ADT and a glucocorticoid for the new indication of treatment of men with metastatic high-risk castration-sensitive prostate cancer.

“So where we stand, at the minute, in terms of guidance: the EAU [European Urology Association] and the NCCN [National Comprehensive Cancer Network] have suggested that we consider treatment for men with hormone-naive metastatic prostatic cancer, but in 2018 the FDA and EMA licensed the drug for high-risk disease, so there’s therefore an evolving uncertainty about what we should be doing in low-risk disease,” Alex Hoyle, MBChB, of Christie NHS Foundation Trust, Manchester, England, said on behalf of colleagues in the STAMPEDE trial group.

The problem is that there is no international consensus on what constitutes low-risk disease, Dr. Hoyle said at the European Society for Medical Oncology Congress.

For example, in the CHAARTED trial, risk was defined by volume, with high-risk patients defined as those with visceral metastases and/or four or more bone metastases with one or more outside the vertebral column or pelvis. In contrast, the LATITUDE investigators defined high-risk patients as those with two or more high-risk features, including three or more bone metastases, visceral metastases, and/or a Gleason score of 8 or more.

To determine whether men with low-risk disease could also benefit from the combination, Dr. Hoyle and colleagues performed a retrospective analysis of the STAMPEDE trial, using staging scans to stratify patients with M1 disease into either high- or low-risk categories according to the LATITUDE risk criteria. The reviewers were blinded to the treatment arm for each patient. They also performed a secondary differential analysis by tumor volume according to the CHAARTED criteria.

The investigators then retrospectively reviewed outcomes for 901 evaluable patients, median age 67 years, with a median PSA of 96 ng/mL, followed for a median of 42 months. The sample included 428 patients determined to have low-risk disease, and 473 determined to have high-risk disease.

Overall survival (OS), the primary endpoint, was significantly better for patients treated with the combination vs. ADT alone in both high- and low-risk groups. The 3-year OS in high-risk patients treated with the abiraterone/prednisolone/ADT was 64.7% compared with 45% for patients treated with AD alone, an absolute difference of 19.7% that translated into a hazard ratio (HR) for death of 0.54 (P less than .001).

For patients in the low-risk group, 3-year OS was 82.4% with the combination vs. 78% with ADT alone, an absolute difference of 4.4%, translating into an HR of 0.66 (P = .041).

Three-year prostate cancer-specific survival, a secondary endpoint, was better with abiraterone in the high-risk (67% vs. 47.9%, HR 0.57, P less than .001) and low-risk (88.7% vs. 81.6%, HR 0.51, P = .008) populations.

The results were even more pronounced in favor of the abiraterone combination for the secondary endpoint of failure-free survival (FFS) in both groups, with 45.1% of high-risk patients on abiraterone having no biochemical failure at 3 years vs. 12.2% for those treated with ADT alone (HR 0.48, P less than .001). The respective FFS rates in the low-risk group were 80.8% vs. 56.4% (HR 0.66, P = .041).

ADT was superior in analyses of skeletal related event-free survival (HR 0.48 for high risk and 0.31 for low risk, P less than .001 for both comparisons), and metastasis progression-free survival (HR 0.54, P less than .001 for high risk, HR 0.66, P = .041 for low risk).

An exploratory analysis using the CHAARTED risk criteria showed similar results, with the combination significantly better in every category except prostate cancer–specific survival in patients with low-volume disease, although here, too, there was a clear trend favoring abiraterone.

“Abiraterone plus prednisolone in addition to ADT improves survival endpoints in metastatic hormone-naive prostate cancer,” Dr. Hoyle said.

Invited discussant Karim Fizazi, MD, PhD, of Gustave Roussy Cancer Institute at the University of Paris-Sud, France, said that the study, despite some limitations, was very important.

“For patients with high-risk de novo disease, until today we’ve had two standards of care: castration plus abiraterone or castration plus docetaxel. For patients with low risk, that was strongly debated – either castration alone or castration plus docetaxel. After this publication, I think it’s fair to say that for patients with high-risk disease the role of abiraterone is being strengthened, while for patients with low-risk disease, ADT plus abiraterone probably is going to become the new standard,” he said.

The STAMPEDE trial is supported by the Medical Research Council of the United Kingdom, the Salford Royal and the Christie NHS Foundation trusts, and Manchester Cancer Research Centre. Dr. Hoyle reported having no conflicts of interest. Dr. Fizazi reported advisory board participation and/or honoraria from Amgen, Astellas, AstraZeneca, Bayer, Clovis, CureVac, Essa, Genentech, Janssen, MSD, Orion, and Sanofi.

SOURCE: Hoyle AP et al. ESMO 2018. Abstract LBA4.

MUNICH – The experimental agent capmatinib was associated with a high response rate when used in the first line for patients with advanced non–small cell lung cancers bearing MET exon 14–skipping mutations, said investigators in the Geometry MONO-1 trial.

Neil Osterweil/MDedge News

Among a cohort of 25 patients with treatment-naive, MET exon 14–mutated non–small cell lung cancer (NSCLC), the primary endpoint of overall response rate (ORR) as determined by blinded, independent reviewers was 72%.

In contrast, the ORR among 69 patients who had received one or more prior lines of therapy was 39.1%, reported Juergen Wolf, MD, of University Hospital Cologne (Germany).

“The differential benefit observed between patients treated in the first line and relapsed [settings] highlights the need of early diagnosis of this aberration, and prompt targeted treatment of this challenging patient population,” he said at the European Society for Medical Oncology Congress.

MET exon14–skipping mutations occur in approximately 3%-4% of NSCLC cases. The mutation is thought to be an oncogenic driver and has been shown to be a poor prognostic factor for patients with advanced NSCLC. Patients with this mutation have poor responses to conventional therapy and immune checkpoint inhibitors, even when their tumors have high levels of programmed death–ligand 1 (PD-L1) and high mutational burden, Dr. Wolf said.

Capmatinib (INC280) is an oral, reversible inhibitor of the MET receptor tyrosine kinase and is highly selective for MET, with particular affinity for MET exon 14 mutations. It is also capable of crossing the blood-brain barrier and has shown activity in the brain in preliminary studies.

The Geometry MONO-1 trial is a phase 2 study of capmatinib in patients with stage IIIB/IV NSCLC with tumors that demonstrate MET amplification and/or carry the MET exon 14 mutation. Three study cohorts of patients with MET amplification were closed for futility. Dr. Wolf reported results from two cohorts of patients with MET exon 14–skipping mutations regardless of gene copy number: one with treatment-naive patients and the other with patients being treated in the second or third line.

As noted, the ORR in 25 patients in the treatment-naive cohort after a median follow-up of 5.6 months was 72%, including 18 partial responses and no complete responses. In addition, six patients (24%) had stable disease, for a disease control rate of 96%.

In the pretreated cohort, however, there were no complete responses among 69 patients, and 27 patients (39.1%) had partial responses. In this cohort, an additional 26 patients (37.7%) had stable disease, for an ORR of 39.1% and disease-control rate of 78.3%.

Dr. Wolf also highlighted preliminary evidence of capmatinib activity in the brain. He noted that one patient, an 80-year-old woman with multiple untreated brain metastases as well as lesions in dermal lymph nodes, liver, and pleura, had complete resolution of brain metastases at the first postbaseline CT scan, 42 days after starting capmatinib. The duration of response was 11.3 months, at which point the patient discontinued the drug because of extracranial progressive disease.

Among all patients in all study cohorts (302) the most common grade 3 or 4 adverse events were peripheral edema, dyspnea, fatigue, nausea, vomiting, and decreased appetite. Adverse drug-related events (grade 3 or 4) included peripheral edema, nausea, vomiting, fatigue, and decreased appetite. In all, 10.3% of patients discontinued for adverse events suspected to be related to capmatinib.

Neil Osterweil/MDedge News

Invited discussant James Chih-Hsin Yang, MD, PhD, from the National Taiwan University Hospital in Taipei, said that the study shows that the MET exon 14–skipping mutation is an oncogenic driver and that capmatinib is an effective tyrosine kinase inhibitor (TKI) for patients with NSCLC harboring this mutation.

Questions that still need to be answered, he said, include whether patients with the mutation are heterogeneous and may have differing response to TKIs, how long the duration of response is, how long it will take for resistance to capmatinib to occur, how it compares with other MET inhibitors, and if there are additional biomarkers that could help select patients for treatment with the novel agent.

The study was funded by Novartis. Dr. Wolf reported advisory board participation, institutional research support, and lecture fees from Novartis and others. Dr. Yang reported honoraria from advisory board participation and/or speaking from Novartis and others. His institution participated in the Geometry MONO-1 study, but he was not personally involved.

MUNICH – The experimental agent capmatinib was associated with a high response rate when used in the first line for patients with advanced non–small cell lung cancers bearing MET exon 14–skipping mutations, said investigators in the Geometry MONO-1 trial.

Neil Osterweil/MDedge News

Among a cohort of 25 patients with treatment-naive, MET exon 14–mutated non–small cell lung cancer (NSCLC), the primary endpoint of overall response rate (ORR) as determined by blinded, independent reviewers was 72%.

In contrast, the ORR among 69 patients who had received one or more prior lines of therapy was 39.1%, reported Juergen Wolf, MD, of University Hospital Cologne (Germany).

“The differential benefit observed between patients treated in the first line and relapsed [settings] highlights the need of early diagnosis of this aberration, and prompt targeted treatment of this challenging patient population,” he said at the European Society for Medical Oncology Congress.

MET exon14–skipping mutations occur in approximately 3%-4% of NSCLC cases. The mutation is thought to be an oncogenic driver and has been shown to be a poor prognostic factor for patients with advanced NSCLC. Patients with this mutation have poor responses to conventional therapy and immune checkpoint inhibitors, even when their tumors have high levels of programmed death–ligand 1 (PD-L1) and high mutational burden, Dr. Wolf said.

Capmatinib (INC280) is an oral, reversible inhibitor of the MET receptor tyrosine kinase and is highly selective for MET, with particular affinity for MET exon 14 mutations. It is also capable of crossing the blood-brain barrier and has shown activity in the brain in preliminary studies.

The Geometry MONO-1 trial is a phase 2 study of capmatinib in patients with stage IIIB/IV NSCLC with tumors that demonstrate MET amplification and/or carry the MET exon 14 mutation. Three study cohorts of patients with MET amplification were closed for futility. Dr. Wolf reported results from two cohorts of patients with MET exon 14–skipping mutations regardless of gene copy number: one with treatment-naive patients and the other with patients being treated in the second or third line.

As noted, the ORR in 25 patients in the treatment-naive cohort after a median follow-up of 5.6 months was 72%, including 18 partial responses and no complete responses. In addition, six patients (24%) had stable disease, for a disease control rate of 96%.

In the pretreated cohort, however, there were no complete responses among 69 patients, and 27 patients (39.1%) had partial responses. In this cohort, an additional 26 patients (37.7%) had stable disease, for an ORR of 39.1% and disease-control rate of 78.3%.

Dr. Wolf also highlighted preliminary evidence of capmatinib activity in the brain. He noted that one patient, an 80-year-old woman with multiple untreated brain metastases as well as lesions in dermal lymph nodes, liver, and pleura, had complete resolution of brain metastases at the first postbaseline CT scan, 42 days after starting capmatinib. The duration of response was 11.3 months, at which point the patient discontinued the drug because of extracranial progressive disease.

Among all patients in all study cohorts (302) the most common grade 3 or 4 adverse events were peripheral edema, dyspnea, fatigue, nausea, vomiting, and decreased appetite. Adverse drug-related events (grade 3 or 4) included peripheral edema, nausea, vomiting, fatigue, and decreased appetite. In all, 10.3% of patients discontinued for adverse events suspected to be related to capmatinib.

Neil Osterweil/MDedge News

Invited discussant James Chih-Hsin Yang, MD, PhD, from the National Taiwan University Hospital in Taipei, said that the study shows that the MET exon 14–skipping mutation is an oncogenic driver and that capmatinib is an effective tyrosine kinase inhibitor (TKI) for patients with NSCLC harboring this mutation.

Questions that still need to be answered, he said, include whether patients with the mutation are heterogeneous and may have differing response to TKIs, how long the duration of response is, how long it will take for resistance to capmatinib to occur, how it compares with other MET inhibitors, and if there are additional biomarkers that could help select patients for treatment with the novel agent.

The study was funded by Novartis. Dr. Wolf reported advisory board participation, institutional research support, and lecture fees from Novartis and others. Dr. Yang reported honoraria from advisory board participation and/or speaking from Novartis and others. His institution participated in the Geometry MONO-1 study, but he was not personally involved.

MUNICH – The experimental agent capmatinib was associated with a high response rate when used in the first line for patients with advanced non–small cell lung cancers bearing MET exon 14–skipping mutations, said investigators in the Geometry MONO-1 trial.

Neil Osterweil/MDedge News

Among a cohort of 25 patients with treatment-naive, MET exon 14–mutated non–small cell lung cancer (NSCLC), the primary endpoint of overall response rate (ORR) as determined by blinded, independent reviewers was 72%.

In contrast, the ORR among 69 patients who had received one or more prior lines of therapy was 39.1%, reported Juergen Wolf, MD, of University Hospital Cologne (Germany).

“The differential benefit observed between patients treated in the first line and relapsed [settings] highlights the need of early diagnosis of this aberration, and prompt targeted treatment of this challenging patient population,” he said at the European Society for Medical Oncology Congress.

MET exon14–skipping mutations occur in approximately 3%-4% of NSCLC cases. The mutation is thought to be an oncogenic driver and has been shown to be a poor prognostic factor for patients with advanced NSCLC. Patients with this mutation have poor responses to conventional therapy and immune checkpoint inhibitors, even when their tumors have high levels of programmed death–ligand 1 (PD-L1) and high mutational burden, Dr. Wolf said.

Capmatinib (INC280) is an oral, reversible inhibitor of the MET receptor tyrosine kinase and is highly selective for MET, with particular affinity for MET exon 14 mutations. It is also capable of crossing the blood-brain barrier and has shown activity in the brain in preliminary studies.

The Geometry MONO-1 trial is a phase 2 study of capmatinib in patients with stage IIIB/IV NSCLC with tumors that demonstrate MET amplification and/or carry the MET exon 14 mutation. Three study cohorts of patients with MET amplification were closed for futility. Dr. Wolf reported results from two cohorts of patients with MET exon 14–skipping mutations regardless of gene copy number: one with treatment-naive patients and the other with patients being treated in the second or third line.

