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Stereotactic body radiation therapy safe, effective for moderately central NSCLC
Trial success with a stereotactic body radiation therapy (SBRT) regimen for centrally located non–small cell lung cancer (NSCLC) can be largely replicated in real-world practice, suggests a prospective cohort study published in Clinical Oncology.
The Radiation Therapy Oncology Group (RTOG) 0813 trial established the safety and efficacy of 50 Gy or 60 Gy given in five fractions to patients with early-stage central NSCLC (J Clin Oncol. 2019;37:1316-25). But whether similar outcomes can be achieved in routine care and how the degree of tumor centrality affects outcomes remain unclear.
Investigators led by Robert Rulach, MBChB, from the Beatson West of Scotland Cancer Centre, Glasgow, analyzed outcomes for 50 patients treated with the regimen of 50-Gy in five fractions at their institution for T1-2N0M0 stage NSCLC. All had tumors that were moderately central (within 2 cm of the trachea, bronchi, or proximal bronchial tree or having a planning target volume that abutted mediastinal pleura or pericardium); one had an additional tumor that was ultracentral (having a planning target volume that abutted the trachea).
The patients had a median age of 75.1 years. Notably, the majority were medically unfit for surgery (84%) and had an Eastern Cooperative Oncology Group performance status score of 2 or worse (56%). In 60% of patients, the diagnosis was made radiographically using PET/CT imaging; in the rest, the diagnosis was biopsy proven.
Study results showed that all patients completed the radiotherapy regimen of 50 Gy in 5 fractions on alternate days as planned, without treatment delays.
Two patients (4%) died within 90 days of treatment (1 from a chest infection, 1 from an unknown cause). A single patient each experienced early grade 3 esophagitis and grade 3 late dyspnea, for an overall rate of grade 3 toxicity of 4%. None of the patients experienced grade 4 toxicity. The 90-day rate of hospital admission was 20%.
With a median follow-up of 25.2 months, 34 patients died: 18 from causes unrelated to cancer and 16 from cancer recurrence. The cohort had a median overall survival of 27.0 months and a median cancer-specific survival of 39.8 months. The 2-year overall survival rate was 67.6%.
“For patients with early stage moderately central NSCLC, SABR [stereotactic ablative body radiotherapy] using a schedule of 50 Gy/five fractions has acceptable toxicity and overall survival comparable with the published literature, despite treating a majority of patients with a performance status of 2 or worse,” the investigators concluded.
Dr. Rulach disclosed no conflicts of interest. The study did not receive any specific funding.
SOURCE: Rulach R et al. Clin Oncol. 2019 Oct 10. doi: 10.1016/j.clon.2019.09.055.
Trial success with a stereotactic body radiation therapy (SBRT) regimen for centrally located non–small cell lung cancer (NSCLC) can be largely replicated in real-world practice, suggests a prospective cohort study published in Clinical Oncology.
The Radiation Therapy Oncology Group (RTOG) 0813 trial established the safety and efficacy of 50 Gy or 60 Gy given in five fractions to patients with early-stage central NSCLC (J Clin Oncol. 2019;37:1316-25). But whether similar outcomes can be achieved in routine care and how the degree of tumor centrality affects outcomes remain unclear.
Investigators led by Robert Rulach, MBChB, from the Beatson West of Scotland Cancer Centre, Glasgow, analyzed outcomes for 50 patients treated with the regimen of 50-Gy in five fractions at their institution for T1-2N0M0 stage NSCLC. All had tumors that were moderately central (within 2 cm of the trachea, bronchi, or proximal bronchial tree or having a planning target volume that abutted mediastinal pleura or pericardium); one had an additional tumor that was ultracentral (having a planning target volume that abutted the trachea).
The patients had a median age of 75.1 years. Notably, the majority were medically unfit for surgery (84%) and had an Eastern Cooperative Oncology Group performance status score of 2 or worse (56%). In 60% of patients, the diagnosis was made radiographically using PET/CT imaging; in the rest, the diagnosis was biopsy proven.
Study results showed that all patients completed the radiotherapy regimen of 50 Gy in 5 fractions on alternate days as planned, without treatment delays.
Two patients (4%) died within 90 days of treatment (1 from a chest infection, 1 from an unknown cause). A single patient each experienced early grade 3 esophagitis and grade 3 late dyspnea, for an overall rate of grade 3 toxicity of 4%. None of the patients experienced grade 4 toxicity. The 90-day rate of hospital admission was 20%.
With a median follow-up of 25.2 months, 34 patients died: 18 from causes unrelated to cancer and 16 from cancer recurrence. The cohort had a median overall survival of 27.0 months and a median cancer-specific survival of 39.8 months. The 2-year overall survival rate was 67.6%.
“For patients with early stage moderately central NSCLC, SABR [stereotactic ablative body radiotherapy] using a schedule of 50 Gy/five fractions has acceptable toxicity and overall survival comparable with the published literature, despite treating a majority of patients with a performance status of 2 or worse,” the investigators concluded.
Dr. Rulach disclosed no conflicts of interest. The study did not receive any specific funding.
SOURCE: Rulach R et al. Clin Oncol. 2019 Oct 10. doi: 10.1016/j.clon.2019.09.055.
Trial success with a stereotactic body radiation therapy (SBRT) regimen for centrally located non–small cell lung cancer (NSCLC) can be largely replicated in real-world practice, suggests a prospective cohort study published in Clinical Oncology.
The Radiation Therapy Oncology Group (RTOG) 0813 trial established the safety and efficacy of 50 Gy or 60 Gy given in five fractions to patients with early-stage central NSCLC (J Clin Oncol. 2019;37:1316-25). But whether similar outcomes can be achieved in routine care and how the degree of tumor centrality affects outcomes remain unclear.
Investigators led by Robert Rulach, MBChB, from the Beatson West of Scotland Cancer Centre, Glasgow, analyzed outcomes for 50 patients treated with the regimen of 50-Gy in five fractions at their institution for T1-2N0M0 stage NSCLC. All had tumors that were moderately central (within 2 cm of the trachea, bronchi, or proximal bronchial tree or having a planning target volume that abutted mediastinal pleura or pericardium); one had an additional tumor that was ultracentral (having a planning target volume that abutted the trachea).
The patients had a median age of 75.1 years. Notably, the majority were medically unfit for surgery (84%) and had an Eastern Cooperative Oncology Group performance status score of 2 or worse (56%). In 60% of patients, the diagnosis was made radiographically using PET/CT imaging; in the rest, the diagnosis was biopsy proven.
Study results showed that all patients completed the radiotherapy regimen of 50 Gy in 5 fractions on alternate days as planned, without treatment delays.
Two patients (4%) died within 90 days of treatment (1 from a chest infection, 1 from an unknown cause). A single patient each experienced early grade 3 esophagitis and grade 3 late dyspnea, for an overall rate of grade 3 toxicity of 4%. None of the patients experienced grade 4 toxicity. The 90-day rate of hospital admission was 20%.
With a median follow-up of 25.2 months, 34 patients died: 18 from causes unrelated to cancer and 16 from cancer recurrence. The cohort had a median overall survival of 27.0 months and a median cancer-specific survival of 39.8 months. The 2-year overall survival rate was 67.6%.
“For patients with early stage moderately central NSCLC, SABR [stereotactic ablative body radiotherapy] using a schedule of 50 Gy/five fractions has acceptable toxicity and overall survival comparable with the published literature, despite treating a majority of patients with a performance status of 2 or worse,” the investigators concluded.
Dr. Rulach disclosed no conflicts of interest. The study did not receive any specific funding.
SOURCE: Rulach R et al. Clin Oncol. 2019 Oct 10. doi: 10.1016/j.clon.2019.09.055.
FROM CLINICAL ONCOLOGY
Adding ramucirumab extends PFS in EGFR-mutated lung cancer
For patients with epidermal growth factor receptor–mutated non–small cell lung cancer (NSCLC), adding the vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor ramucirumab to standard erlotinib therapy may extend progression-free survival, based on results from the phase 3 RELAY trial.
Considering the acceptable safety profile, this dual regimen should be considered for first-line treatment of epidermal growth factor receptor (EGFR)–mutated disease, according to lead author Kazuhiko Nakagawa, MD, PhD, of the Kindai University faculty of medicine in Osaka, Japan, and colleagues.
Dual blockade of the EGFR and VEGF pathways is supported by previous studies which pointed to efficacy among EGFR-mutated subgroups, the investigators explained in Lancet Oncology, noting that ramucirumab appeared to be the best candidate for VEGF pathway inhibition. “Ramucirumab, a human monoclonal IgG1 antibody, selectively targets VEGFR-2, thereby blocking signaling mediated by VEGF-A, VEGF-C, and VEGF-D in NSCLC,” the investigators wrote. “Therefore, ramucirumab has the potential for broader antitumor activity than inhibitors of VEGF-A.”
The trial involved 449 patients with stage IV NSCLC and an EGFR exon 21 substitution or exon 19 deletion. Patients were randomized in a 1:1 ratio to receive either erlotinib (150 mg/day) plus placebo, or erlotinib plus ramucirumab (10 mg/kg every 2 weeks). The primary endpoint was progression-free survival. Secondary endpoints included safety and toxicity, overall survival, and various measures of response.
After a median follow-up of 20.7 months, the addition of ramucirumab was associated with a significantly better median progression-free survival, at 19.4 months, compared with 12.4 months among patients who received erlotinib alone, which translates to a hazard ratio of 0.59 (P less than .0001). In each cohort, 1% of patients achieved a complete response. Partial responses were also highly similar at 75% for ramucirumab versus 74% for placebo.
Turning to safety, ramucirumab was associated with more safety concerns, including a higher rate of grade 3-4 treatment-emergent adverse events (72% vs. 54%), most often hypertension. Serious adverse events were also more frequent with ramucirumab at a rate of 29%, compared with 21% among those who received erlotinib alone.
Despite these differences, the investigators concluded that the dual regimen still offers acceptable tolerability. “Safety was consistent with the established safety profiles of the individual compounds and a metastatic NSCLC population,” they wrote. “The RELAY regimen is therefore a viable new treatment option for the initial treatment of patients with metastatic EGFR-mutated NSCLC.”
The RELAY trial was funded by Eli Lilly. The investigators reported additional relationships with AstraZeneca, Bristol-Myers Squibb, Novartis, and others.
SOURCE: Nakagawa K et al. Lancet Oncol. 2019 Oct 4. doi: 10.1016/S1470-2045(19)30634-5.
The study by Nakagawa et al. suggests that epidermal growth factor receptor tyrosine kinase inhibitors may feasibly be combined with other drugs, but concerns remain about the infrequency of complete responses, which were uncommon in this trial, at 1%, and only slightly higher, at 7%, in a previous, similar trial that involved the addition of bevacizumab to erlotinib (Lancet Oncol. 2019 Apr 8. doi: 10.1016/S1470-2045(19)30035-X). A lack of complete responses may be caused by vascular endothelial growth factor inhibition, which reduces tumor burden, but also may increase risks of tumor invasion, metastases, hypoxia, and other malignant processes.
Hypothetically, multitargeted receptor tyrosine kinases, such as cabozantinib or foretinib, could counteract the above drawbacks, but this remains to be seen. In the meantime, investigators should aim to design trials based on preclinical data instead of empirical reasoning. Despite the complexity of the molecular pathophysiology involved, research is bringing us closer to a clear understanding of the network of relationships between pathways, which could ultimately enable effective use of available combinations.
Rafael Rosell, MD, PhD, and Carlos Pedraz-Valdunciel are with Germans Trias i Pujol Research Institute and Hospital and the Universitat Autónoma de Barcelona. Both authors declared no competing interests. Their remarks are adapted from an accompanying editorial (Lancet Oncol. 2019 Oct 4. doi: 10.1016/S1470-2045(19)30636-9).