As noted, the ORR in 25 patients in the treatment-naive cohort after a median follow-up of 5.6 months was 72%, including 18 partial responses and no complete responses. In addition, six patients (24%) had stable disease, for a disease control rate of 96%.

In the pretreated cohort, however, there were no complete responses among 69 patients, and 27 patients (39.1%) had partial responses. In this cohort, an additional 26 patients (37.7%) had stable disease, for an ORR of 39.1% and disease-control rate of 78.3%.

Dr. Wolf also highlighted preliminary evidence of capmatinib activity in the brain. He noted that one patient, an 80-year-old woman with multiple untreated brain metastases as well as lesions in dermal lymph nodes, liver, and pleura, had complete resolution of brain metastases at the first postbaseline CT scan, 42 days after starting capmatinib. The duration of response was 11.3 months, at which point the patient discontinued the drug because of extracranial progressive disease.

Among all patients in all study cohorts (302) the most common grade 3 or 4 adverse events were peripheral edema, dyspnea, fatigue, nausea, vomiting, and decreased appetite. Adverse drug-related events (grade 3 or 4) included peripheral edema, nausea, vomiting, fatigue, and decreased appetite. In all, 10.3% of patients discontinued for adverse events suspected to be related to capmatinib.

Neil Osterweil/MDedge News

Invited discussant James Chih-Hsin Yang, MD, PhD, from the National Taiwan University Hospital in Taipei, said that the study shows that the MET exon 14–skipping mutation is an oncogenic driver and that capmatinib is an effective tyrosine kinase inhibitor (TKI) for patients with NSCLC harboring this mutation.

Questions that still need to be answered, he said, include whether patients with the mutation are heterogeneous and may have differing response to TKIs, how long the duration of response is, how long it will take for resistance to capmatinib to occur, how it compares with other MET inhibitors, and if there are additional biomarkers that could help select patients for treatment with the novel agent.

The study was funded by Novartis. Dr. Wolf reported advisory board participation, institutional research support, and lecture fees from Novartis and others. Dr. Yang reported honoraria from advisory board participation and/or speaking from Novartis and others. His institution participated in the Geometry MONO-1 study, but he was not personally involved.

MUNICH – Four years on, the combination of the immune checkpoint inhibitors nivolumab and ipilimumab as well as nivolumab alone continue to show benefit as first-line therapies for patients with advanced malignant melanoma, compared with ipilimumab monotherapy, reported investigators in the CheckMate O67 trial.

Among 945 patients with previously untreated and unresectable stage III or IV malignant melanoma, median overall survival at a minimum of 48 months follow-up had not been reached for patients assigned to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), compared with 36.9 months for patients assigned to nivolumab alone, and 19.9 months for patients assigned to ipilimumab alone, reported F. Stephen Hodi Jr., MD, of Dana-Farber Cancer Institute, Boston, and his colleagues.

“There’s a durable, sustained clinical benefit that can be achieved with first-line nivo plus ipi combination or nivo alone in patients with advanced melanoma,” he said at the European Society for Medical Oncology Congress. The study results were published online in The Lancet Oncology to coincide with the presentation.

The benefit of immunotherapy also was seen in patients whose tumors had BRAF mutations, and both the combination and nivolumab alone showed improved efficacy compared with ipilimumab alone regardless of tumor expression of the programmed death ligand-1 (PD-L1), the investigators reported.

As previously reported, investigators in CheckMate 067 randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses then nivolumab 3 mg/kg every 2 weeks, or ipilimumab 3 mg/kg every 3 weeks for four doses. Patients were stratified at baseline by PD-L1 expression, BRAF status, and American Joint Commission on Cancer M stage.

Earlier results from the trial, reported at the 2015 annual meeting of the American Society of Clinical Oncology, showed that after a minimum of 9 months follow-up, the risk of disease progression or death was reduced by 43% with nivolumab versus ipilimumab (hazard ratio, 0.57; P less than .001) and by 58% with nivolumab plus ipilimumab vs. ipilimumab (HR, 0.42; P less than .001).

At ESMO 2018, Dr. Hodi presented 4-year follow-up results from the trial, with the analysis conducted at a minimum of 4 years after randomization of the last patient to be enrolled.

Median follow-up was 46.9 months for the nivolumab-plus-ipilimumab arm, 36 months in the nivolumab arm, and 18.6 months in the ipilimumab arm.

Median overall survival in the intention-to-treat population, a coprimary endpoint with progression-free survival (PFS), was as noted before. The HR for death with the combination compared with ipilimumab was 0.54 (P less than .0001) and for nivolumab versus ipilimumab it was 0.65 (P less than .0001).

The 4-year OS rates were 53% in the combination arm, 46% in the nivolumab-alone arm, and 30% in the ipilimumab-alone arm.

Median PFS was 11.5 months with the checkpoint inhibitor combination, 6.9 months in the nivolumab-alone arm, and 2.9 months in the ipilimumab arm.

The HR for PFS with the combination compared with ipilimumab was 0.42 (P less than .0001), and for nivolumab versus ipilimumab it was 0.53 (P less than .0001).

The safety analysis, conducted in all patients who received at least one dose of study drugs, showed that 59% of patients treated with the nivolumab/ipilimumab combination had treatment-related grade 3 or 4 adverse events, compared with 22% for patients treated with nivolumab alone, and 28% of those who received ipilimumab alone.

The most common treatment-related grade 3 adverse events were diarrhea in the combination and nivolumab-alone arms, and colitis in the ipilimumab group. In all three study arms the most common grade 4 adverse event was increased lipase.

Over the 4 years of follow-up, four patients died from treatment-related causes: one patient from cardiomyopathy and one from liver necrosis in the combination group, one from neutropenia in the nivolumab group, and one from colon perforation in the ipilimumab group. All of the deaths occurred within the first 3 years of the follow-up.

The investigators did not report on serious adverse events in the current analysis.

Invited discussant Reinhard Dummer, MD, of University Hospital Zurich Skin Cancer Center in Switzerland, said that while the study shows improved response rates and duration of response and longer PFS and OS with the combination, it’s premature to state conclusively that the combination is superior, because the study was not powered to compare efficacy between the two nivolumab-containing arms.

“So unfortunately, we have results, but we are not really convinced that the combination is so much better,” he said.

He added that the 4-year overall survival results for each arm show a consistent difference in the curves between the nivolumab and ipilimumab-alone arms. He also pointed to encouraging data showing that among patients alive at 4 years, 71% in the combination group did not require subsequent therapy, compared with 50% in the nivolumab group, and 39% in the ipilimumab group.

Dr. Hodi has received grant/research support from, and is a nonpaid consultant to, Bristol-Myers Squibb, which supported Checkmate 067. Dr. Dummer reported advising/consulting roles with the company.

SOURCE: Hodi FS et al. Lancet Oncol. 2018 Oct 22. doi: 10.1016/S1470-2045(18)30700-9.

MUNICH – Four years on, the combination of the immune checkpoint inhibitors nivolumab and ipilimumab as well as nivolumab alone continue to show benefit as first-line therapies for patients with advanced malignant melanoma, compared with ipilimumab monotherapy, reported investigators in the CheckMate O67 trial.

Among 945 patients with previously untreated and unresectable stage III or IV malignant melanoma, median overall survival at a minimum of 48 months follow-up had not been reached for patients assigned to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), compared with 36.9 months for patients assigned to nivolumab alone, and 19.9 months for patients assigned to ipilimumab alone, reported F. Stephen Hodi Jr., MD, of Dana-Farber Cancer Institute, Boston, and his colleagues.

“There’s a durable, sustained clinical benefit that can be achieved with first-line nivo plus ipi combination or nivo alone in patients with advanced melanoma,” he said at the European Society for Medical Oncology Congress. The study results were published online in The Lancet Oncology to coincide with the presentation.

The benefit of immunotherapy also was seen in patients whose tumors had BRAF mutations, and both the combination and nivolumab alone showed improved efficacy compared with ipilimumab alone regardless of tumor expression of the programmed death ligand-1 (PD-L1), the investigators reported.

As previously reported, investigators in CheckMate 067 randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses then nivolumab 3 mg/kg every 2 weeks, or ipilimumab 3 mg/kg every 3 weeks for four doses. Patients were stratified at baseline by PD-L1 expression, BRAF status, and American Joint Commission on Cancer M stage.

Earlier results from the trial, reported at the 2015 annual meeting of the American Society of Clinical Oncology, showed that after a minimum of 9 months follow-up, the risk of disease progression or death was reduced by 43% with nivolumab versus ipilimumab (hazard ratio, 0.57; P less than .001) and by 58% with nivolumab plus ipilimumab vs. ipilimumab (HR, 0.42; P less than .001).

At ESMO 2018, Dr. Hodi presented 4-year follow-up results from the trial, with the analysis conducted at a minimum of 4 years after randomization of the last patient to be enrolled.

Median follow-up was 46.9 months for the nivolumab-plus-ipilimumab arm, 36 months in the nivolumab arm, and 18.6 months in the ipilimumab arm.

Median overall survival in the intention-to-treat population, a coprimary endpoint with progression-free survival (PFS), was as noted before. The HR for death with the combination compared with ipilimumab was 0.54 (P less than .0001) and for nivolumab versus ipilimumab it was 0.65 (P less than .0001).

The 4-year OS rates were 53% in the combination arm, 46% in the nivolumab-alone arm, and 30% in the ipilimumab-alone arm.

Median PFS was 11.5 months with the checkpoint inhibitor combination, 6.9 months in the nivolumab-alone arm, and 2.9 months in the ipilimumab arm.

The HR for PFS with the combination compared with ipilimumab was 0.42 (P less than .0001), and for nivolumab versus ipilimumab it was 0.53 (P less than .0001).

The safety analysis, conducted in all patients who received at least one dose of study drugs, showed that 59% of patients treated with the nivolumab/ipilimumab combination had treatment-related grade 3 or 4 adverse events, compared with 22% for patients treated with nivolumab alone, and 28% of those who received ipilimumab alone.

The most common treatment-related grade 3 adverse events were diarrhea in the combination and nivolumab-alone arms, and colitis in the ipilimumab group. In all three study arms the most common grade 4 adverse event was increased lipase.

Over the 4 years of follow-up, four patients died from treatment-related causes: one patient from cardiomyopathy and one from liver necrosis in the combination group, one from neutropenia in the nivolumab group, and one from colon perforation in the ipilimumab group. All of the deaths occurred within the first 3 years of the follow-up.

The investigators did not report on serious adverse events in the current analysis.

Invited discussant Reinhard Dummer, MD, of University Hospital Zurich Skin Cancer Center in Switzerland, said that while the study shows improved response rates and duration of response and longer PFS and OS with the combination, it’s premature to state conclusively that the combination is superior, because the study was not powered to compare efficacy between the two nivolumab-containing arms.

“So unfortunately, we have results, but we are not really convinced that the combination is so much better,” he said.

He added that the 4-year overall survival results for each arm show a consistent difference in the curves between the nivolumab and ipilimumab-alone arms. He also pointed to encouraging data showing that among patients alive at 4 years, 71% in the combination group did not require subsequent therapy, compared with 50% in the nivolumab group, and 39% in the ipilimumab group.

Dr. Hodi has received grant/research support from, and is a nonpaid consultant to, Bristol-Myers Squibb, which supported Checkmate 067. Dr. Dummer reported advising/consulting roles with the company.

SOURCE: Hodi FS et al. Lancet Oncol. 2018 Oct 22. doi: 10.1016/S1470-2045(18)30700-9.

MUNICH – Four years on, the combination of the immune checkpoint inhibitors nivolumab and ipilimumab as well as nivolumab alone continue to show benefit as first-line therapies for patients with advanced malignant melanoma, compared with ipilimumab monotherapy, reported investigators in the CheckMate O67 trial.

Among 945 patients with previously untreated and unresectable stage III or IV malignant melanoma, median overall survival at a minimum of 48 months follow-up had not been reached for patients assigned to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), compared with 36.9 months for patients assigned to nivolumab alone, and 19.9 months for patients assigned to ipilimumab alone, reported F. Stephen Hodi Jr., MD, of Dana-Farber Cancer Institute, Boston, and his colleagues.

“There’s a durable, sustained clinical benefit that can be achieved with first-line nivo plus ipi combination or nivo alone in patients with advanced melanoma,” he said at the European Society for Medical Oncology Congress. The study results were published online in The Lancet Oncology to coincide with the presentation.

The benefit of immunotherapy also was seen in patients whose tumors had BRAF mutations, and both the combination and nivolumab alone showed improved efficacy compared with ipilimumab alone regardless of tumor expression of the programmed death ligand-1 (PD-L1), the investigators reported.

As previously reported, investigators in CheckMate 067 randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses then nivolumab 3 mg/kg every 2 weeks, or ipilimumab 3 mg/kg every 3 weeks for four doses. Patients were stratified at baseline by PD-L1 expression, BRAF status, and American Joint Commission on Cancer M stage.

Earlier results from the trial, reported at the 2015 annual meeting of the American Society of Clinical Oncology, showed that after a minimum of 9 months follow-up, the risk of disease progression or death was reduced by 43% with nivolumab versus ipilimumab (hazard ratio, 0.57; P less than .001) and by 58% with nivolumab plus ipilimumab vs. ipilimumab (HR, 0.42; P less than .001).

At ESMO 2018, Dr. Hodi presented 4-year follow-up results from the trial, with the analysis conducted at a minimum of 4 years after randomization of the last patient to be enrolled.

Median follow-up was 46.9 months for the nivolumab-plus-ipilimumab arm, 36 months in the nivolumab arm, and 18.6 months in the ipilimumab arm.

Median overall survival in the intention-to-treat population, a coprimary endpoint with progression-free survival (PFS), was as noted before. The HR for death with the combination compared with ipilimumab was 0.54 (P less than .0001) and for nivolumab versus ipilimumab it was 0.65 (P less than .0001).

The 4-year OS rates were 53% in the combination arm, 46% in the nivolumab-alone arm, and 30% in the ipilimumab-alone arm.

Median PFS was 11.5 months with the checkpoint inhibitor combination, 6.9 months in the nivolumab-alone arm, and 2.9 months in the ipilimumab arm.

The HR for PFS with the combination compared with ipilimumab was 0.42 (P less than .0001), and for nivolumab versus ipilimumab it was 0.53 (P less than .0001).

The safety analysis, conducted in all patients who received at least one dose of study drugs, showed that 59% of patients treated with the nivolumab/ipilimumab combination had treatment-related grade 3 or 4 adverse events, compared with 22% for patients treated with nivolumab alone, and 28% of those who received ipilimumab alone.

The most common treatment-related grade 3 adverse events were diarrhea in the combination and nivolumab-alone arms, and colitis in the ipilimumab group. In all three study arms the most common grade 4 adverse event was increased lipase.

Over the 4 years of follow-up, four patients died from treatment-related causes: one patient from cardiomyopathy and one from liver necrosis in the combination group, one from neutropenia in the nivolumab group, and one from colon perforation in the ipilimumab group. All of the deaths occurred within the first 3 years of the follow-up.

The investigators did not report on serious adverse events in the current analysis.

Invited discussant Reinhard Dummer, MD, of University Hospital Zurich Skin Cancer Center in Switzerland, said that while the study shows improved response rates and duration of response and longer PFS and OS with the combination, it’s premature to state conclusively that the combination is superior, because the study was not powered to compare efficacy between the two nivolumab-containing arms.

“So unfortunately, we have results, but we are not really convinced that the combination is so much better,” he said.

He added that the 4-year overall survival results for each arm show a consistent difference in the curves between the nivolumab and ipilimumab-alone arms. He also pointed to encouraging data showing that among patients alive at 4 years, 71% in the combination group did not require subsequent therapy, compared with 50% in the nivolumab group, and 39% in the ipilimumab group.

Dr. Hodi has received grant/research support from, and is a nonpaid consultant to, Bristol-Myers Squibb, which supported Checkmate 067. Dr. Dummer reported advising/consulting roles with the company.

SOURCE: Hodi FS et al. Lancet Oncol. 2018 Oct 22. doi: 10.1016/S1470-2045(18)30700-9.

MUNICH – The term “practice-changing trial” usually implies change for the better, but results of a study comparing two regimens for patients with low-risk human papillomavirus–positive oropharyngeal cancer showed that cetuximab plus radiation was associated with worse local control and worse overall survival than the older standard of cisplatin plus radiation, investigators in the De-Escalate HPV trial reported.

Although rates of severe toxicity, the primary endpoint, were similar between cisplatin and radiation and cetuximab (Erbitux) plus radiation, 2-year overall survival was significantly worse with cetuximab, a finding that caught the investigators off guard, admitted Hisham Mehanna, PhD, a surgeon at the Institute of Head and Neck Studies and Education at the University of Birmingham (England).

Neil Osterweil/MDedge News

“This difference in overall survival was underpinned by a significantly higher recurrence rate with cetuximab,” he said at the European Society of Medical Oncology Congress. “And that recurrence rate was both in locoregional control as well as in distant control.”

The results of the study reaffirm that cisplatin remains the standard of care in patients with low-risk human papillomavirus (HPV)–positive oropharyngeal cancer, and highlight the vital importance of carefully controlled clinical trials.

“I think there’s a salutary lesson: Changes in standard of care really should only be done of the basis of high-level, phase 3 comparative evidence, even, as was in our case, when treatments have been approved by regulatory bodies,” he said.

The trial raises the question of whether deintensification strategies should continue to be used in locally advanced HPV-positive oropharyngeal cancer, and suggests that clinicians should rethink the use of targeted agents in these patients in the absence of predictive biomarkers, commented Amanda Psyrri, MD, PhD, from the University of Athens and Attikon University Hospital.

The standard of care for patients with head and neck cancers is radiotherapy with concomitant cisplatin, which has been shown to improve absolute overall survival at the cost of increases in both acute and late severe toxicities.

The De-Escalate HPV trial was designed to see whether replacing cisplatin with cetuximab, a tyrosine kinase inhibitor targeted against the epidermal growth factor receptor, could be associated with less toxicity, better quality of life, and better swallowing in patients with low-risk HPV-positive oropharyngeal cancer.

The investigators enrolled 334 patients from 32 centers in the United Kingdom, Ireland, and the Netherlands, and randomly assigned them to therapy with 70 Gy radiotherapy given in 35 fractions over 7 weeks, plus either intravenous cisplatin 100 mg/m² per day on days 1, 22, and 43, or IV cetuximab at a 400 mg pretreatment loading dose, then 250 mg weekly.

There were no significant differences between treatment arms in the primary endpoint of toxicity, either severe (grade 3-5) or all grades of toxicity (1-5). In addition, there were no significant differences between the treatment arms in global health status assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire – Core Questionnaire (EORTC QLQ-C30) or in swallowing as evaluated by the MD Anderson Dysphagia Inventory-Global.

There were, however, significantly more serious adverse events in the cisplatin arm, at 162 versus 95 in the cetuximab arm.

But as noted before, the investigators were surprised to see that 2-year overall survival was worse with cetuximab at 89.4%, compared with 97.5% for cisplatin (P = .001). The hazard ratio for death with cetuximab was 4.99 and the adjusted HR was 5.94 (P = .001). Dr. Mehanna did not report factors considered in the adjusted HR.

The number needed to treat for harm was 12.

“Our study was not powered to identify a difference in survival, and hence our surprise to find a significantly worse overall survival with cetuximab,” he said.

The 2-year recurrence rates were 6.0% in the cisplatin arm versus 16.1% in the cetuximab arm (HR, 3.39; P = .0007).

Locoregional recurrence rates were 3% in the cisplatin arm versus 12% in the cetuximab arm and rates of distant recurrence were 3% versus 9%, respectively.

The results suggest that clinicians should be cautious when considering deescalation treatments that reduce the use of systemic chemotherapy, either with radiotherapy alone or with surgery, Dr. Mehanna said.

Neil Osterweil/MDedge News

In a briefing prior to the presentation of the data in a presidential symposium, discussant Jean-Pascal Machiels, MD, from the University Clinic Saint-Luc in Brussels, said that, prior to this study, “the common belief was that [cetuximab and radiation] could be used, maybe, instead of chemoradiation in these patients, because also we believed that this may decrease toxicity.

“But clearly we have a signal that the chemoradiation has more activity in this setting, and it should remain the standard of care,” he continued.

Dr. Machiels cautioned that the findings cannot be extrapolated to patients with HPV-negative disease.

The study was sponsored by the University of Warwick (England), University of Birmingham, University of Oxford (England), and Cancer Research UK. Dr. Mehanna reported honoraria from AstraZeneca, MSD, Sanofi Pasteur, and Merck, and is a director and stockholder of the Warwickshire Head and Neck Clinic. Dr. Psyrri reported honoraria from Merck Serono, Roche, MSD, AstraZeneca, Bristol-Myers Squibb, Bayer, Pfizer, Medscape, and Prime Oncology. Dr. Machiels reported a consulting or advisory role with Boehringer Ingelheim, Debiopharm Group, Innate Pharma, Merck, Nanobiotix, and Pfizer, and research funding from Bayer, Janssen Pharmaceuticals, Novartis, and Sanofi.

SOURCE: Mehanna H et al. ESMO 2018, Abstract LBA9_PR.

MUNICH – The term “practice-changing trial” usually implies change for the better, but results of a study comparing two regimens for patients with low-risk human papillomavirus–positive oropharyngeal cancer showed that cetuximab plus radiation was associated with worse local control and worse overall survival than the older standard of cisplatin plus radiation, investigators in the De-Escalate HPV trial reported.

Although rates of severe toxicity, the primary endpoint, were similar between cisplatin and radiation and cetuximab (Erbitux) plus radiation, 2-year overall survival was significantly worse with cetuximab, a finding that caught the investigators off guard, admitted Hisham Mehanna, PhD, a surgeon at the Institute of Head and Neck Studies and Education at the University of Birmingham (England).

Neil Osterweil/MDedge News

“This difference in overall survival was underpinned by a significantly higher recurrence rate with cetuximab,” he said at the European Society of Medical Oncology Congress. “And that recurrence rate was both in locoregional control as well as in distant control.”

The results of the study reaffirm that cisplatin remains the standard of care in patients with low-risk human papillomavirus (HPV)–positive oropharyngeal cancer, and highlight the vital importance of carefully controlled clinical trials.

“I think there’s a salutary lesson: Changes in standard of care really should only be done of the basis of high-level, phase 3 comparative evidence, even, as was in our case, when treatments have been approved by regulatory bodies,” he said.

The trial raises the question of whether deintensification strategies should continue to be used in locally advanced HPV-positive oropharyngeal cancer, and suggests that clinicians should rethink the use of targeted agents in these patients in the absence of predictive biomarkers, commented Amanda Psyrri, MD, PhD, from the University of Athens and Attikon University Hospital.

The standard of care for patients with head and neck cancers is radiotherapy with concomitant cisplatin, which has been shown to improve absolute overall survival at the cost of increases in both acute and late severe toxicities.

The De-Escalate HPV trial was designed to see whether replacing cisplatin with cetuximab, a tyrosine kinase inhibitor targeted against the epidermal growth factor receptor, could be associated with less toxicity, better quality of life, and better swallowing in patients with low-risk HPV-positive oropharyngeal cancer.

The investigators enrolled 334 patients from 32 centers in the United Kingdom, Ireland, and the Netherlands, and randomly assigned them to therapy with 70 Gy radiotherapy given in 35 fractions over 7 weeks, plus either intravenous cisplatin 100 mg/m² per day on days 1, 22, and 43, or IV cetuximab at a 400 mg pretreatment loading dose, then 250 mg weekly.

There were no significant differences between treatment arms in the primary endpoint of toxicity, either severe (grade 3-5) or all grades of toxicity (1-5). In addition, there were no significant differences between the treatment arms in global health status assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire – Core Questionnaire (EORTC QLQ-C30) or in swallowing as evaluated by the MD Anderson Dysphagia Inventory-Global.

There were, however, significantly more serious adverse events in the cisplatin arm, at 162 versus 95 in the cetuximab arm.

But as noted before, the investigators were surprised to see that 2-year overall survival was worse with cetuximab at 89.4%, compared with 97.5% for cisplatin (P = .001). The hazard ratio for death with cetuximab was 4.99 and the adjusted HR was 5.94 (P = .001). Dr. Mehanna did not report factors considered in the adjusted HR.

The number needed to treat for harm was 12.

“Our study was not powered to identify a difference in survival, and hence our surprise to find a significantly worse overall survival with cetuximab,” he said.

The 2-year recurrence rates were 6.0% in the cisplatin arm versus 16.1% in the cetuximab arm (HR, 3.39; P = .0007).

Locoregional recurrence rates were 3% in the cisplatin arm versus 12% in the cetuximab arm and rates of distant recurrence were 3% versus 9%, respectively.

The results suggest that clinicians should be cautious when considering deescalation treatments that reduce the use of systemic chemotherapy, either with radiotherapy alone or with surgery, Dr. Mehanna said.

Neil Osterweil/MDedge News

In a briefing prior to the presentation of the data in a presidential symposium, discussant Jean-Pascal Machiels, MD, from the University Clinic Saint-Luc in Brussels, said that, prior to this study, “the common belief was that [cetuximab and radiation] could be used, maybe, instead of chemoradiation in these patients, because also we believed that this may decrease toxicity.

“But clearly we have a signal that the chemoradiation has more activity in this setting, and it should remain the standard of care,” he continued.

Dr. Machiels cautioned that the findings cannot be extrapolated to patients with HPV-negative disease.

The study was sponsored by the University of Warwick (England), University of Birmingham, University of Oxford (England), and Cancer Research UK. Dr. Mehanna reported honoraria from AstraZeneca, MSD, Sanofi Pasteur, and Merck, and is a director and stockholder of the Warwickshire Head and Neck Clinic. Dr. Psyrri reported honoraria from Merck Serono, Roche, MSD, AstraZeneca, Bristol-Myers Squibb, Bayer, Pfizer, Medscape, and Prime Oncology. Dr. Machiels reported a consulting or advisory role with Boehringer Ingelheim, Debiopharm Group, Innate Pharma, Merck, Nanobiotix, and Pfizer, and research funding from Bayer, Janssen Pharmaceuticals, Novartis, and Sanofi.

SOURCE: Mehanna H et al. ESMO 2018, Abstract LBA9_PR.

MUNICH – The term “practice-changing trial” usually implies change for the better, but results of a study comparing two regimens for patients with low-risk human papillomavirus–positive oropharyngeal cancer showed that cetuximab plus radiation was associated with worse local control and worse overall survival than the older standard of cisplatin plus radiation, investigators in the De-Escalate HPV trial reported.

Although rates of severe toxicity, the primary endpoint, were similar between cisplatin and radiation and cetuximab (Erbitux) plus radiation, 2-year overall survival was significantly worse with cetuximab, a finding that caught the investigators off guard, admitted Hisham Mehanna, PhD, a surgeon at the Institute of Head and Neck Studies and Education at the University of Birmingham (England).

Neil Osterweil/MDedge News

“This difference in overall survival was underpinned by a significantly higher recurrence rate with cetuximab,” he said at the European Society of Medical Oncology Congress. “And that recurrence rate was both in locoregional control as well as in distant control.”

The results of the study reaffirm that cisplatin remains the standard of care in patients with low-risk human papillomavirus (HPV)–positive oropharyngeal cancer, and highlight the vital importance of carefully controlled clinical trials.

“I think there’s a salutary lesson: Changes in standard of care really should only be done of the basis of high-level, phase 3 comparative evidence, even, as was in our case, when treatments have been approved by regulatory bodies,” he said.

The trial raises the question of whether deintensification strategies should continue to be used in locally advanced HPV-positive oropharyngeal cancer, and suggests that clinicians should rethink the use of targeted agents in these patients in the absence of predictive biomarkers, commented Amanda Psyrri, MD, PhD, from the University of Athens and Attikon University Hospital.

The standard of care for patients with head and neck cancers is radiotherapy with concomitant cisplatin, which has been shown to improve absolute overall survival at the cost of increases in both acute and late severe toxicities.

The De-Escalate HPV trial was designed to see whether replacing cisplatin with cetuximab, a tyrosine kinase inhibitor targeted against the epidermal growth factor receptor, could be associated with less toxicity, better quality of life, and better swallowing in patients with low-risk HPV-positive oropharyngeal cancer.

The investigators enrolled 334 patients from 32 centers in the United Kingdom, Ireland, and the Netherlands, and randomly assigned them to therapy with 70 Gy radiotherapy given in 35 fractions over 7 weeks, plus either intravenous cisplatin 100 mg/m² per day on days 1, 22, and 43, or IV cetuximab at a 400 mg pretreatment loading dose, then 250 mg weekly.