The study by Nakagawa et al. suggests that epidermal growth factor receptor tyrosine kinase inhibitors may feasibly be combined with other drugs, but concerns remain about the infrequency of complete responses, which were uncommon in this trial, at 1%, and only slightly higher, at 7%, in a previous, similar trial that involved the addition of bevacizumab to erlotinib (Lancet Oncol. 2019 Apr 8. doi: 10.1016/S1470-2045(19)30035-X). A lack of complete responses may be caused by vascular endothelial growth factor inhibition, which reduces tumor burden, but also may increase risks of tumor invasion, metastases, hypoxia, and other malignant processes.
Hypothetically, multitargeted receptor tyrosine kinases, such as cabozantinib or foretinib, could counteract the above drawbacks, but this remains to be seen. In the meantime, investigators should aim to design trials based on preclinical data instead of empirical reasoning. Despite the complexity of the molecular pathophysiology involved, research is bringing us closer to a clear understanding of the network of relationships between pathways, which could ultimately enable effective use of available combinations.
Rafael Rosell, MD, PhD, and Carlos Pedraz-Valdunciel are with Germans Trias i Pujol Research Institute and Hospital and the Universitat Autónoma de Barcelona. Both authors declared no competing interests. Their remarks are adapted from an accompanying editorial (Lancet Oncol. 2019 Oct 4. doi: 10.1016/S1470-2045(19)30636-9).
The study by Nakagawa et al. suggests that epidermal growth factor receptor tyrosine kinase inhibitors may feasibly be combined with other drugs, but concerns remain about the infrequency of complete responses, which were uncommon in this trial, at 1%, and only slightly higher, at 7%, in a previous, similar trial that involved the addition of bevacizumab to erlotinib (Lancet Oncol. 2019 Apr 8. doi: 10.1016/S1470-2045(19)30035-X). A lack of complete responses may be caused by vascular endothelial growth factor inhibition, which reduces tumor burden, but also may increase risks of tumor invasion, metastases, hypoxia, and other malignant processes.
Hypothetically, multitargeted receptor tyrosine kinases, such as cabozantinib or foretinib, could counteract the above drawbacks, but this remains to be seen. In the meantime, investigators should aim to design trials based on preclinical data instead of empirical reasoning. Despite the complexity of the molecular pathophysiology involved, research is bringing us closer to a clear understanding of the network of relationships between pathways, which could ultimately enable effective use of available combinations.
Rafael Rosell, MD, PhD, and Carlos Pedraz-Valdunciel are with Germans Trias i Pujol Research Institute and Hospital and the Universitat Autónoma de Barcelona. Both authors declared no competing interests. Their remarks are adapted from an accompanying editorial (Lancet Oncol. 2019 Oct 4. doi: 10.1016/S1470-2045(19)30636-9).
For patients with epidermal growth factor receptor–mutated non–small cell lung cancer (NSCLC), adding the vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor ramucirumab to standard erlotinib therapy may extend progression-free survival, based on results from the phase 3 RELAY trial.
Considering the acceptable safety profile, this dual regimen should be considered for first-line treatment of epidermal growth factor receptor (EGFR)–mutated disease, according to lead author Kazuhiko Nakagawa, MD, PhD, of the Kindai University faculty of medicine in Osaka, Japan, and colleagues.
Dual blockade of the EGFR and VEGF pathways is supported by previous studies which pointed to efficacy among EGFR-mutated subgroups, the investigators explained in Lancet Oncology, noting that ramucirumab appeared to be the best candidate for VEGF pathway inhibition. “Ramucirumab, a human monoclonal IgG1 antibody, selectively targets VEGFR-2, thereby blocking signaling mediated by VEGF-A, VEGF-C, and VEGF-D in NSCLC,” the investigators wrote. “Therefore, ramucirumab has the potential for broader antitumor activity than inhibitors of VEGF-A.”
The trial involved 449 patients with stage IV NSCLC and an EGFR exon 21 substitution or exon 19 deletion. Patients were randomized in a 1:1 ratio to receive either erlotinib (150 mg/day) plus placebo, or erlotinib plus ramucirumab (10 mg/kg every 2 weeks). The primary endpoint was progression-free survival. Secondary endpoints included safety and toxicity, overall survival, and various measures of response.
After a median follow-up of 20.7 months, the addition of ramucirumab was associated with a significantly better median progression-free survival, at 19.4 months, compared with 12.4 months among patients who received erlotinib alone, which translates to a hazard ratio of 0.59 (P less than .0001). In each cohort, 1% of patients achieved a complete response. Partial responses were also highly similar at 75% for ramucirumab versus 74% for placebo.
Turning to safety, ramucirumab was associated with more safety concerns, including a higher rate of grade 3-4 treatment-emergent adverse events (72% vs. 54%), most often hypertension. Serious adverse events were also more frequent with ramucirumab at a rate of 29%, compared with 21% among those who received erlotinib alone.
Despite these differences, the investigators concluded that the dual regimen still offers acceptable tolerability. “Safety was consistent with the established safety profiles of the individual compounds and a metastatic NSCLC population,” they wrote. “The RELAY regimen is therefore a viable new treatment option for the initial treatment of patients with metastatic EGFR-mutated NSCLC.”
The RELAY trial was funded by Eli Lilly. The investigators reported additional relationships with AstraZeneca, Bristol-Myers Squibb, Novartis, and others.
SOURCE: Nakagawa K et al. Lancet Oncol. 2019 Oct 4. doi: 10.1016/S1470-2045(19)30634-5.
For patients with epidermal growth factor receptor–mutated non–small cell lung cancer (NSCLC), adding the vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor ramucirumab to standard erlotinib therapy may extend progression-free survival, based on results from the phase 3 RELAY trial.
Considering the acceptable safety profile, this dual regimen should be considered for first-line treatment of epidermal growth factor receptor (EGFR)–mutated disease, according to lead author Kazuhiko Nakagawa, MD, PhD, of the Kindai University faculty of medicine in Osaka, Japan, and colleagues.
Dual blockade of the EGFR and VEGF pathways is supported by previous studies which pointed to efficacy among EGFR-mutated subgroups, the investigators explained in Lancet Oncology, noting that ramucirumab appeared to be the best candidate for VEGF pathway inhibition. “Ramucirumab, a human monoclonal IgG1 antibody, selectively targets VEGFR-2, thereby blocking signaling mediated by VEGF-A, VEGF-C, and VEGF-D in NSCLC,” the investigators wrote. “Therefore, ramucirumab has the potential for broader antitumor activity than inhibitors of VEGF-A.”
The trial involved 449 patients with stage IV NSCLC and an EGFR exon 21 substitution or exon 19 deletion. Patients were randomized in a 1:1 ratio to receive either erlotinib (150 mg/day) plus placebo, or erlotinib plus ramucirumab (10 mg/kg every 2 weeks). The primary endpoint was progression-free survival. Secondary endpoints included safety and toxicity, overall survival, and various measures of response.
After a median follow-up of 20.7 months, the addition of ramucirumab was associated with a significantly better median progression-free survival, at 19.4 months, compared with 12.4 months among patients who received erlotinib alone, which translates to a hazard ratio of 0.59 (P less than .0001). In each cohort, 1% of patients achieved a complete response. Partial responses were also highly similar at 75% for ramucirumab versus 74% for placebo.
Turning to safety, ramucirumab was associated with more safety concerns, including a higher rate of grade 3-4 treatment-emergent adverse events (72% vs. 54%), most often hypertension. Serious adverse events were also more frequent with ramucirumab at a rate of 29%, compared with 21% among those who received erlotinib alone.
Despite these differences, the investigators concluded that the dual regimen still offers acceptable tolerability. “Safety was consistent with the established safety profiles of the individual compounds and a metastatic NSCLC population,” they wrote. “The RELAY regimen is therefore a viable new treatment option for the initial treatment of patients with metastatic EGFR-mutated NSCLC.”
The RELAY trial was funded by Eli Lilly. The investigators reported additional relationships with AstraZeneca, Bristol-Myers Squibb, Novartis, and others.
SOURCE: Nakagawa K et al. Lancet Oncol. 2019 Oct 4. doi: 10.1016/S1470-2045(19)30634-5.
FROM LANCET ONCOLOGY
Lazertinib has good showing in EGFR-mutated advanced NSCLC
Lazertinib, an investigational third-generation oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has good safety and antitumor activity in patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC), finds a phase 1/2 trial.
Only about one in six patients experienced a grade 3 or 4 adverse event when given the drug at various doses, according to results reported in The Lancet Oncology.
Meanwhile, 54% of patients achieved a response, with a higher rate seen among those whose tumors were positive versus negative for the T790M resistance mutation. Notably, 44% of the subgroup with brain metastases had an intracranial response.
“[O]ur results show that lazertinib is well tolerated, with responses frequently observed in patients with NSCLC harbouring both activating EGFR mutations and EGFR T790M TKI resistance mutations. Intracranial responses were also frequently seen, indicating effective blood-brain barrier penetration,” wrote senior investigator Byoung Chul Cho, MD, PhD, Cancer Center, Yonsei University College of Medicine, Seoul, South Korea, and coinvestigators.
“Lazertinib has a potential therapeutic role in the treatment of NSCLC harbouring EGFR T790M mutations, either alone or in combination with other drugs,” they concluded.
The trial was conducted in Korea among adults having advanced NSCLC with an activating EGFR mutation who experienced progression after treatment with a first- or second-generation EGFR TKI. All were treated on an open-label basis with lazertinib at dose levels from 20 mg to 320 mg once daily, continuously in 21-day cycles.
Dr. Cho and coinvestigators reported results for 127 patients (38 in a dose escalation cohort and 89 in a dose expansion cohort).
Results showed that there were no dose-limiting toxicities and no dose-dependent increases in adverse events. The leading adverse events were grade 1 or 2 rash or acne (30%) and pruritus (27%). Overall, 16% of patients experienced grade 3 or grade 4 adverse events, most commonly grade 3 pneumonia (3%). Only 3% of patients had treatment-related grade 3 or 4 adverse events, while 5% had treatment-related serious adverse events. None experienced adverse events leading to death or treatment-related death.
On independent central review, 54% of patients overall had an objective response (52% had a partial response, 2% had a complete response). The response rate was 57% in patients with T790M-positive tumors compared with 37% in patients with T790M-negative tumors.
The median duration of response was 15.2 months. With a median follow-up of 11.0 months, the median progression-free survival was 9.5 months for the whole study cohort; it was longer in patients whose tumors were positive versus negative for the T790M resistance mutations (9.7 months vs 5.4 months).
Among evaluable patients with brain metastases, the intracranial response rate was 44%, and median intracranial progression-free survival was not reached.
Dr. Cho disclosed relationships with numerous pharmaceutical companies, including Yuhan Corporation, which funded the trial.
SOURCE: Cho BC et al. Lancet Oncol. 2019 Oct 3. doi: 10.1016/S1470-2045(19)30504-2.
“[W]hy should anyone care about all these data for lazertinib?” Tejas Patil, MD, and D. Ross Camidge, MD, PhD, asked in a commentary, noting that another third-generation EGFR TKI, osimertinib (Tagrisso), has already received Food and Drug Administration approval for use in this setting and has generally similar activity and tolerability.
“Beyond any potential competitive price advantage that could be introduced after licensing, or idiosyncratic tolerance of one drug over another in individual patients, the real potential advantage of lazertinib might be hiding in plain sight. Specifically, lazertinib’s incompletely explored potential to treat CNS metastases,” they noted.
Although osimertinib appears to have good CNS activity, patients with CNS metastases continue to experience poorer progression-free survival. And even at higher doses causing greater toxicity, CNS penetration of that drug is limited.
“[T]he ideal drug for dedicated CNS dose regimen exploration is one in which the standard dosing has been set in the absence of substantial toxicity and in the absence of any plateauing of pharmacokinetic exposures,” Dr. Patil and Dr. Camidge maintained. And lazertinib appears to fit that bill.
The 44% intracranial response rate “is encouraging but still leaves a substantial amount of important data to be generated,” they contended. Although progression in the CNS was uncommon among patients without CNS metastases at baseline, the longer median progression-free survival at higher doses may indicate better CNS control and support further dose escalation.