There were no significant differences between treatment arms in the primary endpoint of toxicity, either severe (grade 3-5) or all grades of toxicity (1-5). In addition, there were no significant differences between the treatment arms in global health status assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire – Core Questionnaire (EORTC QLQ-C30) or in swallowing as evaluated by the MD Anderson Dysphagia Inventory-Global.

There were, however, significantly more serious adverse events in the cisplatin arm, at 162 versus 95 in the cetuximab arm.

But as noted before, the investigators were surprised to see that 2-year overall survival was worse with cetuximab at 89.4%, compared with 97.5% for cisplatin (P = .001). The hazard ratio for death with cetuximab was 4.99 and the adjusted HR was 5.94 (P = .001). Dr. Mehanna did not report factors considered in the adjusted HR.

The number needed to treat for harm was 12.

“Our study was not powered to identify a difference in survival, and hence our surprise to find a significantly worse overall survival with cetuximab,” he said.

The 2-year recurrence rates were 6.0% in the cisplatin arm versus 16.1% in the cetuximab arm (HR, 3.39; P = .0007).

Locoregional recurrence rates were 3% in the cisplatin arm versus 12% in the cetuximab arm and rates of distant recurrence were 3% versus 9%, respectively.

The results suggest that clinicians should be cautious when considering deescalation treatments that reduce the use of systemic chemotherapy, either with radiotherapy alone or with surgery, Dr. Mehanna said.

Neil Osterweil/MDedge News

In a briefing prior to the presentation of the data in a presidential symposium, discussant Jean-Pascal Machiels, MD, from the University Clinic Saint-Luc in Brussels, said that, prior to this study, “the common belief was that [cetuximab and radiation] could be used, maybe, instead of chemoradiation in these patients, because also we believed that this may decrease toxicity.

“But clearly we have a signal that the chemoradiation has more activity in this setting, and it should remain the standard of care,” he continued.

Dr. Machiels cautioned that the findings cannot be extrapolated to patients with HPV-negative disease.

The study was sponsored by the University of Warwick (England), University of Birmingham, University of Oxford (England), and Cancer Research UK. Dr. Mehanna reported honoraria from AstraZeneca, MSD, Sanofi Pasteur, and Merck, and is a director and stockholder of the Warwickshire Head and Neck Clinic. Dr. Psyrri reported honoraria from Merck Serono, Roche, MSD, AstraZeneca, Bristol-Myers Squibb, Bayer, Pfizer, Medscape, and Prime Oncology. Dr. Machiels reported a consulting or advisory role with Boehringer Ingelheim, Debiopharm Group, Innate Pharma, Merck, Nanobiotix, and Pfizer, and research funding from Bayer, Janssen Pharmaceuticals, Novartis, and Sanofi.

SOURCE: Mehanna H et al. ESMO 2018, Abstract LBA9_PR.

MUNICH – Men with metastatic breast cancer (MBC) have a similar prognosis, compared with women, but gonadal suppression remains a topic of debate, according to recent trials and conference proceedings.

Male breast cancer is a rare, little-studied disease that was highlighted at the annual meeting of the European Society for Medical Oncology.

“This is a truly magnificent effort made by these authors,” said invited discussant Carolien Schroeder, MD, PhD, of the University Medical Center Groningen in the Netherlands, noting the challenges inherent to studies of niche cancer populations.

Previous studies have shown that men with MBC are usually hormone receptor positive (HR+) and older than women with MBC. Male patients also tend to present with more severe disease.

“[Male breast cancer patients] usually present with higher stages of disease; larger tumors, more nodal involvement, and more metastatic disease,” Dr. Schroeder said. “And 4%-16% may have genetic predisposition, usually due to a BRCA2 mutation.”

One retrospective study used data from the Epidemiological Strategy and Medical Economics Metastatic Breast Cancer (ESME MBC) platform to further knowledge of male patient characteristics, treatment types, and disease outcomes. ESME is a national database that stores patient information from 18 cancer centers in France.

“We have reported on one of the biggest series of men with metastatic disease, with comprehensive data on their management and outcome with different types of treatment,” said principal investigator Jean-Sébastien Frénel, MD, of the Institut de Cancérologie de l’Ouest in Nantes, France, in an interview.

The ESME study evaluated 16,701 patients with MBC: 16,552 women (99.11%) and 149 men (0.89%). Patients received at least one treatment between January 2008 and December 2014.

On average, male patients were older than females (mean: 68.1 years vs. 60.6 years), which lines up with existing data; in contrast, 78.4% of men were HR+, which is slightly lower than the widely described figure of 90%. Almost half of the HR+/human epidermal growth factor 2– (HER2–) male patients were given a frontline hormonal therapy (43%); of those, 44% received tamoxifen, 40% received an aromatase inhibitor (with or without a gonadotropin-releasing hormone analog [GnRH]), and 16% received other therapies. Outcomes were relatively similar between men and women: median progression-free survival (PFS) was 9.8 months for men, compared with 13.0 months for women. About one-quarter of HR+/HER2– men (27.6%) received frontline chemotherapy, resulting in a PFS of 6.9 months compared with 6.3 months for matched women. Overall survival was also slightly longer for men than matched women (41.8 months vs 34.9 months). In general, these statistics show that men and women received similar treatments and had similar outcomes.

“Most of the patients receiving hormonal therapy were treated with tamoxifen and the remainder received aromatase inhibitors,” Dr. Frénel said. “But few patients received aromatase inhibitors plus [GnRH] analogs despite some guidelines recommending that they should be given in combination.”

GnRH for men remains a topic of debate. Although aromatase inhibitors should be given with GnRH to avoid a negative feedback loop, gonadal suppression causes erectile dysfunction, thereby decreasing well-being. This dilemma is made worse by a lack of data on hormonal therapy for men with breast cancer.

To address this shortcoming, a prospective, randomized trial compared three different hormonal regimens for men. Male-GBG54 involved 55 men with breast cancer. For 6 months, patients received 1 of 3 treatment regimens: tamoxifen (20 mg/day), tamoxifen + GnRH (subcutaneous every 3 months), or exemestane (25 mg daily) + GnRH. Median estradiol levels were measured at 3 months and 6 months, and wellbeing was measured using questionnaires.

As expected, the results showed increased estradiol levels in the tamoxifen group and decreased levels in the GnRH group. Men were generally dissatisfied with GnRH therapy because of the erectile dysfunction it caused.

“Tamoxifen monotherapy should be kept as standard hormonal therapy for men with breast cancer. The side effects are moderate, hardly impairing sexual behavior. The combination with GnRH influenced patients’ well-being and erectile function profoundly,” lead author Mattea Reinisch, MD, of Klinikum Essen-Mitte (Germany), said in an interview.

Dr. Schroeder agreed that tamoxifen should remain the standard treatment but suggested that the benefits of gonadal suppression may outweigh the downsides. “We need efficacy data for gonadal suppression,” she said. “After all, we are advising our premenopausal breast cancer patients to undergo the gonadal suppression therapy on a daily basis because of the oncological superiority, despite the toxicity they are also experiencing.”

Dr. Schroeder again called for efficacy data and described shortcomings of Male-GBG54: “[Dr. Reinisch and her colleagues] have chosen a biological surrogate endpoint, but what we’d really like, of course, [are] the efficacy data. The quality of life data are not breast-cancer specific, and these are only data for 6 months, whereas, particularly in the metastatic setting, the compliance issue after 6 months is also relevant.”

Reflecting on the data from ESME and Male-GBG54, Dr. Schroeder said, “I think this field is maturing, and intervention trials have proven themselves to be possible in this niche population.”

Looking to the future, Dr. Schroeder suggested that male breast cancer can be studied either in separate trials from women (focusing on sex-specific targets), or in shared studies, as many disease characteristics are the same regardless of sex. She also said that worse disease in men is likely due to delayed presentation rather than biological differences between men and women.

“This leaves room for improvement,” Dr. Schroeder said. “We still need to work on the awareness of this disease.”

Discussant Dr. Schroeder disclosed financial relationships with Novartis, Roche, Genentech, and others. Male-GBG54 was funded by Claudia von Schilling Foundation.
 

SOURCES: Sirieix J et al. ESMO 2018, Abstract 294PD; Reinisch et al. ESMO 2018, Abstract 273PD.

MUNICH – Men with metastatic breast cancer (MBC) have a similar prognosis, compared with women, but gonadal suppression remains a topic of debate, according to recent trials and conference proceedings.

Male breast cancer is a rare, little-studied disease that was highlighted at the annual meeting of the European Society for Medical Oncology.

“This is a truly magnificent effort made by these authors,” said invited discussant Carolien Schroeder, MD, PhD, of the University Medical Center Groningen in the Netherlands, noting the challenges inherent to studies of niche cancer populations.

Previous studies have shown that men with MBC are usually hormone receptor positive (HR+) and older than women with MBC. Male patients also tend to present with more severe disease.

“[Male breast cancer patients] usually present with higher stages of disease; larger tumors, more nodal involvement, and more metastatic disease,” Dr. Schroeder said. “And 4%-16% may have genetic predisposition, usually due to a BRCA2 mutation.”

One retrospective study used data from the Epidemiological Strategy and Medical Economics Metastatic Breast Cancer (ESME MBC) platform to further knowledge of male patient characteristics, treatment types, and disease outcomes. ESME is a national database that stores patient information from 18 cancer centers in France.

“We have reported on one of the biggest series of men with metastatic disease, with comprehensive data on their management and outcome with different types of treatment,” said principal investigator Jean-Sébastien Frénel, MD, of the Institut de Cancérologie de l’Ouest in Nantes, France, in an interview.

The ESME study evaluated 16,701 patients with MBC: 16,552 women (99.11%) and 149 men (0.89%). Patients received at least one treatment between January 2008 and December 2014.

On average, male patients were older than females (mean: 68.1 years vs. 60.6 years), which lines up with existing data; in contrast, 78.4% of men were HR+, which is slightly lower than the widely described figure of 90%. Almost half of the HR+/human epidermal growth factor 2– (HER2–) male patients were given a frontline hormonal therapy (43%); of those, 44% received tamoxifen, 40% received an aromatase inhibitor (with or without a gonadotropin-releasing hormone analog [GnRH]), and 16% received other therapies. Outcomes were relatively similar between men and women: median progression-free survival (PFS) was 9.8 months for men, compared with 13.0 months for women. About one-quarter of HR+/HER2– men (27.6%) received frontline chemotherapy, resulting in a PFS of 6.9 months compared with 6.3 months for matched women. Overall survival was also slightly longer for men than matched women (41.8 months vs 34.9 months). In general, these statistics show that men and women received similar treatments and had similar outcomes.

“Most of the patients receiving hormonal therapy were treated with tamoxifen and the remainder received aromatase inhibitors,” Dr. Frénel said. “But few patients received aromatase inhibitors plus [GnRH] analogs despite some guidelines recommending that they should be given in combination.”

GnRH for men remains a topic of debate. Although aromatase inhibitors should be given with GnRH to avoid a negative feedback loop, gonadal suppression causes erectile dysfunction, thereby decreasing well-being. This dilemma is made worse by a lack of data on hormonal therapy for men with breast cancer.

To address this shortcoming, a prospective, randomized trial compared three different hormonal regimens for men. Male-GBG54 involved 55 men with breast cancer. For 6 months, patients received 1 of 3 treatment regimens: tamoxifen (20 mg/day), tamoxifen + GnRH (subcutaneous every 3 months), or exemestane (25 mg daily) + GnRH. Median estradiol levels were measured at 3 months and 6 months, and wellbeing was measured using questionnaires.

As expected, the results showed increased estradiol levels in the tamoxifen group and decreased levels in the GnRH group. Men were generally dissatisfied with GnRH therapy because of the erectile dysfunction it caused.

“Tamoxifen monotherapy should be kept as standard hormonal therapy for men with breast cancer. The side effects are moderate, hardly impairing sexual behavior. The combination with GnRH influenced patients’ well-being and erectile function profoundly,” lead author Mattea Reinisch, MD, of Klinikum Essen-Mitte (Germany), said in an interview.

Dr. Schroeder agreed that tamoxifen should remain the standard treatment but suggested that the benefits of gonadal suppression may outweigh the downsides. “We need efficacy data for gonadal suppression,” she said. “After all, we are advising our premenopausal breast cancer patients to undergo the gonadal suppression therapy on a daily basis because of the oncological superiority, despite the toxicity they are also experiencing.”

Dr. Schroeder again called for efficacy data and described shortcomings of Male-GBG54: “[Dr. Reinisch and her colleagues] have chosen a biological surrogate endpoint, but what we’d really like, of course, [are] the efficacy data. The quality of life data are not breast-cancer specific, and these are only data for 6 months, whereas, particularly in the metastatic setting, the compliance issue after 6 months is also relevant.”

Reflecting on the data from ESME and Male-GBG54, Dr. Schroeder said, “I think this field is maturing, and intervention trials have proven themselves to be possible in this niche population.”

Looking to the future, Dr. Schroeder suggested that male breast cancer can be studied either in separate trials from women (focusing on sex-specific targets), or in shared studies, as many disease characteristics are the same regardless of sex. She also said that worse disease in men is likely due to delayed presentation rather than biological differences between men and women.

“This leaves room for improvement,” Dr. Schroeder said. “We still need to work on the awareness of this disease.”

Discussant Dr. Schroeder disclosed financial relationships with Novartis, Roche, Genentech, and others. Male-GBG54 was funded by Claudia von Schilling Foundation.
 

SOURCES: Sirieix J et al. ESMO 2018, Abstract 294PD; Reinisch et al. ESMO 2018, Abstract 273PD.

MUNICH – Men with metastatic breast cancer (MBC) have a similar prognosis, compared with women, but gonadal suppression remains a topic of debate, according to recent trials and conference proceedings.

Male breast cancer is a rare, little-studied disease that was highlighted at the annual meeting of the European Society for Medical Oncology.

“This is a truly magnificent effort made by these authors,” said invited discussant Carolien Schroeder, MD, PhD, of the University Medical Center Groningen in the Netherlands, noting the challenges inherent to studies of niche cancer populations.

Previous studies have shown that men with MBC are usually hormone receptor positive (HR+) and older than women with MBC. Male patients also tend to present with more severe disease.

“[Male breast cancer patients] usually present with higher stages of disease; larger tumors, more nodal involvement, and more metastatic disease,” Dr. Schroeder said. “And 4%-16% may have genetic predisposition, usually due to a BRCA2 mutation.”

One retrospective study used data from the Epidemiological Strategy and Medical Economics Metastatic Breast Cancer (ESME MBC) platform to further knowledge of male patient characteristics, treatment types, and disease outcomes. ESME is a national database that stores patient information from 18 cancer centers in France.

“We have reported on one of the biggest series of men with metastatic disease, with comprehensive data on their management and outcome with different types of treatment,” said principal investigator Jean-Sébastien Frénel, MD, of the Institut de Cancérologie de l’Ouest in Nantes, France, in an interview.

The ESME study evaluated 16,701 patients with MBC: 16,552 women (99.11%) and 149 men (0.89%). Patients received at least one treatment between January 2008 and December 2014.

On average, male patients were older than females (mean: 68.1 years vs. 60.6 years), which lines up with existing data; in contrast, 78.4% of men were HR+, which is slightly lower than the widely described figure of 90%. Almost half of the HR+/human epidermal growth factor 2– (HER2–) male patients were given a frontline hormonal therapy (43%); of those, 44% received tamoxifen, 40% received an aromatase inhibitor (with or without a gonadotropin-releasing hormone analog [GnRH]), and 16% received other therapies. Outcomes were relatively similar between men and women: median progression-free survival (PFS) was 9.8 months for men, compared with 13.0 months for women. About one-quarter of HR+/HER2– men (27.6%) received frontline chemotherapy, resulting in a PFS of 6.9 months compared with 6.3 months for matched women. Overall survival was also slightly longer for men than matched women (41.8 months vs 34.9 months). In general, these statistics show that men and women received similar treatments and had similar outcomes.

“Most of the patients receiving hormonal therapy were treated with tamoxifen and the remainder received aromatase inhibitors,” Dr. Frénel said. “But few patients received aromatase inhibitors plus [GnRH] analogs despite some guidelines recommending that they should be given in combination.”

GnRH for men remains a topic of debate. Although aromatase inhibitors should be given with GnRH to avoid a negative feedback loop, gonadal suppression causes erectile dysfunction, thereby decreasing well-being. This dilemma is made worse by a lack of data on hormonal therapy for men with breast cancer.

To address this shortcoming, a prospective, randomized trial compared three different hormonal regimens for men. Male-GBG54 involved 55 men with breast cancer. For 6 months, patients received 1 of 3 treatment regimens: tamoxifen (20 mg/day), tamoxifen + GnRH (subcutaneous every 3 months), or exemestane (25 mg daily) + GnRH. Median estradiol levels were measured at 3 months and 6 months, and wellbeing was measured using questionnaires.

As expected, the results showed increased estradiol levels in the tamoxifen group and decreased levels in the GnRH group. Men were generally dissatisfied with GnRH therapy because of the erectile dysfunction it caused.

“Tamoxifen monotherapy should be kept as standard hormonal therapy for men with breast cancer. The side effects are moderate, hardly impairing sexual behavior. The combination with GnRH influenced patients’ well-being and erectile function profoundly,” lead author Mattea Reinisch, MD, of Klinikum Essen-Mitte (Germany), said in an interview.

Dr. Schroeder agreed that tamoxifen should remain the standard treatment but suggested that the benefits of gonadal suppression may outweigh the downsides. “We need efficacy data for gonadal suppression,” she said. “After all, we are advising our premenopausal breast cancer patients to undergo the gonadal suppression therapy on a daily basis because of the oncological superiority, despite the toxicity they are also experiencing.”

Dr. Schroeder again called for efficacy data and described shortcomings of Male-GBG54: “[Dr. Reinisch and her colleagues] have chosen a biological surrogate endpoint, but what we’d really like, of course, [are] the efficacy data. The quality of life data are not breast-cancer specific, and these are only data for 6 months, whereas, particularly in the metastatic setting, the compliance issue after 6 months is also relevant.”

Reflecting on the data from ESME and Male-GBG54, Dr. Schroeder said, “I think this field is maturing, and intervention trials have proven themselves to be possible in this niche population.”

Looking to the future, Dr. Schroeder suggested that male breast cancer can be studied either in separate trials from women (focusing on sex-specific targets), or in shared studies, as many disease characteristics are the same regardless of sex. She also said that worse disease in men is likely due to delayed presentation rather than biological differences between men and women.

“This leaves room for improvement,” Dr. Schroeder said. “We still need to work on the awareness of this disease.”

Discussant Dr. Schroeder disclosed financial relationships with Novartis, Roche, Genentech, and others. Male-GBG54 was funded by Claudia von Schilling Foundation.
 

SOURCES: Sirieix J et al. ESMO 2018, Abstract 294PD; Reinisch et al. ESMO 2018, Abstract 273PD.

MUNICH – A combination of the selective phosphoinositide 3-kinase inhibitor alpelisib and fulvestrant (Faslodex) was associated with significantly better progression-free survival than placebo plus fulvestrant in patients with hormone receptor–positive, HER2-negative breast cancer with PIK3CA mutations, investigators in the SOLAR-1 trial reported.

Neil Osterweil/MDedge News

The addition of alpelisib, an inhibitor of the alpha isoform of the phosphoinositide 3-kinase (PI3K), to fulvestrant, a selective estrogen receptor modifier, was associated with a 35% improvement in progression-free survival (PFS), reported Fabrice André, MD, of Institut Gustave Roussy, Villejuif, France.

“Alpelisib plus fulvestrant is a potential new treatment option for patients with PIK3CA-mutant, hormone receptor–positive, HER2-negative advanced breast cancer who have progressed on prior endocrine therapy, with or without a CDK 4/6 [cyclin-dependent kinases 4/6] inhibitor,” he said in a podium presentation at the European Society for Medical Oncology Congress.

Unlike other PI3K inhibitors which have activity spanning the alpha, beta, gamma, and delta isoforms of PI3K, alpelisib is specific for only the alpha isoform, giving it a safety profile that compares favorably with other agents in its class, Dr. André said.

Results of other studies combining PI3K inhibition with endocrine therapy have not borne especially sweet fruit. For example, the SANDPIPER trial, a study of the combination of fulvestrant and the PI3K inhibitor idelalisib (Zydelig) presented at the 2018 annual meeting of the American Society of Clinical Oncology, showed a benefit of 2 months more PFS, compared with fulvestrant alone, but at the cost of serious toxicities in half of all patients treated with the combination.

In the SOLAR-1 trial, investigators randomized 572 postmenopausal women, or men (sex of patients not shown), with hormone receptor–positive, HER2-negative advanced breast cancer. Of the 572 patients, 341 were determined to have PIK3CA mutations.

To be eligible for the study, patients had to have good Eastern Cooperative Oncology Group performance status (1 or less) and have received one or more prior lines of endocrine therapy but no chemotherapy for advanced breast cancer.

Patients who had previously received fulvestrant, any PI3K inhibitor, Akt inhibitor, or mammalian target of rapamycin inhibitor were excluded.

The patients were randomly assigned to receive intramuscular fulvestrant 500 mg on days 1 and 15 of treatment cycle 1 and then every 28 days, plus either oral alpelisib (300 mg daily) or placebo.

Locally assessed PFS in patients with PIK3CA mutations, the primary endpoint, favored alpelisib. At a median follow-up of 20 months, the median PFS with alpelisib was 11 months, versus 5.7 months for placebo. The hazard ratio for progression with alpelisib was 0.65 (P = .00065).

A blinded independent review committee assessment of 50% of patients in the PIK3CA-mutant cohort supported the investigator-assessed findings, with a median PFS of 11.1 months with alpelisib, versus 3.7 months with placebo.

In contrast, a proof-of-concept analysis of the 231 patients without PIK3CA mutations could not show a benefit for alpelisib over placebo.

In the PIK3CA-mutant cohort, the overall response rates among patients with measurable disease were 35.7% with alpelisib versus 16.2% with placebo (P = .0002). Respective response rates among all patients were 26.6% and 12.8% (P = .0006).

Adverse events in the entire trial population included hyperglycemia leading to discontinuation of alpelisib in 6.3% of patients and rash leading to discontinuation of the drug in 3.2% of patients. There were no discontinuations for either hyperglycemia or rash in the placebo arm.

The hyperglycemia can be managed with metformin, Dr. André said.

At a briefing prior to presentation of the SOLAR-1 data in a symposium, briefing discussant Nadia Harbeck, MD, of the University of Munich Medical Center said that the trial represents a significant advance.

“We have numerous talks, also phase 3 trials, with PI3-kinase inhibitors where we saw marginal benefit, and the drugs weren’t usable in clinical practice because the tolerability was so bad. So this is now the first phase 3 data proving that if you have a targeted drug and the tumor has the target, you can actually almost double progression-free survival, and I think this will change the way we practice,” she said.

Neil Osterweil/MDedge News

Rebecca Dent, MD, a senior consultant at the National Cancer Centre Singapore, the invited discussant at the symposium, complimented the SOLAR-1 investigators for conducting a “clinically homogeneous, biomarker-driven clinical trial reflecting new pathways to registration.”

She suggested that the significant clinical toxicities seen with PI3K inhibitors might be ameliorated with different dosing schedules, pharmacodynamic endpoints such as hyperglycemia, or potential prophylaxis.

The trial demonstrated a clinically meaningful absolute PFS benefit, the best in class, but updated data, including overall survival data, are still needed, Dr. Dent said. “We also need to see the quality-of-life data; this is what’s important for our patients. Is this improving progression-free survival, is it improving quality of life, and is it improving overall survival? Only the future will tell.”

SOLAR-1 was sponsored by Novartis. Dr. André disclosed research grants from Novartis and others. Dr. Dent disclosed advisory board, honoraria, or travel support from Novartis and others. Dr. Harbeck disclosed honoraria for consulting and lecturing for Pfizer and others.

SOURCE: Andre F et al. ESMO 2018, Abstract LBA3_PR.

MUNICH – A combination of the selective phosphoinositide 3-kinase inhibitor alpelisib and fulvestrant (Faslodex) was associated with significantly better progression-free survival than placebo plus fulvestrant in patients with hormone receptor–positive, HER2-negative breast cancer with PIK3CA mutations, investigators in the SOLAR-1 trial reported.

Neil Osterweil/MDedge News

The addition of alpelisib, an inhibitor of the alpha isoform of the phosphoinositide 3-kinase (PI3K), to fulvestrant, a selective estrogen receptor modifier, was associated with a 35% improvement in progression-free survival (PFS), reported Fabrice André, MD, of Institut Gustave Roussy, Villejuif, France.

“Alpelisib plus fulvestrant is a potential new treatment option for patients with PIK3CA-mutant, hormone receptor–positive, HER2-negative advanced breast cancer who have progressed on prior endocrine therapy, with or without a CDK 4/6 [cyclin-dependent kinases 4/6] inhibitor,” he said in a podium presentation at the European Society for Medical Oncology Congress.

Unlike other PI3K inhibitors which have activity spanning the alpha, beta, gamma, and delta isoforms of PI3K, alpelisib is specific for only the alpha isoform, giving it a safety profile that compares favorably with other agents in its class, Dr. André said.

Results of other studies combining PI3K inhibition with endocrine therapy have not borne especially sweet fruit. For example, the SANDPIPER trial, a study of the combination of fulvestrant and the PI3K inhibitor idelalisib (Zydelig) presented at the 2018 annual meeting of the American Society of Clinical Oncology, showed a benefit of 2 months more PFS, compared with fulvestrant alone, but at the cost of serious toxicities in half of all patients treated with the combination.

In the SOLAR-1 trial, investigators randomized 572 postmenopausal women, or men (sex of patients not shown), with hormone receptor–positive, HER2-negative advanced breast cancer. Of the 572 patients, 341 were determined to have PIK3CA mutations.

To be eligible for the study, patients had to have good Eastern Cooperative Oncology Group performance status (1 or less) and have received one or more prior lines of endocrine therapy but no chemotherapy for advanced breast cancer.

Patients who had previously received fulvestrant, any PI3K inhibitor, Akt inhibitor, or mammalian target of rapamycin inhibitor were excluded.

The patients were randomly assigned to receive intramuscular fulvestrant 500 mg on days 1 and 15 of treatment cycle 1 and then every 28 days, plus either oral alpelisib (300 mg daily) or placebo.

Locally assessed PFS in patients with PIK3CA mutations, the primary endpoint, favored alpelisib. At a median follow-up of 20 months, the median PFS with alpelisib was 11 months, versus 5.7 months for placebo. The hazard ratio for progression with alpelisib was 0.65 (P = .00065).

A blinded independent review committee assessment of 50% of patients in the PIK3CA-mutant cohort supported the investigator-assessed findings, with a median PFS of 11.1 months with alpelisib, versus 3.7 months with placebo.

In contrast, a proof-of-concept analysis of the 231 patients without PIK3CA mutations could not show a benefit for alpelisib over placebo.

In the PIK3CA-mutant cohort, the overall response rates among patients with measurable disease were 35.7% with alpelisib versus 16.2% with placebo (P = .0002). Respective response rates among all patients were 26.6% and 12.8% (P = .0006).

Adverse events in the entire trial population included hyperglycemia leading to discontinuation of alpelisib in 6.3% of patients and rash leading to discontinuation of the drug in 3.2% of patients. There were no discontinuations for either hyperglycemia or rash in the placebo arm.

The hyperglycemia can be managed with metformin, Dr. André said.

At a briefing prior to presentation of the SOLAR-1 data in a symposium, briefing discussant Nadia Harbeck, MD, of the University of Munich Medical Center said that the trial represents a significant advance.

“We have numerous talks, also phase 3 trials, with PI3-kinase inhibitors where we saw marginal benefit, and the drugs weren’t usable in clinical practice because the tolerability was so bad. So this is now the first phase 3 data proving that if you have a targeted drug and the tumor has the target, you can actually almost double progression-free survival, and I think this will change the way we practice,” she said.

Neil Osterweil/MDedge News

Rebecca Dent, MD, a senior consultant at the National Cancer Centre Singapore, the invited discussant at the symposium, complimented the SOLAR-1 investigators for conducting a “clinically homogeneous, biomarker-driven clinical trial reflecting new pathways to registration.”

She suggested that the significant clinical toxicities seen with PI3K inhibitors might be ameliorated with different dosing schedules, pharmacodynamic endpoints such as hyperglycemia, or potential prophylaxis.