“Lazertinib could be one of the pioneer drugs for redefining how we optimally address the CNS in oncology drug development,” they concluded. “Taking full advantage of the early drug-development process to explore the CNS potential of any oncology drug being considered in disease types with a high rate of CNS metastases should be part of a future that we can all look forward to.”
Dr. Patil is instructor of medicine, and Dr. Camidge is professor of medicine, in the division of medical oncology, department of medicine, at the University of Colorado, Anschutz Medical Campus, Aurora.
“[W]hy should anyone care about all these data for lazertinib?” Tejas Patil, MD, and D. Ross Camidge, MD, PhD, asked in a commentary, noting that another third-generation EGFR TKI, osimertinib (Tagrisso), has already received Food and Drug Administration approval for use in this setting and has generally similar activity and tolerability.
“Beyond any potential competitive price advantage that could be introduced after licensing, or idiosyncratic tolerance of one drug over another in individual patients, the real potential advantage of lazertinib might be hiding in plain sight. Specifically, lazertinib’s incompletely explored potential to treat CNS metastases,” they noted.
Although osimertinib appears to have good CNS activity, patients with CNS metastases continue to experience poorer progression-free survival. And even at higher doses causing greater toxicity, CNS penetration of that drug is limited.
“[T]he ideal drug for dedicated CNS dose regimen exploration is one in which the standard dosing has been set in the absence of substantial toxicity and in the absence of any plateauing of pharmacokinetic exposures,” Dr. Patil and Dr. Camidge maintained. And lazertinib appears to fit that bill.
The 44% intracranial response rate “is encouraging but still leaves a substantial amount of important data to be generated,” they contended. Although progression in the CNS was uncommon among patients without CNS metastases at baseline, the longer median progression-free survival at higher doses may indicate better CNS control and support further dose escalation.
“Lazertinib could be one of the pioneer drugs for redefining how we optimally address the CNS in oncology drug development,” they concluded. “Taking full advantage of the early drug-development process to explore the CNS potential of any oncology drug being considered in disease types with a high rate of CNS metastases should be part of a future that we can all look forward to.”
Dr. Patil is instructor of medicine, and Dr. Camidge is professor of medicine, in the division of medical oncology, department of medicine, at the University of Colorado, Anschutz Medical Campus, Aurora.
“[W]hy should anyone care about all these data for lazertinib?” Tejas Patil, MD, and D. Ross Camidge, MD, PhD, asked in a commentary, noting that another third-generation EGFR TKI, osimertinib (Tagrisso), has already received Food and Drug Administration approval for use in this setting and has generally similar activity and tolerability.
“Beyond any potential competitive price advantage that could be introduced after licensing, or idiosyncratic tolerance of one drug over another in individual patients, the real potential advantage of lazertinib might be hiding in plain sight. Specifically, lazertinib’s incompletely explored potential to treat CNS metastases,” they noted.
Although osimertinib appears to have good CNS activity, patients with CNS metastases continue to experience poorer progression-free survival. And even at higher doses causing greater toxicity, CNS penetration of that drug is limited.
“[T]he ideal drug for dedicated CNS dose regimen exploration is one in which the standard dosing has been set in the absence of substantial toxicity and in the absence of any plateauing of pharmacokinetic exposures,” Dr. Patil and Dr. Camidge maintained. And lazertinib appears to fit that bill.
The 44% intracranial response rate “is encouraging but still leaves a substantial amount of important data to be generated,” they contended. Although progression in the CNS was uncommon among patients without CNS metastases at baseline, the longer median progression-free survival at higher doses may indicate better CNS control and support further dose escalation.
“Lazertinib could be one of the pioneer drugs for redefining how we optimally address the CNS in oncology drug development,” they concluded. “Taking full advantage of the early drug-development process to explore the CNS potential of any oncology drug being considered in disease types with a high rate of CNS metastases should be part of a future that we can all look forward to.”
Dr. Patil is instructor of medicine, and Dr. Camidge is professor of medicine, in the division of medical oncology, department of medicine, at the University of Colorado, Anschutz Medical Campus, Aurora.
Lazertinib, an investigational third-generation oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has good safety and antitumor activity in patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC), finds a phase 1/2 trial.
Only about one in six patients experienced a grade 3 or 4 adverse event when given the drug at various doses, according to results reported in The Lancet Oncology.
Meanwhile, 54% of patients achieved a response, with a higher rate seen among those whose tumors were positive versus negative for the T790M resistance mutation. Notably, 44% of the subgroup with brain metastases had an intracranial response.
“[O]ur results show that lazertinib is well tolerated, with responses frequently observed in patients with NSCLC harbouring both activating EGFR mutations and EGFR T790M TKI resistance mutations. Intracranial responses were also frequently seen, indicating effective blood-brain barrier penetration,” wrote senior investigator Byoung Chul Cho, MD, PhD, Cancer Center, Yonsei University College of Medicine, Seoul, South Korea, and coinvestigators.
“Lazertinib has a potential therapeutic role in the treatment of NSCLC harbouring EGFR T790M mutations, either alone or in combination with other drugs,” they concluded.
The trial was conducted in Korea among adults having advanced NSCLC with an activating EGFR mutation who experienced progression after treatment with a first- or second-generation EGFR TKI. All were treated on an open-label basis with lazertinib at dose levels from 20 mg to 320 mg once daily, continuously in 21-day cycles.
Dr. Cho and coinvestigators reported results for 127 patients (38 in a dose escalation cohort and 89 in a dose expansion cohort).
Results showed that there were no dose-limiting toxicities and no dose-dependent increases in adverse events. The leading adverse events were grade 1 or 2 rash or acne (30%) and pruritus (27%). Overall, 16% of patients experienced grade 3 or grade 4 adverse events, most commonly grade 3 pneumonia (3%). Only 3% of patients had treatment-related grade 3 or 4 adverse events, while 5% had treatment-related serious adverse events. None experienced adverse events leading to death or treatment-related death.
On independent central review, 54% of patients overall had an objective response (52% had a partial response, 2% had a complete response). The response rate was 57% in patients with T790M-positive tumors compared with 37% in patients with T790M-negative tumors.
The median duration of response was 15.2 months. With a median follow-up of 11.0 months, the median progression-free survival was 9.5 months for the whole study cohort; it was longer in patients whose tumors were positive versus negative for the T790M resistance mutations (9.7 months vs 5.4 months).
Among evaluable patients with brain metastases, the intracranial response rate was 44%, and median intracranial progression-free survival was not reached.
Dr. Cho disclosed relationships with numerous pharmaceutical companies, including Yuhan Corporation, which funded the trial.
SOURCE: Cho BC et al. Lancet Oncol. 2019 Oct 3. doi: 10.1016/S1470-2045(19)30504-2.
Lazertinib, an investigational third-generation oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has good safety and antitumor activity in patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC), finds a phase 1/2 trial.
Only about one in six patients experienced a grade 3 or 4 adverse event when given the drug at various doses, according to results reported in The Lancet Oncology.
Meanwhile, 54% of patients achieved a response, with a higher rate seen among those whose tumors were positive versus negative for the T790M resistance mutation. Notably, 44% of the subgroup with brain metastases had an intracranial response.
“[O]ur results show that lazertinib is well tolerated, with responses frequently observed in patients with NSCLC harbouring both activating EGFR mutations and EGFR T790M TKI resistance mutations. Intracranial responses were also frequently seen, indicating effective blood-brain barrier penetration,” wrote senior investigator Byoung Chul Cho, MD, PhD, Cancer Center, Yonsei University College of Medicine, Seoul, South Korea, and coinvestigators.
“Lazertinib has a potential therapeutic role in the treatment of NSCLC harbouring EGFR T790M mutations, either alone or in combination with other drugs,” they concluded.
The trial was conducted in Korea among adults having advanced NSCLC with an activating EGFR mutation who experienced progression after treatment with a first- or second-generation EGFR TKI. All were treated on an open-label basis with lazertinib at dose levels from 20 mg to 320 mg once daily, continuously in 21-day cycles.
Dr. Cho and coinvestigators reported results for 127 patients (38 in a dose escalation cohort and 89 in a dose expansion cohort).
Results showed that there were no dose-limiting toxicities and no dose-dependent increases in adverse events. The leading adverse events were grade 1 or 2 rash or acne (30%) and pruritus (27%). Overall, 16% of patients experienced grade 3 or grade 4 adverse events, most commonly grade 3 pneumonia (3%). Only 3% of patients had treatment-related grade 3 or 4 adverse events, while 5% had treatment-related serious adverse events. None experienced adverse events leading to death or treatment-related death.
On independent central review, 54% of patients overall had an objective response (52% had a partial response, 2% had a complete response). The response rate was 57% in patients with T790M-positive tumors compared with 37% in patients with T790M-negative tumors.
The median duration of response was 15.2 months. With a median follow-up of 11.0 months, the median progression-free survival was 9.5 months for the whole study cohort; it was longer in patients whose tumors were positive versus negative for the T790M resistance mutations (9.7 months vs 5.4 months).
Among evaluable patients with brain metastases, the intracranial response rate was 44%, and median intracranial progression-free survival was not reached.
Dr. Cho disclosed relationships with numerous pharmaceutical companies, including Yuhan Corporation, which funded the trial.
SOURCE: Cho BC et al. Lancet Oncol. 2019 Oct 3. doi: 10.1016/S1470-2045(19)30504-2.
FROM LANCET ONCOLOGY
Next-gen genomic test plus bronchoscopy may improve lung nodule management
NEW ORLEANS – The use of a results of a recent clinical validation study suggest.
The Percepta Genomic Sequencing Classifier (GSC) was able to up- and down-classify probability of malignancy for a considerable proportion of nondiagnostic bronchoscopies in the study, Peter J. Mazzone MD, FCCP, reported at the annual meeting of the American College of Chest Physicians.
The test is seen as complementary to bronchoscopy, improving the sensitivity of bronchoscopy overall and showing a combined sensitivity of greater than 95% in low- and intermediate-risk groups, according to Dr. Mazzone.
While the clinical utility of this genomic test needs to be further tested, the eventual goal is to improve clinician decision making when bronchoscopy results don’t clearly classify nodules as malignant or benign, Dr. Mazzone said in an interview.
“In that situation, you’re often left wondering, ‘what should I do next? Can I just watch this, and see if it grows and changes, or do I have to be even more aggressive – do another biopsy, or have a surgery to take it out?’ ” he explained. “So the test hopes to help make a more informed decision by further stratifying those patients as being quite low risk and maybe safe to follow, or quite high risk and maybe you should be considering more aggressive management.”
The GSC improves on the performance of an earlier molecular test, the Percepta Bronchial Genomic Classifier, which uses a brushing of bronchial epithelium to enhance nodule management in smokers, according to the researcher.
The next-generation GSC uses 1,232 gene transcripts from whole-transcriptome RNA sequencing, along with clinical factors, to help with nodule diagnosis, he said.
To establish the diagnostic accuracy of the GSC, Dr. Mazzone and colleagues evaluated data on 412 patients from three independent cohorts, all of whom had bronchoscopies for lung nodule evaluation that were nondiagnostic. Of those patients, 5% had nodules that physicians had deemed as low probability of malignancy prior to bronchoscopy, 28% deemed intermediate risk, and 74% high risk.
They found that the Percepta GSC down-classified the low–pretest risk patients with 100% negative predictive value (NPV) and down-classified intermediate–pretest risk patients with a 91.0% NPV, Dr. Mazzone reported, while patients with intermediate pretest risk were up-classified with a 65.4% positive predictive value (PPV) and patients with high pretest risk were upclassified with a 91.5% PPV.
The proportion of patients reclassified was about 55% for the low-risk group, 42% for the intermediate-risk group, and 27% for the high-risk group, according to the report at the meeting.
These results suggest the Percepta GSC could help in the “sticky situation” where a bronchoscopy result is inconclusive, Dr. Mazzone told attendees.
“When a bronchoscopy is recommended, despite fantastic advances in navigation systems to get to those nodules, we often come back without a solid answer, and that leaves the clinician in a bit of a predicament,” he said in a late-breaking clinical trial presentation.
Dr. Mazzone provided disclosures related to Veracyte, Exact Sciences, SEER, Tencent, and PCORI (research support to institution).
SOURCE: Mazzone PJ et al. CHEST 2019, Abstract. doi: 10.1016/j.chest.2019.08.307.
NEW ORLEANS – The use of a results of a recent clinical validation study suggest.
The Percepta Genomic Sequencing Classifier (GSC) was able to up- and down-classify probability of malignancy for a considerable proportion of nondiagnostic bronchoscopies in the study, Peter J. Mazzone MD, FCCP, reported at the annual meeting of the American College of Chest Physicians.
The test is seen as complementary to bronchoscopy, improving the sensitivity of bronchoscopy overall and showing a combined sensitivity of greater than 95% in low- and intermediate-risk groups, according to Dr. Mazzone.
While the clinical utility of this genomic test needs to be further tested, the eventual goal is to improve clinician decision making when bronchoscopy results don’t clearly classify nodules as malignant or benign, Dr. Mazzone said in an interview.
“In that situation, you’re often left wondering, ‘what should I do next? Can I just watch this, and see if it grows and changes, or do I have to be even more aggressive – do another biopsy, or have a surgery to take it out?’ ” he explained. “So the test hopes to help make a more informed decision by further stratifying those patients as being quite low risk and maybe safe to follow, or quite high risk and maybe you should be considering more aggressive management.”
The GSC improves on the performance of an earlier molecular test, the Percepta Bronchial Genomic Classifier, which uses a brushing of bronchial epithelium to enhance nodule management in smokers, according to the researcher.
The next-generation GSC uses 1,232 gene transcripts from whole-transcriptome RNA sequencing, along with clinical factors, to help with nodule diagnosis, he said.
To establish the diagnostic accuracy of the GSC, Dr. Mazzone and colleagues evaluated data on 412 patients from three independent cohorts, all of whom had bronchoscopies for lung nodule evaluation that were nondiagnostic. Of those patients, 5% had nodules that physicians had deemed as low probability of malignancy prior to bronchoscopy, 28% deemed intermediate risk, and 74% high risk.
They found that the Percepta GSC down-classified the low–pretest risk patients with 100% negative predictive value (NPV) and down-classified intermediate–pretest risk patients with a 91.0% NPV, Dr. Mazzone reported, while patients with intermediate pretest risk were up-classified with a 65.4% positive predictive value (PPV) and patients with high pretest risk were upclassified with a 91.5% PPV.
The proportion of patients reclassified was about 55% for the low-risk group, 42% for the intermediate-risk group, and 27% for the high-risk group, according to the report at the meeting.
These results suggest the Percepta GSC could help in the “sticky situation” where a bronchoscopy result is inconclusive, Dr. Mazzone told attendees.
“When a bronchoscopy is recommended, despite fantastic advances in navigation systems to get to those nodules, we often come back without a solid answer, and that leaves the clinician in a bit of a predicament,” he said in a late-breaking clinical trial presentation.
Dr. Mazzone provided disclosures related to Veracyte, Exact Sciences, SEER, Tencent, and PCORI (research support to institution).
SOURCE: Mazzone PJ et al. CHEST 2019, Abstract. doi: 10.1016/j.chest.2019.08.307.
NEW ORLEANS – The use of a results of a recent clinical validation study suggest.
The Percepta Genomic Sequencing Classifier (GSC) was able to up- and down-classify probability of malignancy for a considerable proportion of nondiagnostic bronchoscopies in the study, Peter J. Mazzone MD, FCCP, reported at the annual meeting of the American College of Chest Physicians.
The test is seen as complementary to bronchoscopy, improving the sensitivity of bronchoscopy overall and showing a combined sensitivity of greater than 95% in low- and intermediate-risk groups, according to Dr. Mazzone.
While the clinical utility of this genomic test needs to be further tested, the eventual goal is to improve clinician decision making when bronchoscopy results don’t clearly classify nodules as malignant or benign, Dr. Mazzone said in an interview.
“In that situation, you’re often left wondering, ‘what should I do next? Can I just watch this, and see if it grows and changes, or do I have to be even more aggressive – do another biopsy, or have a surgery to take it out?’ ” he explained. “So the test hopes to help make a more informed decision by further stratifying those patients as being quite low risk and maybe safe to follow, or quite high risk and maybe you should be considering more aggressive management.”
The GSC improves on the performance of an earlier molecular test, the Percepta Bronchial Genomic Classifier, which uses a brushing of bronchial epithelium to enhance nodule management in smokers, according to the researcher.
The next-generation GSC uses 1,232 gene transcripts from whole-transcriptome RNA sequencing, along with clinical factors, to help with nodule diagnosis, he said.
To establish the diagnostic accuracy of the GSC, Dr. Mazzone and colleagues evaluated data on 412 patients from three independent cohorts, all of whom had bronchoscopies for lung nodule evaluation that were nondiagnostic. Of those patients, 5% had nodules that physicians had deemed as low probability of malignancy prior to bronchoscopy, 28% deemed intermediate risk, and 74% high risk.
They found that the Percepta GSC down-classified the low–pretest risk patients with 100% negative predictive value (NPV) and down-classified intermediate–pretest risk patients with a 91.0% NPV, Dr. Mazzone reported, while patients with intermediate pretest risk were up-classified with a 65.4% positive predictive value (PPV) and patients with high pretest risk were upclassified with a 91.5% PPV.
The proportion of patients reclassified was about 55% for the low-risk group, 42% for the intermediate-risk group, and 27% for the high-risk group, according to the report at the meeting.
These results suggest the Percepta GSC could help in the “sticky situation” where a bronchoscopy result is inconclusive, Dr. Mazzone told attendees.
“When a bronchoscopy is recommended, despite fantastic advances in navigation systems to get to those nodules, we often come back without a solid answer, and that leaves the clinician in a bit of a predicament,” he said in a late-breaking clinical trial presentation.
Dr. Mazzone provided disclosures related to Veracyte, Exact Sciences, SEER, Tencent, and PCORI (research support to institution).
SOURCE: Mazzone PJ et al. CHEST 2019, Abstract. doi: 10.1016/j.chest.2019.08.307.
REPORTING FROM CHEST 2019
The law of unintended consequences
In this edition of “How I will treat my next patient,” I focus on a recent presentation at the American Society for Radiation Oncology meeting regarding the association of recent closures in women’s health clinics with cervical cancer outcomes and on a publication regarding guideline-concordant radiation exposure and organizational characteristics of lung cancer screening programs.
Cervical cancer screening and outcomes
Between 2010 and 2013, nearly 100 women’s health clinics closed in the United States because of a variety of factors, including concerns by state legislatures about reproductive services. Amar J. Srivastava, MD, and colleagues, performed a database search to determine the effect of closures on cervical cancer screening, stage, and mortality (ASTRO 2019, Abstract 202). The researchers used the Behavioral Risk Factors Surveillance Study, which provided data from 197,143 cases, to assess differences in screening availability in 2008-2009 (before the closures). They used the Surveillance, Epidemiology, and End Results (SEER) registry data from 2014-2015 (after) on 10,652 patients to compare stage at diagnosis and disease-specific mortality in states with women’s health clinic closures and states without closures.
They found that the cervical cancer screening rate in states that had a decline in the number of women’s health clinics was 1.63% lower than in states that did not lose clinics. The disparity was greater in medically underserved subgroups: Hispanic women, women aged 21-34 years, unmarried women, and uninsured women.
Early-stage diagnosis was also significantly less common in states that had a decreased number of women’s health clinics – a 13.2% drop – and the overall mortality rate from cervical cancer was 36% higher. The difference was even higher (40%) when comparing only metro residents. All of these differences between states with and without closures were statistically significant.
How these results influence clinical practice
The law of unintended consequences is that the actions of people, and especially of governments, will have effects that are unanticipated or unintended. All oncologists understand this law – we live it every day.
The data generated by Dr. Srivastava and colleagues bring to mind two presentations at the 2019 annual meeting of the American Society of Clinical Oncology: the impact of Medicaid Expansion on racial disparities in time to cancer treatment (LBA 1) and the impact of the Affordable Care Act on early-stage diagnosis and treatment for women with ovarian cancer (LBA 5563). Collectively, they remind us that health care policy changes influence the timeliness of cancer care delivery and disparities in cancer care. Of course, these analyses describe associations, not necessarily causation. Large databases have quality and completeness limitations. Nonetheless, these abstracts and the associated presentations and discussions support the concept that improved access can be associated with improved cancer care outcomes.
In 1936, American sociologist Robert K. Merton described “imperious immediacy of interest,” referring to instances in which an individual wants the intended consequence of an action so badly that he or she purposefully chooses to ignore unintended effects. As a clinical and research community, we are obliged to highlight those effects when they influence our patients’ suffering.
Lung cancer screening
As a component of the Centers for Medicare & Medicaid Services’ requirements for lung cancer screening payment, institutions performing screening must use low-dose techniques and participate in a dose registry. The American College of Radiology (ACR) recommends the dose levels per CT slice (CTDIvol; 3 mGy or lower) and the effective dose (ED; 1 mSr or lower) that would qualify an examination as “low dose,” thereby hoping to minimize the risk of radiation-induced cancers.
Joshua Demb, PhD, and colleagues prospectively collected lung cancer screening examination dose metrics at U.S. institutions in the University of California, San Francisco, International Dose Registry (JAMA Intern Med. 2019 Sep 23. doi: 10.1001/jamainternmed.2019.3893). Only U.S. institutions that performed more than 24 lung cancer screening scans from 2016-2017 were included in the survey (n = 72, more than 12,500 patients). Institution-level factors were collected via the Partnership for Dose trial, including how CT scans are performed and how CT protocols are established at the institutional level.
In a data-dense analysis, the authors found that 65% of institutions delivered, and more than half of patients received, radiation doses above ACR targets. This suggests that both the potential screening benefits and the margins of benefits over risks might be reduced for patients at those institutions. Factors associated with exceeding ACR guidelines for radiation dose were using an “external” medical physicist, although having a medical physicist of any type was more beneficial than not having one; allowing any radiologist to establish or modify the screening protocol, instead of limiting that role to “lead” radiologists; and updating CT protocols as needed, compared with updating the protocols annually.
How these results influence clinical practice
As with the ASTRO 2019 presentation, the law of unintended consequences applies here. Whenever potentially healthy people are subjected to medical procedures to prevent illness or detect disease at early stages, protecting safety is paramount. For that reason, National Comprehensive Cancer Network (NCCN) guidelines are explicit that all lung cancer screening and follow-up scans should use low-dose techniques, unless evaluating mediastinal abnormalities or adenopathy.
The study by Dr. Demb and colleagues critically examined the proportion of lung cancer screening participants receiving guideline-concordant, low-dose examinations and several factors that could influence conformance with ACR guidelines. The results are instructive despite some of the study’s limits including the fact that the database used did not enable long-term follow-up of screened individuals for lung cancer detection or mortality, the survey relied on self-reporting, and the institutional level data was not solely focused on lung cancer screening examinations.
The survey reminds us that the logistics, quality control, and periodic review of well-intentioned programs like lung cancer screening require the thoughtful, regular involvement of teams of professionals who are cognizant of, adherent to, and vigilant about the guidelines that protect the individuals who entrust their care to us.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I will treat my next patient,” I focus on a recent presentation at the American Society for Radiation Oncology meeting regarding the association of recent closures in women’s health clinics with cervical cancer outcomes and on a publication regarding guideline-concordant radiation exposure and organizational characteristics of lung cancer screening programs.
Cervical cancer screening and outcomes
Between 2010 and 2013, nearly 100 women’s health clinics closed in the United States because of a variety of factors, including concerns by state legislatures about reproductive services. Amar J. Srivastava, MD, and colleagues, performed a database search to determine the effect of closures on cervical cancer screening, stage, and mortality (ASTRO 2019, Abstract 202). The researchers used the Behavioral Risk Factors Surveillance Study, which provided data from 197,143 cases, to assess differences in screening availability in 2008-2009 (before the closures). They used the Surveillance, Epidemiology, and End Results (SEER) registry data from 2014-2015 (after) on 10,652 patients to compare stage at diagnosis and disease-specific mortality in states with women’s health clinic closures and states without closures.