The trial demonstrated a clinically meaningful absolute PFS benefit, the best in class, but updated data, including overall survival data, are still needed, Dr. Dent said. “We also need to see the quality-of-life data; this is what’s important for our patients. Is this improving progression-free survival, is it improving quality of life, and is it improving overall survival? Only the future will tell.”

SOLAR-1 was sponsored by Novartis. Dr. André disclosed research grants from Novartis and others. Dr. Dent disclosed advisory board, honoraria, or travel support from Novartis and others. Dr. Harbeck disclosed honoraria for consulting and lecturing for Pfizer and others.

SOURCE: Andre F et al. ESMO 2018, Abstract LBA3_PR.

MUNICH – A combination of the selective phosphoinositide 3-kinase inhibitor alpelisib and fulvestrant (Faslodex) was associated with significantly better progression-free survival than placebo plus fulvestrant in patients with hormone receptor–positive, HER2-negative breast cancer with PIK3CA mutations, investigators in the SOLAR-1 trial reported.

Neil Osterweil/MDedge News

The addition of alpelisib, an inhibitor of the alpha isoform of the phosphoinositide 3-kinase (PI3K), to fulvestrant, a selective estrogen receptor modifier, was associated with a 35% improvement in progression-free survival (PFS), reported Fabrice André, MD, of Institut Gustave Roussy, Villejuif, France.

“Alpelisib plus fulvestrant is a potential new treatment option for patients with PIK3CA-mutant, hormone receptor–positive, HER2-negative advanced breast cancer who have progressed on prior endocrine therapy, with or without a CDK 4/6 [cyclin-dependent kinases 4/6] inhibitor,” he said in a podium presentation at the European Society for Medical Oncology Congress.

Unlike other PI3K inhibitors which have activity spanning the alpha, beta, gamma, and delta isoforms of PI3K, alpelisib is specific for only the alpha isoform, giving it a safety profile that compares favorably with other agents in its class, Dr. André said.

Results of other studies combining PI3K inhibition with endocrine therapy have not borne especially sweet fruit. For example, the SANDPIPER trial, a study of the combination of fulvestrant and the PI3K inhibitor idelalisib (Zydelig) presented at the 2018 annual meeting of the American Society of Clinical Oncology, showed a benefit of 2 months more PFS, compared with fulvestrant alone, but at the cost of serious toxicities in half of all patients treated with the combination.

In the SOLAR-1 trial, investigators randomized 572 postmenopausal women, or men (sex of patients not shown), with hormone receptor–positive, HER2-negative advanced breast cancer. Of the 572 patients, 341 were determined to have PIK3CA mutations.

To be eligible for the study, patients had to have good Eastern Cooperative Oncology Group performance status (1 or less) and have received one or more prior lines of endocrine therapy but no chemotherapy for advanced breast cancer.

Patients who had previously received fulvestrant, any PI3K inhibitor, Akt inhibitor, or mammalian target of rapamycin inhibitor were excluded.

The patients were randomly assigned to receive intramuscular fulvestrant 500 mg on days 1 and 15 of treatment cycle 1 and then every 28 days, plus either oral alpelisib (300 mg daily) or placebo.

Locally assessed PFS in patients with PIK3CA mutations, the primary endpoint, favored alpelisib. At a median follow-up of 20 months, the median PFS with alpelisib was 11 months, versus 5.7 months for placebo. The hazard ratio for progression with alpelisib was 0.65 (P = .00065).

A blinded independent review committee assessment of 50% of patients in the PIK3CA-mutant cohort supported the investigator-assessed findings, with a median PFS of 11.1 months with alpelisib, versus 3.7 months with placebo.

In contrast, a proof-of-concept analysis of the 231 patients without PIK3CA mutations could not show a benefit for alpelisib over placebo.

In the PIK3CA-mutant cohort, the overall response rates among patients with measurable disease were 35.7% with alpelisib versus 16.2% with placebo (P = .0002). Respective response rates among all patients were 26.6% and 12.8% (P = .0006).

Adverse events in the entire trial population included hyperglycemia leading to discontinuation of alpelisib in 6.3% of patients and rash leading to discontinuation of the drug in 3.2% of patients. There were no discontinuations for either hyperglycemia or rash in the placebo arm.

The hyperglycemia can be managed with metformin, Dr. André said.

At a briefing prior to presentation of the SOLAR-1 data in a symposium, briefing discussant Nadia Harbeck, MD, of the University of Munich Medical Center said that the trial represents a significant advance.

“We have numerous talks, also phase 3 trials, with PI3-kinase inhibitors where we saw marginal benefit, and the drugs weren’t usable in clinical practice because the tolerability was so bad. So this is now the first phase 3 data proving that if you have a targeted drug and the tumor has the target, you can actually almost double progression-free survival, and I think this will change the way we practice,” she said.

Neil Osterweil/MDedge News

Rebecca Dent, MD, a senior consultant at the National Cancer Centre Singapore, the invited discussant at the symposium, complimented the SOLAR-1 investigators for conducting a “clinically homogeneous, biomarker-driven clinical trial reflecting new pathways to registration.”

She suggested that the significant clinical toxicities seen with PI3K inhibitors might be ameliorated with different dosing schedules, pharmacodynamic endpoints such as hyperglycemia, or potential prophylaxis.

The trial demonstrated a clinically meaningful absolute PFS benefit, the best in class, but updated data, including overall survival data, are still needed, Dr. Dent said. “We also need to see the quality-of-life data; this is what’s important for our patients. Is this improving progression-free survival, is it improving quality of life, and is it improving overall survival? Only the future will tell.”

SOLAR-1 was sponsored by Novartis. Dr. André disclosed research grants from Novartis and others. Dr. Dent disclosed advisory board, honoraria, or travel support from Novartis and others. Dr. Harbeck disclosed honoraria for consulting and lecturing for Pfizer and others.

SOURCE: Andre F et al. ESMO 2018, Abstract LBA3_PR.

MUNICH – Patients with HIV who are treated with nivolumab, a programmed death-1 (PD-1) inhibitor, appear to have similar safety and efficacy outcomes compared with HIV-negative patients treated with the same agent, investigators found.

The retrospective study also showed that viral load and CD4 status were largely unchanged by immunotherapy, lead author Aurélien Gobert, MD, of Groupe Hospitalier Pitié Salpêtrière, Paris, reported at the European Society for Medical Oncology Congress.

HIV increases risks of certain cancer types, Dr. Gobert said in a press release. “These patients are at higher risk for a number of cancers: AIDS-defining forms, the diagnosis of which results in the categorization of a person as suffering from AIDS, but also various other types that they are two to three times more likely to develop than in the general population, such as anal, skin, head and neck, and lung cancer,” he said.

Despite the increased risks, few studies have evaluated cancer treatments for patients with HIV due to exclusions from most clinical trials. As HIV is an immune-based disease, concerns have arisen surrounding the safety and efficacy of using anti-neoplastic immunotherapies for HIV-positive patients. Considering that millions of people worldwide are HIV positive, research in this area can have real-world consequences.

Dr. Gobert and his colleagues analyzed data from CANCERVIH, a French national database of patients with cancer and HIV. Since May 2014, nivolumab has been administered to 20 patients. Nineteen had metastatic non–small-cell lung cancer and 1 had metastatic melanoma. At diagnosis, the median CD4 count was 338.5 per cubic millimeter. Seventeen patients had undetectable viral load, two had fewer than 40 copies per millimeter, and one patient’s viral load was unknown. Dr. Gobert described the population as “demographically homogenous,” with “most patients being males around 60 years old.”

Analysis showed that nivolumab had little impact on CD4 count or viral load. One patient had a decreased CD4 count and an increased viral load, but this occurred during an interruption to antiretroviral therapy, which clouds potential associations with nivolumab. No immune-related adverse events or deaths due to drug toxicity occurred. Efficacy was assessed in 17 patients: Four (24%) showed a partial response, 2 (12%) had stable disease, and 11 (64%) had disease progression.

“Based on these preliminary data, treatment with anti-PD-1 ... seems to be feasible in people with HIV,” Dr. Gobert reported. He added that “antiretroviral therapy should not be interrupted.”

In a comment for ESMO, John Haanen, PhD, of the Netherlands Cancer Institute, Amsterdam, said that the results “confirm those of other, smaller cohorts in showing that while on antiretroviral therapy, cancer patients living with HIV can safely receive anti-PD-1 treatment. The efficacy data also suggests that the overall response rate of HIV-positive patients seems to be similar to that of other cancer patients. These promising results need to be confirmed in larger studies – ideally, in a prospective clinical trial.”

Principal investigator Jean-Philippe Spano, MD, PhD, disclosed relationships with Gilead, Roche, BMS, and others.

SOURCE: Gobert et al. ESMO 2018, Abstract 1213P_PR.

MUNICH – Patients with HIV who are treated with nivolumab, a programmed death-1 (PD-1) inhibitor, appear to have similar safety and efficacy outcomes compared with HIV-negative patients treated with the same agent, investigators found.

The retrospective study also showed that viral load and CD4 status were largely unchanged by immunotherapy, lead author Aurélien Gobert, MD, of Groupe Hospitalier Pitié Salpêtrière, Paris, reported at the European Society for Medical Oncology Congress.

HIV increases risks of certain cancer types, Dr. Gobert said in a press release. “These patients are at higher risk for a number of cancers: AIDS-defining forms, the diagnosis of which results in the categorization of a person as suffering from AIDS, but also various other types that they are two to three times more likely to develop than in the general population, such as anal, skin, head and neck, and lung cancer,” he said.

Despite the increased risks, few studies have evaluated cancer treatments for patients with HIV due to exclusions from most clinical trials. As HIV is an immune-based disease, concerns have arisen surrounding the safety and efficacy of using anti-neoplastic immunotherapies for HIV-positive patients. Considering that millions of people worldwide are HIV positive, research in this area can have real-world consequences.

Dr. Gobert and his colleagues analyzed data from CANCERVIH, a French national database of patients with cancer and HIV. Since May 2014, nivolumab has been administered to 20 patients. Nineteen had metastatic non–small-cell lung cancer and 1 had metastatic melanoma. At diagnosis, the median CD4 count was 338.5 per cubic millimeter. Seventeen patients had undetectable viral load, two had fewer than 40 copies per millimeter, and one patient’s viral load was unknown. Dr. Gobert described the population as “demographically homogenous,” with “most patients being males around 60 years old.”

Analysis showed that nivolumab had little impact on CD4 count or viral load. One patient had a decreased CD4 count and an increased viral load, but this occurred during an interruption to antiretroviral therapy, which clouds potential associations with nivolumab. No immune-related adverse events or deaths due to drug toxicity occurred. Efficacy was assessed in 17 patients: Four (24%) showed a partial response, 2 (12%) had stable disease, and 11 (64%) had disease progression.

“Based on these preliminary data, treatment with anti-PD-1 ... seems to be feasible in people with HIV,” Dr. Gobert reported. He added that “antiretroviral therapy should not be interrupted.”

In a comment for ESMO, John Haanen, PhD, of the Netherlands Cancer Institute, Amsterdam, said that the results “confirm those of other, smaller cohorts in showing that while on antiretroviral therapy, cancer patients living with HIV can safely receive anti-PD-1 treatment. The efficacy data also suggests that the overall response rate of HIV-positive patients seems to be similar to that of other cancer patients. These promising results need to be confirmed in larger studies – ideally, in a prospective clinical trial.”

Principal investigator Jean-Philippe Spano, MD, PhD, disclosed relationships with Gilead, Roche, BMS, and others.

SOURCE: Gobert et al. ESMO 2018, Abstract 1213P_PR.

MUNICH – Patients with HIV who are treated with nivolumab, a programmed death-1 (PD-1) inhibitor, appear to have similar safety and efficacy outcomes compared with HIV-negative patients treated with the same agent, investigators found.

The retrospective study also showed that viral load and CD4 status were largely unchanged by immunotherapy, lead author Aurélien Gobert, MD, of Groupe Hospitalier Pitié Salpêtrière, Paris, reported at the European Society for Medical Oncology Congress.

HIV increases risks of certain cancer types, Dr. Gobert said in a press release. “These patients are at higher risk for a number of cancers: AIDS-defining forms, the diagnosis of which results in the categorization of a person as suffering from AIDS, but also various other types that they are two to three times more likely to develop than in the general population, such as anal, skin, head and neck, and lung cancer,” he said.

Despite the increased risks, few studies have evaluated cancer treatments for patients with HIV due to exclusions from most clinical trials. As HIV is an immune-based disease, concerns have arisen surrounding the safety and efficacy of using anti-neoplastic immunotherapies for HIV-positive patients. Considering that millions of people worldwide are HIV positive, research in this area can have real-world consequences.

Dr. Gobert and his colleagues analyzed data from CANCERVIH, a French national database of patients with cancer and HIV. Since May 2014, nivolumab has been administered to 20 patients. Nineteen had metastatic non–small-cell lung cancer and 1 had metastatic melanoma. At diagnosis, the median CD4 count was 338.5 per cubic millimeter. Seventeen patients had undetectable viral load, two had fewer than 40 copies per millimeter, and one patient’s viral load was unknown. Dr. Gobert described the population as “demographically homogenous,” with “most patients being males around 60 years old.”

Analysis showed that nivolumab had little impact on CD4 count or viral load. One patient had a decreased CD4 count and an increased viral load, but this occurred during an interruption to antiretroviral therapy, which clouds potential associations with nivolumab. No immune-related adverse events or deaths due to drug toxicity occurred. Efficacy was assessed in 17 patients: Four (24%) showed a partial response, 2 (12%) had stable disease, and 11 (64%) had disease progression.

“Based on these preliminary data, treatment with anti-PD-1 ... seems to be feasible in people with HIV,” Dr. Gobert reported. He added that “antiretroviral therapy should not be interrupted.”

In a comment for ESMO, John Haanen, PhD, of the Netherlands Cancer Institute, Amsterdam, said that the results “confirm those of other, smaller cohorts in showing that while on antiretroviral therapy, cancer patients living with HIV can safely receive anti-PD-1 treatment. The efficacy data also suggests that the overall response rate of HIV-positive patients seems to be similar to that of other cancer patients. These promising results need to be confirmed in larger studies – ideally, in a prospective clinical trial.”

Principal investigator Jean-Philippe Spano, MD, PhD, disclosed relationships with Gilead, Roche, BMS, and others.