They found that the cervical cancer screening rate in states that had a decline in the number of women’s health clinics was 1.63% lower than in states that did not lose clinics. The disparity was greater in medically underserved subgroups: Hispanic women, women aged 21-34 years, unmarried women, and uninsured women.
Early-stage diagnosis was also significantly less common in states that had a decreased number of women’s health clinics – a 13.2% drop – and the overall mortality rate from cervical cancer was 36% higher. The difference was even higher (40%) when comparing only metro residents. All of these differences between states with and without closures were statistically significant.
How these results influence clinical practice
The law of unintended consequences is that the actions of people, and especially of governments, will have effects that are unanticipated or unintended. All oncologists understand this law – we live it every day.
The data generated by Dr. Srivastava and colleagues bring to mind two presentations at the 2019 annual meeting of the American Society of Clinical Oncology: the impact of Medicaid Expansion on racial disparities in time to cancer treatment (LBA 1) and the impact of the Affordable Care Act on early-stage diagnosis and treatment for women with ovarian cancer (LBA 5563). Collectively, they remind us that health care policy changes influence the timeliness of cancer care delivery and disparities in cancer care. Of course, these analyses describe associations, not necessarily causation. Large databases have quality and completeness limitations. Nonetheless, these abstracts and the associated presentations and discussions support the concept that improved access can be associated with improved cancer care outcomes.
In 1936, American sociologist Robert K. Merton described “imperious immediacy of interest,” referring to instances in which an individual wants the intended consequence of an action so badly that he or she purposefully chooses to ignore unintended effects. As a clinical and research community, we are obliged to highlight those effects when they influence our patients’ suffering.
Lung cancer screening
As a component of the Centers for Medicare & Medicaid Services’ requirements for lung cancer screening payment, institutions performing screening must use low-dose techniques and participate in a dose registry. The American College of Radiology (ACR) recommends the dose levels per CT slice (CTDIvol; 3 mGy or lower) and the effective dose (ED; 1 mSr or lower) that would qualify an examination as “low dose,” thereby hoping to minimize the risk of radiation-induced cancers.
Joshua Demb, PhD, and colleagues prospectively collected lung cancer screening examination dose metrics at U.S. institutions in the University of California, San Francisco, International Dose Registry (JAMA Intern Med. 2019 Sep 23. doi: 10.1001/jamainternmed.2019.3893). Only U.S. institutions that performed more than 24 lung cancer screening scans from 2016-2017 were included in the survey (n = 72, more than 12,500 patients). Institution-level factors were collected via the Partnership for Dose trial, including how CT scans are performed and how CT protocols are established at the institutional level.
In a data-dense analysis, the authors found that 65% of institutions delivered, and more than half of patients received, radiation doses above ACR targets. This suggests that both the potential screening benefits and the margins of benefits over risks might be reduced for patients at those institutions. Factors associated with exceeding ACR guidelines for radiation dose were using an “external” medical physicist, although having a medical physicist of any type was more beneficial than not having one; allowing any radiologist to establish or modify the screening protocol, instead of limiting that role to “lead” radiologists; and updating CT protocols as needed, compared with updating the protocols annually.
How these results influence clinical practice
As with the ASTRO 2019 presentation, the law of unintended consequences applies here. Whenever potentially healthy people are subjected to medical procedures to prevent illness or detect disease at early stages, protecting safety is paramount. For that reason, National Comprehensive Cancer Network (NCCN) guidelines are explicit that all lung cancer screening and follow-up scans should use low-dose techniques, unless evaluating mediastinal abnormalities or adenopathy.
The study by Dr. Demb and colleagues critically examined the proportion of lung cancer screening participants receiving guideline-concordant, low-dose examinations and several factors that could influence conformance with ACR guidelines. The results are instructive despite some of the study’s limits including the fact that the database used did not enable long-term follow-up of screened individuals for lung cancer detection or mortality, the survey relied on self-reporting, and the institutional level data was not solely focused on lung cancer screening examinations.
The survey reminds us that the logistics, quality control, and periodic review of well-intentioned programs like lung cancer screening require the thoughtful, regular involvement of teams of professionals who are cognizant of, adherent to, and vigilant about the guidelines that protect the individuals who entrust their care to us.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I will treat my next patient,” I focus on a recent presentation at the American Society for Radiation Oncology meeting regarding the association of recent closures in women’s health clinics with cervical cancer outcomes and on a publication regarding guideline-concordant radiation exposure and organizational characteristics of lung cancer screening programs.
Cervical cancer screening and outcomes
Between 2010 and 2013, nearly 100 women’s health clinics closed in the United States because of a variety of factors, including concerns by state legislatures about reproductive services. Amar J. Srivastava, MD, and colleagues, performed a database search to determine the effect of closures on cervical cancer screening, stage, and mortality (ASTRO 2019, Abstract 202). The researchers used the Behavioral Risk Factors Surveillance Study, which provided data from 197,143 cases, to assess differences in screening availability in 2008-2009 (before the closures). They used the Surveillance, Epidemiology, and End Results (SEER) registry data from 2014-2015 (after) on 10,652 patients to compare stage at diagnosis and disease-specific mortality in states with women’s health clinic closures and states without closures.
They found that the cervical cancer screening rate in states that had a decline in the number of women’s health clinics was 1.63% lower than in states that did not lose clinics. The disparity was greater in medically underserved subgroups: Hispanic women, women aged 21-34 years, unmarried women, and uninsured women.
Early-stage diagnosis was also significantly less common in states that had a decreased number of women’s health clinics – a 13.2% drop – and the overall mortality rate from cervical cancer was 36% higher. The difference was even higher (40%) when comparing only metro residents. All of these differences between states with and without closures were statistically significant.
How these results influence clinical practice
The law of unintended consequences is that the actions of people, and especially of governments, will have effects that are unanticipated or unintended. All oncologists understand this law – we live it every day.
The data generated by Dr. Srivastava and colleagues bring to mind two presentations at the 2019 annual meeting of the American Society of Clinical Oncology: the impact of Medicaid Expansion on racial disparities in time to cancer treatment (LBA 1) and the impact of the Affordable Care Act on early-stage diagnosis and treatment for women with ovarian cancer (LBA 5563). Collectively, they remind us that health care policy changes influence the timeliness of cancer care delivery and disparities in cancer care. Of course, these analyses describe associations, not necessarily causation. Large databases have quality and completeness limitations. Nonetheless, these abstracts and the associated presentations and discussions support the concept that improved access can be associated with improved cancer care outcomes.
In 1936, American sociologist Robert K. Merton described “imperious immediacy of interest,” referring to instances in which an individual wants the intended consequence of an action so badly that he or she purposefully chooses to ignore unintended effects. As a clinical and research community, we are obliged to highlight those effects when they influence our patients’ suffering.
Lung cancer screening
As a component of the Centers for Medicare & Medicaid Services’ requirements for lung cancer screening payment, institutions performing screening must use low-dose techniques and participate in a dose registry. The American College of Radiology (ACR) recommends the dose levels per CT slice (CTDIvol; 3 mGy or lower) and the effective dose (ED; 1 mSr or lower) that would qualify an examination as “low dose,” thereby hoping to minimize the risk of radiation-induced cancers.
Joshua Demb, PhD, and colleagues prospectively collected lung cancer screening examination dose metrics at U.S. institutions in the University of California, San Francisco, International Dose Registry (JAMA Intern Med. 2019 Sep 23. doi: 10.1001/jamainternmed.2019.3893). Only U.S. institutions that performed more than 24 lung cancer screening scans from 2016-2017 were included in the survey (n = 72, more than 12,500 patients). Institution-level factors were collected via the Partnership for Dose trial, including how CT scans are performed and how CT protocols are established at the institutional level.
In a data-dense analysis, the authors found that 65% of institutions delivered, and more than half of patients received, radiation doses above ACR targets. This suggests that both the potential screening benefits and the margins of benefits over risks might be reduced for patients at those institutions. Factors associated with exceeding ACR guidelines for radiation dose were using an “external” medical physicist, although having a medical physicist of any type was more beneficial than not having one; allowing any radiologist to establish or modify the screening protocol, instead of limiting that role to “lead” radiologists; and updating CT protocols as needed, compared with updating the protocols annually.
How these results influence clinical practice
As with the ASTRO 2019 presentation, the law of unintended consequences applies here. Whenever potentially healthy people are subjected to medical procedures to prevent illness or detect disease at early stages, protecting safety is paramount. For that reason, National Comprehensive Cancer Network (NCCN) guidelines are explicit that all lung cancer screening and follow-up scans should use low-dose techniques, unless evaluating mediastinal abnormalities or adenopathy.
The study by Dr. Demb and colleagues critically examined the proportion of lung cancer screening participants receiving guideline-concordant, low-dose examinations and several factors that could influence conformance with ACR guidelines. The results are instructive despite some of the study’s limits including the fact that the database used did not enable long-term follow-up of screened individuals for lung cancer detection or mortality, the survey relied on self-reporting, and the institutional level data was not solely focused on lung cancer screening examinations.
The survey reminds us that the logistics, quality control, and periodic review of well-intentioned programs like lung cancer screening require the thoughtful, regular involvement of teams of professionals who are cognizant of, adherent to, and vigilant about the guidelines that protect the individuals who entrust their care to us.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
Treatment of Unresectable Stage III Non-small Cell Lung Cancer
With a recent renaissance in cancer diagnostics and treatment, there is hope for many fighting the disease. In this article, Dr. M. Patricia Rivera discusses screening and diagnostic procedures as well as the treatment options that are available for patients with unresectable stage III non-small cell lung cancer.
This article is sponsored by AstraZeneca.
US-33194 Last Updated 9/19
With a recent renaissance in cancer diagnostics and treatment, there is hope for many fighting the disease. In this article, Dr. M. Patricia Rivera discusses screening and diagnostic procedures as well as the treatment options that are available for patients with unresectable stage III non-small cell lung cancer.
This article is sponsored by AstraZeneca.
US-33194 Last Updated 9/19
With a recent renaissance in cancer diagnostics and treatment, there is hope for many fighting the disease. In this article, Dr. M. Patricia Rivera discusses screening and diagnostic procedures as well as the treatment options that are available for patients with unresectable stage III non-small cell lung cancer.
This article is sponsored by AstraZeneca.
US-33194 Last Updated 9/19
NSCLC: Predicting benefit from immunotherapy plus chemo
In this edition of “How I will treat my next patient,” I highlight three studies presented at the World Conference on Lung Cancer (WCLC 2019) regarding the use of tissue biomarkers to predict benefit when immune checkpoint inhibitors (ICIs) are combined with chemotherapy in the treatment of stage IV non–small cell lung cancer (NSCLC) patients.
TMB in nonsquamous NSCLC
Marina C. Garassino, MD, and colleagues examined tumor mutation burden (TMB) to predict benefit from pembrolizumab in the KEYNOTE-189 study. KEYNOTE-189 was a double-blind comparison of first-line chemotherapy plus either pembrolizumab or placebo in 616 patients with stage IV nonsquamous NSCLC who were randomized 2:1 to the treatment arms.
Overall, adding pembrolizumab to pemetrexed and platinum significantly improved overall survival (hazard ratio, 0.49), progression-free survival (HR, 0.52), and overall response rate (47.6% vs. 18.9%). Benefit was observed in all analyzed subgroups, including patients with programmed death-ligand 1 (PD-L1) of less than 1%, 1%-49%, and 50% or greater.
In 293 patients – less than 50% of the total participants in the trial – with evaluable TMB data, TMB as a continuous variable showed no significant association with overall survival, progression-free survival, or overall response rate. There was no cut point at which TMB predicted outcome from treatment.
Similarly, Corey Langer, MD, and colleagues presented an exploratory analysis of the randomized, phase 2 KEYNOTE-021 trial (open label, pembrolizumab plus chemotherapy in 70 stage IV nonsquamous NSCLC patients). There was no association between tissue TMB and overall survival, progression-free survival, or overall response rate. In patients with tissue TMB greater than 175 mutations/exome and less than 175 mutations/exome, the overall response rate was 71% and 61%, respectively.
Both presenters recommended that tissue TMB not yet be used in therapeutic decision making.
How these results influence clinical practice
TMB has been associated with response to ICIs, but there is little information regarding whether TMB predicts for response to chemotherapy, either given alone or with ICIs. Logistical issues have limited the clinical utility of TMB. There are a variety of methodologies to measure TMB and no consensus on the ideal cut point for defining benefit from ICI therapy.
While TMB remains a marker of interest, the two presentations at WCLC 2019 demonstrate that additional research is needed to define whether TMB needs to be combined with other markers in an algorithm or matrix to guide decision making or whether we should focus entirely on identifying better biomarkers of immunogenicity.
PD-L1 expression and overall survival
Federico Cappuzzo, MD, and colleagues reported a subset analysis of IMpower131, a randomized, phase 3 trial of chemotherapy plus or minus atezolizumab as first-line therapy in 1,021 patients with stage IV squamous NSCLC. Patients were randomized to arm A (atezolizumab plus carboplatin plus paclitaxel), arm B (atezolizumab plus carboplatin plus nab-paclitaxel) or arm C (carboplatin plus nab-paclitaxel). Investigator-assessed progression-free survival, reported at the 2018 annual meeting of the American Society of Clinical Oncology, showed a small (about 21 days), but statistically significant, improvement in median progression-free survival in arm B versus arm C. The progression-free survival benefit was seen in all PD-L1-positive subgroups. At WCLC 2019, he reported the final overall survival results of arms B versus C.
Median overall survival in the intent-to-treat population was 14.2 months with atezolizumab versus 13.5 months without it (HR, 0.88). Patients with high PD-L1 expression (14% and 13% of patients in the groups, respectively), experienced dramatic, clinically important improvement in overall survival with atezolizumab plus chemotherapy, compared with chemotherapy alone (median of 23.4 vs. 10.2 months; HR, 0.48).
In IMpower 131, PD-L1-high expression was defined as TC3 or IC3 – expression on greater than 50% of tumor cells or greater than 10% of immune cells. Patients were also categorized as PD-L1 positive (TC 1/2/3 or IC 1/2/3 – expression of PD-L1 on 1% or greater of tumor cells or immune cells) or PD-LI negative (TC 0 or IC 0 – expression on less than 1% of cells). The PD-L1-positive and negative subsets did not demonstrate improved overall survival with atezolizumab.
How these results influence clinical practice
As noted above, in NSCLC patients (regardless of histology), we need biomarkers that predict benefit from ICIs alone and additive benefit when ICIs are combined with other, potentially toxic therapies. In the subset analysis of IMpower 131, despite clinically relevant differences in overall survival for the “PD-L1-high” patients, the PD-L1-positive patients did not benefit, so PD-L1 tumor proportion score remains an imperfect biomarker.
To put this report in its proper context, it will be important to analyze the details of the final manuscript of IMpower 131, particularly the comparison of arms A plus B versus C and the proportion of arm C patients who ultimately received an ICI in the second- or later-line setting. In the meantime, clinicians will select their ICI and chemotherapy regimen of choice, utilizing PD-L1 expression as an “eyebrow raiser,” but not an exclusionary criteria – as they did prior to WCLC 2019.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I will treat my next patient,” I highlight three studies presented at the World Conference on Lung Cancer (WCLC 2019) regarding the use of tissue biomarkers to predict benefit when immune checkpoint inhibitors (ICIs) are combined with chemotherapy in the treatment of stage IV non–small cell lung cancer (NSCLC) patients.
TMB in nonsquamous NSCLC
Marina C. Garassino, MD, and colleagues examined tumor mutation burden (TMB) to predict benefit from pembrolizumab in the KEYNOTE-189 study. KEYNOTE-189 was a double-blind comparison of first-line chemotherapy plus either pembrolizumab or placebo in 616 patients with stage IV nonsquamous NSCLC who were randomized 2:1 to the treatment arms.
Overall, adding pembrolizumab to pemetrexed and platinum significantly improved overall survival (hazard ratio, 0.49), progression-free survival (HR, 0.52), and overall response rate (47.6% vs. 18.9%). Benefit was observed in all analyzed subgroups, including patients with programmed death-ligand 1 (PD-L1) of less than 1%, 1%-49%, and 50% or greater.
In 293 patients – less than 50% of the total participants in the trial – with evaluable TMB data, TMB as a continuous variable showed no significant association with overall survival, progression-free survival, or overall response rate. There was no cut point at which TMB predicted outcome from treatment.
Similarly, Corey Langer, MD, and colleagues presented an exploratory analysis of the randomized, phase 2 KEYNOTE-021 trial (open label, pembrolizumab plus chemotherapy in 70 stage IV nonsquamous NSCLC patients). There was no association between tissue TMB and overall survival, progression-free survival, or overall response rate. In patients with tissue TMB greater than 175 mutations/exome and less than 175 mutations/exome, the overall response rate was 71% and 61%, respectively.
Both presenters recommended that tissue TMB not yet be used in therapeutic decision making.
How these results influence clinical practice
TMB has been associated with response to ICIs, but there is little information regarding whether TMB predicts for response to chemotherapy, either given alone or with ICIs. Logistical issues have limited the clinical utility of TMB. There are a variety of methodologies to measure TMB and no consensus on the ideal cut point for defining benefit from ICI therapy.
While TMB remains a marker of interest, the two presentations at WCLC 2019 demonstrate that additional research is needed to define whether TMB needs to be combined with other markers in an algorithm or matrix to guide decision making or whether we should focus entirely on identifying better biomarkers of immunogenicity.
PD-L1 expression and overall survival
Federico Cappuzzo, MD, and colleagues reported a subset analysis of IMpower131, a randomized, phase 3 trial of chemotherapy plus or minus atezolizumab as first-line therapy in 1,021 patients with stage IV squamous NSCLC. Patients were randomized to arm A (atezolizumab plus carboplatin plus paclitaxel), arm B (atezolizumab plus carboplatin plus nab-paclitaxel) or arm C (carboplatin plus nab-paclitaxel). Investigator-assessed progression-free survival, reported at the 2018 annual meeting of the American Society of Clinical Oncology, showed a small (about 21 days), but statistically significant, improvement in median progression-free survival in arm B versus arm C. The progression-free survival benefit was seen in all PD-L1-positive subgroups. At WCLC 2019, he reported the final overall survival results of arms B versus C.
Median overall survival in the intent-to-treat population was 14.2 months with atezolizumab versus 13.5 months without it (HR, 0.88). Patients with high PD-L1 expression (14% and 13% of patients in the groups, respectively), experienced dramatic, clinically important improvement in overall survival with atezolizumab plus chemotherapy, compared with chemotherapy alone (median of 23.4 vs. 10.2 months; HR, 0.48).
In IMpower 131, PD-L1-high expression was defined as TC3 or IC3 – expression on greater than 50% of tumor cells or greater than 10% of immune cells. Patients were also categorized as PD-L1 positive (TC 1/2/3 or IC 1/2/3 – expression of PD-L1 on 1% or greater of tumor cells or immune cells) or PD-LI negative (TC 0 or IC 0 – expression on less than 1% of cells). The PD-L1-positive and negative subsets did not demonstrate improved overall survival with atezolizumab.
How these results influence clinical practice
As noted above, in NSCLC patients (regardless of histology), we need biomarkers that predict benefit from ICIs alone and additive benefit when ICIs are combined with other, potentially toxic therapies. In the subset analysis of IMpower 131, despite clinically relevant differences in overall survival for the “PD-L1-high” patients, the PD-L1-positive patients did not benefit, so PD-L1 tumor proportion score remains an imperfect biomarker.
To put this report in its proper context, it will be important to analyze the details of the final manuscript of IMpower 131, particularly the comparison of arms A plus B versus C and the proportion of arm C patients who ultimately received an ICI in the second- or later-line setting. In the meantime, clinicians will select their ICI and chemotherapy regimen of choice, utilizing PD-L1 expression as an “eyebrow raiser,” but not an exclusionary criteria – as they did prior to WCLC 2019.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I will treat my next patient,” I highlight three studies presented at the World Conference on Lung Cancer (WCLC 2019) regarding the use of tissue biomarkers to predict benefit when immune checkpoint inhibitors (ICIs) are combined with chemotherapy in the treatment of stage IV non–small cell lung cancer (NSCLC) patients.
TMB in nonsquamous NSCLC
Marina C. Garassino, MD, and colleagues examined tumor mutation burden (TMB) to predict benefit from pembrolizumab in the KEYNOTE-189 study. KEYNOTE-189 was a double-blind comparison of first-line chemotherapy plus either pembrolizumab or placebo in 616 patients with stage IV nonsquamous NSCLC who were randomized 2:1 to the treatment arms.
Overall, adding pembrolizumab to pemetrexed and platinum significantly improved overall survival (hazard ratio, 0.49), progression-free survival (HR, 0.52), and overall response rate (47.6% vs. 18.9%). Benefit was observed in all analyzed subgroups, including patients with programmed death-ligand 1 (PD-L1) of less than 1%, 1%-49%, and 50% or greater.
In 293 patients – less than 50% of the total participants in the trial – with evaluable TMB data, TMB as a continuous variable showed no significant association with overall survival, progression-free survival, or overall response rate. There was no cut point at which TMB predicted outcome from treatment.
Similarly, Corey Langer, MD, and colleagues presented an exploratory analysis of the randomized, phase 2 KEYNOTE-021 trial (open label, pembrolizumab plus chemotherapy in 70 stage IV nonsquamous NSCLC patients). There was no association between tissue TMB and overall survival, progression-free survival, or overall response rate. In patients with tissue TMB greater than 175 mutations/exome and less than 175 mutations/exome, the overall response rate was 71% and 61%, respectively.
Both presenters recommended that tissue TMB not yet be used in therapeutic decision making.
How these results influence clinical practice
TMB has been associated with response to ICIs, but there is little information regarding whether TMB predicts for response to chemotherapy, either given alone or with ICIs. Logistical issues have limited the clinical utility of TMB. There are a variety of methodologies to measure TMB and no consensus on the ideal cut point for defining benefit from ICI therapy.
While TMB remains a marker of interest, the two presentations at WCLC 2019 demonstrate that additional research is needed to define whether TMB needs to be combined with other markers in an algorithm or matrix to guide decision making or whether we should focus entirely on identifying better biomarkers of immunogenicity.
PD-L1 expression and overall survival
Federico Cappuzzo, MD, and colleagues reported a subset analysis of IMpower131, a randomized, phase 3 trial of chemotherapy plus or minus atezolizumab as first-line therapy in 1,021 patients with stage IV squamous NSCLC. Patients were randomized to arm A (atezolizumab plus carboplatin plus paclitaxel), arm B (atezolizumab plus carboplatin plus nab-paclitaxel) or arm C (carboplatin plus nab-paclitaxel). Investigator-assessed progression-free survival, reported at the 2018 annual meeting of the American Society of Clinical Oncology, showed a small (about 21 days), but statistically significant, improvement in median progression-free survival in arm B versus arm C. The progression-free survival benefit was seen in all PD-L1-positive subgroups. At WCLC 2019, he reported the final overall survival results of arms B versus C.
Median overall survival in the intent-to-treat population was 14.2 months with atezolizumab versus 13.5 months without it (HR, 0.88). Patients with high PD-L1 expression (14% and 13% of patients in the groups, respectively), experienced dramatic, clinically important improvement in overall survival with atezolizumab plus chemotherapy, compared with chemotherapy alone (median of 23.4 vs. 10.2 months; HR, 0.48).
In IMpower 131, PD-L1-high expression was defined as TC3 or IC3 – expression on greater than 50% of tumor cells or greater than 10% of immune cells. Patients were also categorized as PD-L1 positive (TC 1/2/3 or IC 1/2/3 – expression of PD-L1 on 1% or greater of tumor cells or immune cells) or PD-LI negative (TC 0 or IC 0 – expression on less than 1% of cells). The PD-L1-positive and negative subsets did not demonstrate improved overall survival with atezolizumab.