SOURCE: Gobert et al. ESMO 2018, Abstract 1213P_PR.

MUNICH – Olaparib maintenance therapy significantly reduces risk of disease progression or death in women with BRCA-mutated advanced ovarian cancer who respond to chemotherapy, according to results from the SOLO-1 trial.

Will Pass/MDedge News

The benefit from olaparib was compelling; compared with placebo, more than twice the number of women were alive and without disease progression after 3 years.

Current guidelines recommend olaparib for relapsed ovarian cancer, but the SOLO-1 results support first-line application, said lead author, Kathleen N. Moore, MD at the European Society for Medical Oncology Congress.

“We believe that the SOLO-1 data really prompts a change in the standard of care for women with advanced ovarian cancer who harbor a BRCA mutation,” said Dr. Moore of the Stephenson Cancer Center at the University of Oklahoma in Oklahoma City.

Olaparib (Lynparza) currently is approved for relapsed ovarian cancer regardless of mutation status, but poor outcomes suggest that this intervention is given too late – many patients relapse, and when they do, most do not survive.

“Although the majority of ... patients have no evidence of disease after [chemotherapy], approximately 70% have a relapse within the subsequent 3 years,” the investigators wrote in an article simultaneously published in the New England Journal of Medicine. “Recurrent ovarian cancer is typically incurable, with most patients receiving multiple additional lines of treatment before ultimately dying from the disease.”

Poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib, are well matched for BRCA-mutated tumors; they interfere with DNA repair, thereby exploiting repair deficits conferred by BRCA mutations. One in six women with advanced ovarian cancer exhibits a BRCA mutation, so eligible patients are relatively common.

The phase 3, placebo-controlled SOLO-1 trial involved 391 patients with advanced ovarian cancer who had a complete or partial response to platinum-based chemotherapy. Patients exhibited mutations in BRCA1, BRCA2, or both (BRCA1/BRCA2). After chemotherapy, patients were randomized to receive either olaparib 300 mg twice daily or placebo (in a 2:1 ratio).

The primary endpoint was progression-free survival (PFS) determined by imaging; MRI or CT was performed at baseline and every 3 months for up to 3 years, with 6-month intervals thereafter. Patients who had no disease progression at 2 years halted therapy, whereas patients with disease progression were allowed to continue olaparib if desired.

The 3-year follow-up period (median, 40.7 months) revealed a dramatic benefit from olaparib; the PFS rate was 60% for olaparib, compared with 27% for placebo (P less than .001). This represents a 70% reduction in risk of disease progression or death. Because of the magnitude of prolonged survival, median PFS could not be determined; however, estimates suggest that olaparib adds 3 years without disease progression.

Dr. Moore noted that these benefits were consistent regardless of stage or level of response to chemotherapy (partial vs. complete). “Everyone benefits,” she said. “It really looks like an all subgroup-beneficial regimen.”

Still, questions of long-term benefit remain unanswered. “It’s too early to know what [the extended PFS] means long term,” Dr. Moore said. “We hope that it means we’ve converted a larger fraction of patients to cure, and that’s what you’re seeing with the flattening of the survival curve, but it took us 3 years just to get to this point, so how long will it take us to comment on overall survival? It’s a good problem to have, but it’s going to remain to be seen.”

As therapy was discontinued at 2 years, and yet patients remained progression free after 3 years, researchers also are left wondering about mechanisms of action. “Has olaparib eradicated all the disease?” asked Jonathan A. Ledermann, MD, member of the ESMO faculty and professor of medical oncology at University College London. “Or is something else happening, such as an immune response that’s taking over when you stop the drug? We don’t know the answer to that, but it’s an intriguing question and one that we need to follow up on.”

Safety data from SOLO-1 were comparable with previous olaparib trials. Overall, olaparib was well tolerated, with 21% of patients experiencing serious adverse events. The most common serious adverse event was neutropenia (7%).

SOLO-1 was sponsored by AstraZeneca and Merck. The authors reported financial affiliations with Clovis, Tesaro, Mateon, Merck, and others.
 

SOURCE: Moore et al. N Eng J Med. 2018 Oct 21. doi: 10.1056/NEJMoa1810858.

MUNICH – Olaparib maintenance therapy significantly reduces risk of disease progression or death in women with BRCA-mutated advanced ovarian cancer who respond to chemotherapy, according to results from the SOLO-1 trial.

Will Pass/MDedge News

The benefit from olaparib was compelling; compared with placebo, more than twice the number of women were alive and without disease progression after 3 years.

Current guidelines recommend olaparib for relapsed ovarian cancer, but the SOLO-1 results support first-line application, said lead author, Kathleen N. Moore, MD at the European Society for Medical Oncology Congress.

“We believe that the SOLO-1 data really prompts a change in the standard of care for women with advanced ovarian cancer who harbor a BRCA mutation,” said Dr. Moore of the Stephenson Cancer Center at the University of Oklahoma in Oklahoma City.

Olaparib (Lynparza) currently is approved for relapsed ovarian cancer regardless of mutation status, but poor outcomes suggest that this intervention is given too late – many patients relapse, and when they do, most do not survive.

“Although the majority of ... patients have no evidence of disease after [chemotherapy], approximately 70% have a relapse within the subsequent 3 years,” the investigators wrote in an article simultaneously published in the New England Journal of Medicine. “Recurrent ovarian cancer is typically incurable, with most patients receiving multiple additional lines of treatment before ultimately dying from the disease.”

Poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib, are well matched for BRCA-mutated tumors; they interfere with DNA repair, thereby exploiting repair deficits conferred by BRCA mutations. One in six women with advanced ovarian cancer exhibits a BRCA mutation, so eligible patients are relatively common.

The phase 3, placebo-controlled SOLO-1 trial involved 391 patients with advanced ovarian cancer who had a complete or partial response to platinum-based chemotherapy. Patients exhibited mutations in BRCA1, BRCA2, or both (BRCA1/BRCA2). After chemotherapy, patients were randomized to receive either olaparib 300 mg twice daily or placebo (in a 2:1 ratio).

The primary endpoint was progression-free survival (PFS) determined by imaging; MRI or CT was performed at baseline and every 3 months for up to 3 years, with 6-month intervals thereafter. Patients who had no disease progression at 2 years halted therapy, whereas patients with disease progression were allowed to continue olaparib if desired.

The 3-year follow-up period (median, 40.7 months) revealed a dramatic benefit from olaparib; the PFS rate was 60% for olaparib, compared with 27% for placebo (P less than .001). This represents a 70% reduction in risk of disease progression or death. Because of the magnitude of prolonged survival, median PFS could not be determined; however, estimates suggest that olaparib adds 3 years without disease progression.

Dr. Moore noted that these benefits were consistent regardless of stage or level of response to chemotherapy (partial vs. complete). “Everyone benefits,” she said. “It really looks like an all subgroup-beneficial regimen.”

Still, questions of long-term benefit remain unanswered. “It’s too early to know what [the extended PFS] means long term,” Dr. Moore said. “We hope that it means we’ve converted a larger fraction of patients to cure, and that’s what you’re seeing with the flattening of the survival curve, but it took us 3 years just to get to this point, so how long will it take us to comment on overall survival? It’s a good problem to have, but it’s going to remain to be seen.”

As therapy was discontinued at 2 years, and yet patients remained progression free after 3 years, researchers also are left wondering about mechanisms of action. “Has olaparib eradicated all the disease?” asked Jonathan A. Ledermann, MD, member of the ESMO faculty and professor of medical oncology at University College London. “Or is something else happening, such as an immune response that’s taking over when you stop the drug? We don’t know the answer to that, but it’s an intriguing question and one that we need to follow up on.”

Safety data from SOLO-1 were comparable with previous olaparib trials. Overall, olaparib was well tolerated, with 21% of patients experiencing serious adverse events. The most common serious adverse event was neutropenia (7%).

SOLO-1 was sponsored by AstraZeneca and Merck. The authors reported financial affiliations with Clovis, Tesaro, Mateon, Merck, and others.
 

SOURCE: Moore et al. N Eng J Med. 2018 Oct 21. doi: 10.1056/NEJMoa1810858.

MUNICH – Olaparib maintenance therapy significantly reduces risk of disease progression or death in women with BRCA-mutated advanced ovarian cancer who respond to chemotherapy, according to results from the SOLO-1 trial.

Will Pass/MDedge News

The benefit from olaparib was compelling; compared with placebo, more than twice the number of women were alive and without disease progression after 3 years.

Current guidelines recommend olaparib for relapsed ovarian cancer, but the SOLO-1 results support first-line application, said lead author, Kathleen N. Moore, MD at the European Society for Medical Oncology Congress.

“We believe that the SOLO-1 data really prompts a change in the standard of care for women with advanced ovarian cancer who harbor a BRCA mutation,” said Dr. Moore of the Stephenson Cancer Center at the University of Oklahoma in Oklahoma City.

Olaparib (Lynparza) currently is approved for relapsed ovarian cancer regardless of mutation status, but poor outcomes suggest that this intervention is given too late – many patients relapse, and when they do, most do not survive.

“Although the majority of ... patients have no evidence of disease after [chemotherapy], approximately 70% have a relapse within the subsequent 3 years,” the investigators wrote in an article simultaneously published in the New England Journal of Medicine. “Recurrent ovarian cancer is typically incurable, with most patients receiving multiple additional lines of treatment before ultimately dying from the disease.”

Poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib, are well matched for BRCA-mutated tumors; they interfere with DNA repair, thereby exploiting repair deficits conferred by BRCA mutations. One in six women with advanced ovarian cancer exhibits a BRCA mutation, so eligible patients are relatively common.

The phase 3, placebo-controlled SOLO-1 trial involved 391 patients with advanced ovarian cancer who had a complete or partial response to platinum-based chemotherapy. Patients exhibited mutations in BRCA1, BRCA2, or both (BRCA1/BRCA2). After chemotherapy, patients were randomized to receive either olaparib 300 mg twice daily or placebo (in a 2:1 ratio).

The primary endpoint was progression-free survival (PFS) determined by imaging; MRI or CT was performed at baseline and every 3 months for up to 3 years, with 6-month intervals thereafter. Patients who had no disease progression at 2 years halted therapy, whereas patients with disease progression were allowed to continue olaparib if desired.

The 3-year follow-up period (median, 40.7 months) revealed a dramatic benefit from olaparib; the PFS rate was 60% for olaparib, compared with 27% for placebo (P less than .001). This represents a 70% reduction in risk of disease progression or death. Because of the magnitude of prolonged survival, median PFS could not be determined; however, estimates suggest that olaparib adds 3 years without disease progression.

Dr. Moore noted that these benefits were consistent regardless of stage or level of response to chemotherapy (partial vs. complete). “Everyone benefits,” she said. “It really looks like an all subgroup-beneficial regimen.”

Still, questions of long-term benefit remain unanswered. “It’s too early to know what [the extended PFS] means long term,” Dr. Moore said. “We hope that it means we’ve converted a larger fraction of patients to cure, and that’s what you’re seeing with the flattening of the survival curve, but it took us 3 years just to get to this point, so how long will it take us to comment on overall survival? It’s a good problem to have, but it’s going to remain to be seen.”

As therapy was discontinued at 2 years, and yet patients remained progression free after 3 years, researchers also are left wondering about mechanisms of action. “Has olaparib eradicated all the disease?” asked Jonathan A. Ledermann, MD, member of the ESMO faculty and professor of medical oncology at University College London. “Or is something else happening, such as an immune response that’s taking over when you stop the drug? We don’t know the answer to that, but it’s an intriguing question and one that we need to follow up on.”

Safety data from SOLO-1 were comparable with previous olaparib trials. Overall, olaparib was well tolerated, with 21% of patients experiencing serious adverse events. The most common serious adverse event was neutropenia (7%).

SOLO-1 was sponsored by AstraZeneca and Merck. The authors reported financial affiliations with Clovis, Tesaro, Mateon, Merck, and others.
 

SOURCE: Moore et al. N Eng J Med. 2018 Oct 21. doi: 10.1056/NEJMoa1810858.

MUNICH – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the tyrosine kinase inhibitor axitinib (Inlyta) was associated with longer progression-free survival and higher objective response rates than was sunitinib as frontline therapy for patients with advanced renal cell carcinoma, investigators found.

Neil Osterweil/MDedge News

The progression-free survival (PFS) benefit of the combination was seen both in the subset of patients with tumors expressing programmed death-1 ligand 1 (PD-L1) on at least 1% of their cells as well as in the overall study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, on behalf of colleagues in the JAVELIN Renal 101 trial.

“This was very early on, at an interim analysis, showing a profound effect,” he said at a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.

“The results support this being a new first-line standard of care, and possibly a first-line option for advanced RCC based on these data,” he added.

Briefing discussant John Haanen, PhD, of the Netherlands Cancer Institute in Amsterdam, said that “based on preclinical data, it makes sense to combine angiogenesis inhibitors and immunotherapy, because we know angiogenesis, VEGF [vascular endothelial growth factor] especially impacts on the way the immune system can respond to the kidney cancer, and by taking away some of these negative effects of the VEGF by using an anti-VEGF drug, the immunotherapy may work better,” he said.

Neil Osterweil/MDedge News

MUNICH – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the tyrosine kinase inhibitor axitinib (Inlyta) was associated with longer progression-free survival and higher objective response rates than was sunitinib as frontline therapy for patients with advanced renal cell carcinoma, investigators found.

Neil Osterweil/MDedge News

The progression-free survival (PFS) benefit of the combination was seen both in the subset of patients with tumors expressing programmed death-1 ligand 1 (PD-L1) on at least 1% of their cells as well as in the overall study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, on behalf of colleagues in the JAVELIN Renal 101 trial.

“This was very early on, at an interim analysis, showing a profound effect,” he said at a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.

“The results support this being a new first-line standard of care, and possibly a first-line option for advanced RCC based on these data,” he added.

Briefing discussant John Haanen, PhD, of the Netherlands Cancer Institute in Amsterdam, said that “based on preclinical data, it makes sense to combine angiogenesis inhibitors and immunotherapy, because we know angiogenesis, VEGF [vascular endothelial growth factor] especially impacts on the way the immune system can respond to the kidney cancer, and by taking away some of these negative effects of the VEGF by using an anti-VEGF drug, the immunotherapy may work better,” he said.

Neil Osterweil/MDedge News

MUNICH – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the tyrosine kinase inhibitor axitinib (Inlyta) was associated with longer progression-free survival and higher objective response rates than was sunitinib as frontline therapy for patients with advanced renal cell carcinoma, investigators found.