How these results influence clinical practice
As noted above, in NSCLC patients (regardless of histology), we need biomarkers that predict benefit from ICIs alone and additive benefit when ICIs are combined with other, potentially toxic therapies. In the subset analysis of IMpower 131, despite clinically relevant differences in overall survival for the “PD-L1-high” patients, the PD-L1-positive patients did not benefit, so PD-L1 tumor proportion score remains an imperfect biomarker.
To put this report in its proper context, it will be important to analyze the details of the final manuscript of IMpower 131, particularly the comparison of arms A plus B versus C and the proportion of arm C patients who ultimately received an ICI in the second- or later-line setting. In the meantime, clinicians will select their ICI and chemotherapy regimen of choice, utilizing PD-L1 expression as an “eyebrow raiser,” but not an exclusionary criteria – as they did prior to WCLC 2019.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
Immunotherapy duo extends survival in first line for advanced NSCLC
BARCELONA – Patients with than patients treated with chemotherapy, reported investigators in the Checkmate 227 trial.
Among 793 patients with treatment-naive metastatic NSCLC with programmed death-ligand 1 (PD-L1) expression of at least 1%, median overall survival (OS) was 17.1 months for patients treated with the combination versus 14.9 months for patients treated with chemotherapy, a difference that translated into a hazard ratio with the combination of 0.79 (P = .007). Two-year overall survival rates were 40% and 32.8%, respectively.
The improvement in OS with the combination occurred regardless of PD-L1 status, suggesting that it can be a chemotherapy-free option for patients with previously untreated metastatic NSCLC, Solange Peters, MD, of Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said at the European Society for Medical Oncology Congress.
Checkmate 227 “is the first phase 3 study proving the concept in an evidence-based fashion of the combination of CTLA4 and anti–PD-1/PD-L1 in non–small cell lung cancer,” Dr. Peters said at a briefing prior to her presentation of the data in a symposium.
CheckMate 227 investigators enrolled patients with stage IV or recurrent NSCLC who had not received any treatment previously. Part one of the multipart study was designed to compare different nivolumab-based regimens versus chemotherapy in patients with PD-L1 expression of 1% or greater, or less than 1%.
The trial has two independent primary endpoints, the first of which, progression-free survival (PFS) with nivolumab and ipilimumab versus chemotherapy, was reported at the 2018 annual meeting of the American Association for Cancer Research.
Dr. Peters presented the overall survival endpoint at ESMO 2019. Results of the study were published simultaneously in the New England Journal of Medicine (2019 Sep 28. doi: 10.1056/NEJMoa1910231).
In part one of the trial, patients with PD-L1 expression of at least 1% (1,189 patients) were randomized on a 1:1:1 basis to one of three treatment options: nivolumab plus low-dose ipilimumab, nivolumab alone, or histology-based chemotherapy. Patients with PD-L1 expression less than 1% (550 patients) were randomized to nivolumab plus low-dose ipilimumab, nivolumab plus chemotherapy, or chemotherapy.
The survival benefit seen with the immunotherapy combination was durable, with 2-year OS rates of 40% for nivolumab/ipilimumab versus 32.8% for chemotherapy. The median durations of response were 23.2 months vs. 6.2 months, respectively.
Patients with low or no PD-L1 expression levels also benefited from the immunotherapy combination, with a median OS of 17.2 months with nivolumab plus ipilimumab, compared with 12.2 months with chemotherapy.
Among all enrolled patients, the median OS duration was 17.1 months with nivolumab plus ipilimumab versus 13.9 months with chemotherapy.
Grade 3 or 4 treatment-related adverse events in the overall study population occurred in 32.8% of patients treated with combined immunotherapy and in 36% of those treated with chemotherapy.
“A key question remains: Is the addition of ipilimumab providing additional benefit on top of nivolumab?” Dr. Peters asked. The answer to that question appears to be “yes,” she said, pointing to a comparison of OS among patients with PD-L1 expression below 1%. Although this subanalysis was not powered for statistical significance, the survival curves indicated a significant advantage for the combination, compared with nivolumab alone or chemotherapy, with respective median OS rates of 17.2, 15.2, and 12.2 months.
“What have we learned from Checkmate 227 so far? Caveat emptor – buyer beware. Beware of the adverse event profile for this doublet chemotherapy combination,” said Sanjay Popat, MD, PhD, of the Royal Marsden Hospital in London, who was the invited discussant at the symposium.
He noted that among PD-L1–positive patients, the OS benefit appears to be driven by patients with high levels of PD-L1 expression (50% or greater).
Additional questions that need addressing, he said, include how immune-related adverse events evolve over time; whether the combination can be made less toxic without impairing efficacy; and what is the optimum duration, dosing, and scheduling of ipilimumab.
“What is the promise of [Checkmate] 227? The promise of the 227 is to have long-lasting responses. That means long life for our patients with a chemo-sparing regimen,” commented Marina Garassino, MD, from the Istituto Nazionale dei Tumori in Milan, who was the invited discussant at the presymposium briefing.
“At the same time, we have to go back to the bench, to the scientists, and to ask the scientists to [help us] understand who are the patients to be treated with the combination of immunotherapy and immunotherapy, with the combination of chemotherapy and immunotherapy, and just with a single agent,” she said.
The study was funded by Bristol-Myers Squibb. Dr. Peters reported a consultant/advisory role, speakers bureau activity, and research support from BMS and others. Dr. Popat disclosed honoraria from BMS and others. Dr. Garrassino disclosed personal fees from BMS and others.
SOURCE: Hellmann MD et al. ESMO 2019. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910231.
BARCELONA – Patients with than patients treated with chemotherapy, reported investigators in the Checkmate 227 trial.
Among 793 patients with treatment-naive metastatic NSCLC with programmed death-ligand 1 (PD-L1) expression of at least 1%, median overall survival (OS) was 17.1 months for patients treated with the combination versus 14.9 months for patients treated with chemotherapy, a difference that translated into a hazard ratio with the combination of 0.79 (P = .007). Two-year overall survival rates were 40% and 32.8%, respectively.
The improvement in OS with the combination occurred regardless of PD-L1 status, suggesting that it can be a chemotherapy-free option for patients with previously untreated metastatic NSCLC, Solange Peters, MD, of Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said at the European Society for Medical Oncology Congress.
Checkmate 227 “is the first phase 3 study proving the concept in an evidence-based fashion of the combination of CTLA4 and anti–PD-1/PD-L1 in non–small cell lung cancer,” Dr. Peters said at a briefing prior to her presentation of the data in a symposium.
CheckMate 227 investigators enrolled patients with stage IV or recurrent NSCLC who had not received any treatment previously. Part one of the multipart study was designed to compare different nivolumab-based regimens versus chemotherapy in patients with PD-L1 expression of 1% or greater, or less than 1%.
The trial has two independent primary endpoints, the first of which, progression-free survival (PFS) with nivolumab and ipilimumab versus chemotherapy, was reported at the 2018 annual meeting of the American Association for Cancer Research.
Dr. Peters presented the overall survival endpoint at ESMO 2019. Results of the study were published simultaneously in the New England Journal of Medicine (2019 Sep 28. doi: 10.1056/NEJMoa1910231).
In part one of the trial, patients with PD-L1 expression of at least 1% (1,189 patients) were randomized on a 1:1:1 basis to one of three treatment options: nivolumab plus low-dose ipilimumab, nivolumab alone, or histology-based chemotherapy. Patients with PD-L1 expression less than 1% (550 patients) were randomized to nivolumab plus low-dose ipilimumab, nivolumab plus chemotherapy, or chemotherapy.
The survival benefit seen with the immunotherapy combination was durable, with 2-year OS rates of 40% for nivolumab/ipilimumab versus 32.8% for chemotherapy. The median durations of response were 23.2 months vs. 6.2 months, respectively.
Patients with low or no PD-L1 expression levels also benefited from the immunotherapy combination, with a median OS of 17.2 months with nivolumab plus ipilimumab, compared with 12.2 months with chemotherapy.
Among all enrolled patients, the median OS duration was 17.1 months with nivolumab plus ipilimumab versus 13.9 months with chemotherapy.
Grade 3 or 4 treatment-related adverse events in the overall study population occurred in 32.8% of patients treated with combined immunotherapy and in 36% of those treated with chemotherapy.
“A key question remains: Is the addition of ipilimumab providing additional benefit on top of nivolumab?” Dr. Peters asked. The answer to that question appears to be “yes,” she said, pointing to a comparison of OS among patients with PD-L1 expression below 1%. Although this subanalysis was not powered for statistical significance, the survival curves indicated a significant advantage for the combination, compared with nivolumab alone or chemotherapy, with respective median OS rates of 17.2, 15.2, and 12.2 months.
“What have we learned from Checkmate 227 so far? Caveat emptor – buyer beware. Beware of the adverse event profile for this doublet chemotherapy combination,” said Sanjay Popat, MD, PhD, of the Royal Marsden Hospital in London, who was the invited discussant at the symposium.
He noted that among PD-L1–positive patients, the OS benefit appears to be driven by patients with high levels of PD-L1 expression (50% or greater).
Additional questions that need addressing, he said, include how immune-related adverse events evolve over time; whether the combination can be made less toxic without impairing efficacy; and what is the optimum duration, dosing, and scheduling of ipilimumab.
“What is the promise of [Checkmate] 227? The promise of the 227 is to have long-lasting responses. That means long life for our patients with a chemo-sparing regimen,” commented Marina Garassino, MD, from the Istituto Nazionale dei Tumori in Milan, who was the invited discussant at the presymposium briefing.
“At the same time, we have to go back to the bench, to the scientists, and to ask the scientists to [help us] understand who are the patients to be treated with the combination of immunotherapy and immunotherapy, with the combination of chemotherapy and immunotherapy, and just with a single agent,” she said.
The study was funded by Bristol-Myers Squibb. Dr. Peters reported a consultant/advisory role, speakers bureau activity, and research support from BMS and others. Dr. Popat disclosed honoraria from BMS and others. Dr. Garrassino disclosed personal fees from BMS and others.
SOURCE: Hellmann MD et al. ESMO 2019. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910231.
BARCELONA – Patients with than patients treated with chemotherapy, reported investigators in the Checkmate 227 trial.
Among 793 patients with treatment-naive metastatic NSCLC with programmed death-ligand 1 (PD-L1) expression of at least 1%, median overall survival (OS) was 17.1 months for patients treated with the combination versus 14.9 months for patients treated with chemotherapy, a difference that translated into a hazard ratio with the combination of 0.79 (P = .007). Two-year overall survival rates were 40% and 32.8%, respectively.
The improvement in OS with the combination occurred regardless of PD-L1 status, suggesting that it can be a chemotherapy-free option for patients with previously untreated metastatic NSCLC, Solange Peters, MD, of Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said at the European Society for Medical Oncology Congress.
Checkmate 227 “is the first phase 3 study proving the concept in an evidence-based fashion of the combination of CTLA4 and anti–PD-1/PD-L1 in non–small cell lung cancer,” Dr. Peters said at a briefing prior to her presentation of the data in a symposium.
CheckMate 227 investigators enrolled patients with stage IV or recurrent NSCLC who had not received any treatment previously. Part one of the multipart study was designed to compare different nivolumab-based regimens versus chemotherapy in patients with PD-L1 expression of 1% or greater, or less than 1%.
The trial has two independent primary endpoints, the first of which, progression-free survival (PFS) with nivolumab and ipilimumab versus chemotherapy, was reported at the 2018 annual meeting of the American Association for Cancer Research.
Dr. Peters presented the overall survival endpoint at ESMO 2019. Results of the study were published simultaneously in the New England Journal of Medicine (2019 Sep 28. doi: 10.1056/NEJMoa1910231).
In part one of the trial, patients with PD-L1 expression of at least 1% (1,189 patients) were randomized on a 1:1:1 basis to one of three treatment options: nivolumab plus low-dose ipilimumab, nivolumab alone, or histology-based chemotherapy. Patients with PD-L1 expression less than 1% (550 patients) were randomized to nivolumab plus low-dose ipilimumab, nivolumab plus chemotherapy, or chemotherapy.