Neil Osterweil/MDedge News

The progression-free survival (PFS) benefit of the combination was seen both in the subset of patients with tumors expressing programmed death-1 ligand 1 (PD-L1) on at least 1% of their cells as well as in the overall study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, on behalf of colleagues in the JAVELIN Renal 101 trial.

“This was very early on, at an interim analysis, showing a profound effect,” he said at a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.

“The results support this being a new first-line standard of care, and possibly a first-line option for advanced RCC based on these data,” he added.

Briefing discussant John Haanen, PhD, of the Netherlands Cancer Institute in Amsterdam, said that “based on preclinical data, it makes sense to combine angiogenesis inhibitors and immunotherapy, because we know angiogenesis, VEGF [vascular endothelial growth factor] especially impacts on the way the immune system can respond to the kidney cancer, and by taking away some of these negative effects of the VEGF by using an anti-VEGF drug, the immunotherapy may work better,” he said.

Neil Osterweil/MDedge News

MUNICH – Neoadjuvant erlotinib for patients with stage IIIA (N2) non–small cell lung cancer (NSCLC) increased progression-free survival (PFS), compared with gemcitabine and cisplatin, according to results from the recent CTONG 1103 trial.

Will Pass/MDedge News

Despite beating chemotherapy, erlotinib, an epithelial growth factor receptor (EGFR)–mutant tyrosine kinase inhibitor (TKI), fell short of benchmarks set by adjuvant therapy, so it is unlikely that neoadjuvant erlotinib will see clinical use anytime soon.

Lead author Wen-Zhao Zhong, MD, PhD, of Guangdong Lung Cancer Institute and Guangdong General Hospital in Guangzhou, China, presenting at the European Society for Medical Oncology Congress, said that the recent findings support further investigation into biomarker-guided neoadjuvant therapy for stage IIIA (N2) NSCLC, as identifying patient subgroups could potentially improve outcomes.

Principal investigator Yi-Long Wu, MD, described the impetus for CTONG 1103 in an interview. “Recently, the CTONG 1104 trial showed for the first time that adjuvant EGFR-TKI gefitinib could improve disease-free survival ... compared to adjuvant chemotherapy ... in N1N2-resected NSCLC. This raises the possibility that EGFR-TKIs may play a beneficial role in the neoadjuvant setting for this subgroup,” he said.

CTONG 1103 is an ongoing, phase 2, open-label trial. Out of 386 patients screened, 72 were enrolled based on treatment naivety and EGFR mutation positivity (exon 19 or 21). Following randomization, patients received either erlotinib 150 mg daily for 42 days or gemcitabine 1,250 mg/m² (days 1 and 8) and cisplatin 75 mg/m2 (day 1) every 3 weeks for two cycles. After surgery, patients in the erlotinib group continued therapy for 1 year, while patients in the chemotherapy cohort received two more cycles of treatment.

The primary endpoint was objective response rate, and secondary endpoints included PFS, pathological lymph node downstaging, overall survival, safety measures, and complete pathological response. The investigators also highlighted major pathological response (less than 10% viable cancer cells after preoperative therapy).

The results showed that about half of the patients receiving erlotinib had an objective response (54.1%), compared with approximately one-third in the chemotherapy group (34.3%); however, this difference was not statistically significant (P = .092). Erlotinib also provided a median PFS nearly twice that of chemotherapy (21.5 months vs. 11.9 months; P = .003) and more frequent lymph node downstaging (10.8% vs. 2.9%), but no patients achieved complete pathological response. The number of patients achieving major pathological response with erlotinib was limited but still more than chemotherapy (10.7% vs. 0%). The investigators are awaiting an overall survival rate.

Erlotinib showed similar adverse events to previous trials, most commonly, rash, diarrhea, cough, and oral ulcers, compared with chemotherapy, which was associated with GI issues, hematologic disturbances, and fatigue.

Will Pass/MDedge News

In response to these findings, Suresh S. Ramalingam, MD, invited discussant and deputy director of the Winship Cancer Institute of Emory University, Atlanta, first discussed relevant efficacy measures. “The best predictor of long-term outcomes in these patients is nodal downstaging,” Dr. Ramalingam said. In previous studies, “patients who had clearance of the nodes had the best outcomes, and that continues to be an important prognostic marker.”

While major pathological response is valuable, and previous studies have revealed prognostic value, evidence is too limited to suggest that this is equivalent with cure, and it should not be considered as significant as complete pathological response, he said.

Considering that “only 11% of the patients” treated with erlotinib had nodal downstaging and/or major pathological response, and none achieved complete pathological response, Dr. Ramalingam suggested that the results were modest at best.

“While erlotinib seems to be doing better than chemo, I feel that the chemo group here is underperforming, compared to historical controls,” Dr. Ramalingam said, noting higher benchmark objective response rates (61% vs. 34%) and complete pathological response rates (4% vs. 0%).

Instead of focusing on neoadjuvant studies, Dr. Ramalingam suggested that ongoing adjuvant trials (ALCHEMIST and ADAURA) hold more promise and are more likely to serve as inroads for TKIs like erlotinib.

“Adjuvant care has withstood the test of time,” Dr. Ramalingam said. “Neoadjuvant EGFR-TKI in N2 disease I don’t think is ready for center stage.”

CTONG 1103 was sponsored by CTONG and Roche. The authors reported financial affiliations with AstraZeneca, Pfizer, Roche, and others. Dr. Ramalingam reported compensation from Amgen, Bristol-Myers Squibb, Loxo Oncology, and others.

MUNICH – Neoadjuvant erlotinib for patients with stage IIIA (N2) non–small cell lung cancer (NSCLC) increased progression-free survival (PFS), compared with gemcitabine and cisplatin, according to results from the recent CTONG 1103 trial.

Will Pass/MDedge News

Despite beating chemotherapy, erlotinib, an epithelial growth factor receptor (EGFR)–mutant tyrosine kinase inhibitor (TKI), fell short of benchmarks set by adjuvant therapy, so it is unlikely that neoadjuvant erlotinib will see clinical use anytime soon.

Lead author Wen-Zhao Zhong, MD, PhD, of Guangdong Lung Cancer Institute and Guangdong General Hospital in Guangzhou, China, presenting at the European Society for Medical Oncology Congress, said that the recent findings support further investigation into biomarker-guided neoadjuvant therapy for stage IIIA (N2) NSCLC, as identifying patient subgroups could potentially improve outcomes.

Principal investigator Yi-Long Wu, MD, described the impetus for CTONG 1103 in an interview. “Recently, the CTONG 1104 trial showed for the first time that adjuvant EGFR-TKI gefitinib could improve disease-free survival ... compared to adjuvant chemotherapy ... in N1N2-resected NSCLC. This raises the possibility that EGFR-TKIs may play a beneficial role in the neoadjuvant setting for this subgroup,” he said.

CTONG 1103 is an ongoing, phase 2, open-label trial. Out of 386 patients screened, 72 were enrolled based on treatment naivety and EGFR mutation positivity (exon 19 or 21). Following randomization, patients received either erlotinib 150 mg daily for 42 days or gemcitabine 1,250 mg/m² (days 1 and 8) and cisplatin 75 mg/m2 (day 1) every 3 weeks for two cycles. After surgery, patients in the erlotinib group continued therapy for 1 year, while patients in the chemotherapy cohort received two more cycles of treatment.

The primary endpoint was objective response rate, and secondary endpoints included PFS, pathological lymph node downstaging, overall survival, safety measures, and complete pathological response. The investigators also highlighted major pathological response (less than 10% viable cancer cells after preoperative therapy).

The results showed that about half of the patients receiving erlotinib had an objective response (54.1%), compared with approximately one-third in the chemotherapy group (34.3%); however, this difference was not statistically significant (P = .092). Erlotinib also provided a median PFS nearly twice that of chemotherapy (21.5 months vs. 11.9 months; P = .003) and more frequent lymph node downstaging (10.8% vs. 2.9%), but no patients achieved complete pathological response. The number of patients achieving major pathological response with erlotinib was limited but still more than chemotherapy (10.7% vs. 0%). The investigators are awaiting an overall survival rate.

Erlotinib showed similar adverse events to previous trials, most commonly, rash, diarrhea, cough, and oral ulcers, compared with chemotherapy, which was associated with GI issues, hematologic disturbances, and fatigue.

Will Pass/MDedge News

In response to these findings, Suresh S. Ramalingam, MD, invited discussant and deputy director of the Winship Cancer Institute of Emory University, Atlanta, first discussed relevant efficacy measures. “The best predictor of long-term outcomes in these patients is nodal downstaging,” Dr. Ramalingam said. In previous studies, “patients who had clearance of the nodes had the best outcomes, and that continues to be an important prognostic marker.”

While major pathological response is valuable, and previous studies have revealed prognostic value, evidence is too limited to suggest that this is equivalent with cure, and it should not be considered as significant as complete pathological response, he said.

Considering that “only 11% of the patients” treated with erlotinib had nodal downstaging and/or major pathological response, and none achieved complete pathological response, Dr. Ramalingam suggested that the results were modest at best.

“While erlotinib seems to be doing better than chemo, I feel that the chemo group here is underperforming, compared to historical controls,” Dr. Ramalingam said, noting higher benchmark objective response rates (61% vs. 34%) and complete pathological response rates (4% vs. 0%).

Instead of focusing on neoadjuvant studies, Dr. Ramalingam suggested that ongoing adjuvant trials (ALCHEMIST and ADAURA) hold more promise and are more likely to serve as inroads for TKIs like erlotinib.

“Adjuvant care has withstood the test of time,” Dr. Ramalingam said. “Neoadjuvant EGFR-TKI in N2 disease I don’t think is ready for center stage.”

CTONG 1103 was sponsored by CTONG and Roche. The authors reported financial affiliations with AstraZeneca, Pfizer, Roche, and others. Dr. Ramalingam reported compensation from Amgen, Bristol-Myers Squibb, Loxo Oncology, and others.

MUNICH – Neoadjuvant erlotinib for patients with stage IIIA (N2) non–small cell lung cancer (NSCLC) increased progression-free survival (PFS), compared with gemcitabine and cisplatin, according to results from the recent CTONG 1103 trial.

Will Pass/MDedge News

Despite beating chemotherapy, erlotinib, an epithelial growth factor receptor (EGFR)–mutant tyrosine kinase inhibitor (TKI), fell short of benchmarks set by adjuvant therapy, so it is unlikely that neoadjuvant erlotinib will see clinical use anytime soon.

Lead author Wen-Zhao Zhong, MD, PhD, of Guangdong Lung Cancer Institute and Guangdong General Hospital in Guangzhou, China, presenting at the European Society for Medical Oncology Congress, said that the recent findings support further investigation into biomarker-guided neoadjuvant therapy for stage IIIA (N2) NSCLC, as identifying patient subgroups could potentially improve outcomes.

Principal investigator Yi-Long Wu, MD, described the impetus for CTONG 1103 in an interview. “Recently, the CTONG 1104 trial showed for the first time that adjuvant EGFR-TKI gefitinib could improve disease-free survival ... compared to adjuvant chemotherapy ... in N1N2-resected NSCLC. This raises the possibility that EGFR-TKIs may play a beneficial role in the neoadjuvant setting for this subgroup,” he said.

CTONG 1103 is an ongoing, phase 2, open-label trial. Out of 386 patients screened, 72 were enrolled based on treatment naivety and EGFR mutation positivity (exon 19 or 21). Following randomization, patients received either erlotinib 150 mg daily for 42 days or gemcitabine 1,250 mg/m² (days 1 and 8) and cisplatin 75 mg/m2 (day 1) every 3 weeks for two cycles. After surgery, patients in the erlotinib group continued therapy for 1 year, while patients in the chemotherapy cohort received two more cycles of treatment.

The primary endpoint was objective response rate, and secondary endpoints included PFS, pathological lymph node downstaging, overall survival, safety measures, and complete pathological response. The investigators also highlighted major pathological response (less than 10% viable cancer cells after preoperative therapy).

The results showed that about half of the patients receiving erlotinib had an objective response (54.1%), compared with approximately one-third in the chemotherapy group (34.3%); however, this difference was not statistically significant (P = .092). Erlotinib also provided a median PFS nearly twice that of chemotherapy (21.5 months vs. 11.9 months; P = .003) and more frequent lymph node downstaging (10.8% vs. 2.9%), but no patients achieved complete pathological response. The number of patients achieving major pathological response with erlotinib was limited but still more than chemotherapy (10.7% vs. 0%). The investigators are awaiting an overall survival rate.

Erlotinib showed similar adverse events to previous trials, most commonly, rash, diarrhea, cough, and oral ulcers, compared with chemotherapy, which was associated with GI issues, hematologic disturbances, and fatigue.

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In response to these findings, Suresh S. Ramalingam, MD, invited discussant and deputy director of the Winship Cancer Institute of Emory University, Atlanta, first discussed relevant efficacy measures. “The best predictor of long-term outcomes in these patients is nodal downstaging,” Dr. Ramalingam said. In previous studies, “patients who had clearance of the nodes had the best outcomes, and that continues to be an important prognostic marker.”

While major pathological response is valuable, and previous studies have revealed prognostic value, evidence is too limited to suggest that this is equivalent with cure, and it should not be considered as significant as complete pathological response, he said.

Considering that “only 11% of the patients” treated with erlotinib had nodal downstaging and/or major pathological response, and none achieved complete pathological response, Dr. Ramalingam suggested that the results were modest at best.

“While erlotinib seems to be doing better than chemo, I feel that the chemo group here is underperforming, compared to historical controls,” Dr. Ramalingam said, noting higher benchmark objective response rates (61% vs. 34%) and complete pathological response rates (4% vs. 0%).

Instead of focusing on neoadjuvant studies, Dr. Ramalingam suggested that ongoing adjuvant trials (ALCHEMIST and ADAURA) hold more promise and are more likely to serve as inroads for TKIs like erlotinib.

“Adjuvant care has withstood the test of time,” Dr. Ramalingam said. “Neoadjuvant EGFR-TKI in N2 disease I don’t think is ready for center stage.”

CTONG 1103 was sponsored by CTONG and Roche. The authors reported financial affiliations with AstraZeneca, Pfizer, Roche, and others. Dr. Ramalingam reported compensation from Amgen, Bristol-Myers Squibb, Loxo Oncology, and others.