The survival benefit seen with the immunotherapy combination was durable, with 2-year OS rates of 40% for nivolumab/ipilimumab versus 32.8% for chemotherapy. The median durations of response were 23.2 months vs. 6.2 months, respectively.
Patients with low or no PD-L1 expression levels also benefited from the immunotherapy combination, with a median OS of 17.2 months with nivolumab plus ipilimumab, compared with 12.2 months with chemotherapy.
Among all enrolled patients, the median OS duration was 17.1 months with nivolumab plus ipilimumab versus 13.9 months with chemotherapy.
Grade 3 or 4 treatment-related adverse events in the overall study population occurred in 32.8% of patients treated with combined immunotherapy and in 36% of those treated with chemotherapy.
“A key question remains: Is the addition of ipilimumab providing additional benefit on top of nivolumab?” Dr. Peters asked. The answer to that question appears to be “yes,” she said, pointing to a comparison of OS among patients with PD-L1 expression below 1%. Although this subanalysis was not powered for statistical significance, the survival curves indicated a significant advantage for the combination, compared with nivolumab alone or chemotherapy, with respective median OS rates of 17.2, 15.2, and 12.2 months.
“What have we learned from Checkmate 227 so far? Caveat emptor – buyer beware. Beware of the adverse event profile for this doublet chemotherapy combination,” said Sanjay Popat, MD, PhD, of the Royal Marsden Hospital in London, who was the invited discussant at the symposium.
He noted that among PD-L1–positive patients, the OS benefit appears to be driven by patients with high levels of PD-L1 expression (50% or greater).
Additional questions that need addressing, he said, include how immune-related adverse events evolve over time; whether the combination can be made less toxic without impairing efficacy; and what is the optimum duration, dosing, and scheduling of ipilimumab.
“What is the promise of [Checkmate] 227? The promise of the 227 is to have long-lasting responses. That means long life for our patients with a chemo-sparing regimen,” commented Marina Garassino, MD, from the Istituto Nazionale dei Tumori in Milan, who was the invited discussant at the presymposium briefing.
“At the same time, we have to go back to the bench, to the scientists, and to ask the scientists to [help us] understand who are the patients to be treated with the combination of immunotherapy and immunotherapy, with the combination of chemotherapy and immunotherapy, and just with a single agent,” she said.
The study was funded by Bristol-Myers Squibb. Dr. Peters reported a consultant/advisory role, speakers bureau activity, and research support from BMS and others. Dr. Popat disclosed honoraria from BMS and others. Dr. Garrassino disclosed personal fees from BMS and others.
SOURCE: Hellmann MD et al. ESMO 2019. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910231.
REPORTING FROM ESMO 2019
Cardiotoxicity after checkpoint inhibitor treatment seen early, linked to elevated biomarkers
PHILADELPHIA – , and occurred more frequently in patients with elevated biomarkers, in a retrospective cohort study reported at the annual scientific meeting of the Heart Failure Society of America.
The findings support monitoring of cardiac biomarkers in the initial phase of checkpoint inhibitor treatment to identify patient at high cardiac risk, according to Kalyan R. Chitturi, DO, a resident physician with the DeBakey Heart and Vascular Center, Houston Methodist Hospital, who presented the results.
“It’s the early period that warrants the closest monitoring, as within the first 30-40 days, there’s higher risk,” Dr. Chitturi said in an interview. “When there was a biomarker elevation, it markedly increased the risk of MACE, warranting a closer vigilance during that time period.”
The retrospective study conducted by Dr. Chitturi and colleagues included a total of 252 patients with lung cancer who had been treated at one of seven different sites in Houston Methodist Cancer Center between Aug. 1, 2015, and Aug. 1, 2018.
Immune checkpoint inhibitors did not significantly increase the risk of MACE, compared with other lung cancer therapies, with incidences of 13.3% and 10.3%, respectively (P = .632), the investigators found.
However, MACE did occur earlier in the checkpoint inhibitor group, at a median time to event of 40 days, compared with 118 days in the patients not treated with checkpoint inhibitors, they found.
Risk of MACE with checkpoint inhibitor treatment was increased in patients with elevated troponin (hazard ratio, 2.48; 95% confidence interval, 1.18-5.21; P = .017) or elevated brain natriuretic peptide (HR, 5.77; 95% CI, 2.70-12.35; P less than .001), according to multivariate logistic regression analysis results.
These results suggest biomarkers such as cardiac troponin and brain natriuretic peptide are warranted to monitor patients in the early phase of checkpoint inhibitor treatment, according to Dr. Chitturi. “In the cost-benefit ratio of often-lethal MACE, it’s well worth it to collect these,” he said in the interview.
The results corroborate findings from some other recent studies, he noted. These include a recent study that linked elevated serum troponin to myocarditis in patients treated with immune checkpoint inhibitors (J Am Coll Cardiol. 2018 Apr 24;71[16]:1755-64).
Dr. Chitturi and coauthors reported no disclosures related to their presentation at the HFSA meeting.
SOURCE: Chitturi KR et al. HFSA 2019, Abstract 127.
PHILADELPHIA – , and occurred more frequently in patients with elevated biomarkers, in a retrospective cohort study reported at the annual scientific meeting of the Heart Failure Society of America.
The findings support monitoring of cardiac biomarkers in the initial phase of checkpoint inhibitor treatment to identify patient at high cardiac risk, according to Kalyan R. Chitturi, DO, a resident physician with the DeBakey Heart and Vascular Center, Houston Methodist Hospital, who presented the results.
“It’s the early period that warrants the closest monitoring, as within the first 30-40 days, there’s higher risk,” Dr. Chitturi said in an interview. “When there was a biomarker elevation, it markedly increased the risk of MACE, warranting a closer vigilance during that time period.”
The retrospective study conducted by Dr. Chitturi and colleagues included a total of 252 patients with lung cancer who had been treated at one of seven different sites in Houston Methodist Cancer Center between Aug. 1, 2015, and Aug. 1, 2018.
Immune checkpoint inhibitors did not significantly increase the risk of MACE, compared with other lung cancer therapies, with incidences of 13.3% and 10.3%, respectively (P = .632), the investigators found.
However, MACE did occur earlier in the checkpoint inhibitor group, at a median time to event of 40 days, compared with 118 days in the patients not treated with checkpoint inhibitors, they found.
Risk of MACE with checkpoint inhibitor treatment was increased in patients with elevated troponin (hazard ratio, 2.48; 95% confidence interval, 1.18-5.21; P = .017) or elevated brain natriuretic peptide (HR, 5.77; 95% CI, 2.70-12.35; P less than .001), according to multivariate logistic regression analysis results.
These results suggest biomarkers such as cardiac troponin and brain natriuretic peptide are warranted to monitor patients in the early phase of checkpoint inhibitor treatment, according to Dr. Chitturi. “In the cost-benefit ratio of often-lethal MACE, it’s well worth it to collect these,” he said in the interview.
The results corroborate findings from some other recent studies, he noted. These include a recent study that linked elevated serum troponin to myocarditis in patients treated with immune checkpoint inhibitors (J Am Coll Cardiol. 2018 Apr 24;71[16]:1755-64).
Dr. Chitturi and coauthors reported no disclosures related to their presentation at the HFSA meeting.
SOURCE: Chitturi KR et al. HFSA 2019, Abstract 127.
PHILADELPHIA – , and occurred more frequently in patients with elevated biomarkers, in a retrospective cohort study reported at the annual scientific meeting of the Heart Failure Society of America.
The findings support monitoring of cardiac biomarkers in the initial phase of checkpoint inhibitor treatment to identify patient at high cardiac risk, according to Kalyan R. Chitturi, DO, a resident physician with the DeBakey Heart and Vascular Center, Houston Methodist Hospital, who presented the results.
“It’s the early period that warrants the closest monitoring, as within the first 30-40 days, there’s higher risk,” Dr. Chitturi said in an interview. “When there was a biomarker elevation, it markedly increased the risk of MACE, warranting a closer vigilance during that time period.”
The retrospective study conducted by Dr. Chitturi and colleagues included a total of 252 patients with lung cancer who had been treated at one of seven different sites in Houston Methodist Cancer Center between Aug. 1, 2015, and Aug. 1, 2018.
Immune checkpoint inhibitors did not significantly increase the risk of MACE, compared with other lung cancer therapies, with incidences of 13.3% and 10.3%, respectively (P = .632), the investigators found.
However, MACE did occur earlier in the checkpoint inhibitor group, at a median time to event of 40 days, compared with 118 days in the patients not treated with checkpoint inhibitors, they found.
Risk of MACE with checkpoint inhibitor treatment was increased in patients with elevated troponin (hazard ratio, 2.48; 95% confidence interval, 1.18-5.21; P = .017) or elevated brain natriuretic peptide (HR, 5.77; 95% CI, 2.70-12.35; P less than .001), according to multivariate logistic regression analysis results.
These results suggest biomarkers such as cardiac troponin and brain natriuretic peptide are warranted to monitor patients in the early phase of checkpoint inhibitor treatment, according to Dr. Chitturi. “In the cost-benefit ratio of often-lethal MACE, it’s well worth it to collect these,” he said in the interview.
The results corroborate findings from some other recent studies, he noted. These include a recent study that linked elevated serum troponin to myocarditis in patients treated with immune checkpoint inhibitors (J Am Coll Cardiol. 2018 Apr 24;71[16]:1755-64).
Dr. Chitturi and coauthors reported no disclosures related to their presentation at the HFSA meeting.
SOURCE: Chitturi KR et al. HFSA 2019, Abstract 127.
REPORTING FROM HFSA 2019
Osimertinib improves survival in advanced NSCLC
BARCELONA – In patients with , compared with other agents targeted against NSCLC with epidermal growth factor–receptor (EGFR) mutations, investigators for the FLAURA trial reported.
After median follow-up ranging from 27 to 35.8 months, the median overall survival was 38.6 months for patients randomized to osimertinib, compared with 31.8 months for patients assigned to either of two comparator tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) or erlotinib (Tarceva).
The hazard ratio for death with osimertinib was 0.799 (P = .0462), reported Suresh Ramalingam, MD, director of the lung cancer program at Winship Cancer Institute of Emory University, Atlanta.
“I’m excited that the new milestone accomplished with osimertinib in this trial will serve as the platform to build on in our efforts to improve the lives of patients with lung cancer,” he said at the European Society for Medical Oncology Congress.
Osimertinib is the first TKI to show improvement in overall survival over another TKI in the treatment of advanced stage cancers, he noted.
Overall survival was a secondary endpoint of the FLAURA trial. As previously reported, FLAURA met its primary endpoint of improvement in progression-free survival (PFS) in an interim analysis presented at ESMO 2017. In that analysis, osimertinib cut the risk of disease progression by 54%, compared with gefitinib or erlotinib.
Among 279 patients with EGFR-mutated locally advanced or metastatic NSCLC treated with osimertinib, the median PFS was 18.9 months, compared with 10.2 months for 277 patients treated with the standard of care, which translated into a HR of 0.46 (P less than .0001).
The FLAURA results supported Food and Drug Administration approval of osimertinib in April 2018 for first-line treatment of patients with metastatic NSCLC with EGFR mutations as detected by an FDA-approved test.
The current overall survival analysis, although not powered to show differences among patient subgroups, showed trends favoring osimertinib over a comparator TKI among both men and women, older and younger patients, patients with central nervous system metastases at trial entry, and patients with the EGFR exon 19 deletion at randomization.
The 31.8 month median overall survival for the control (comparator-TKI) arm is among the highest reported for patients with EGFR-mutated NSCLC, Dr. Ramalingam noted.
“That is because a lot of patients crossed over from the control group to receive osimertinib on progression,” he said, adding that the magnitude of benefit from osimertinib was greater among non-Asian patients, compared with Asians.
FLAURA details
In the phase 3 FLAURA trial, investigators stratified patients with previously untreated NSCLC positive for EGFR resistance mutations according to mutation status (exon 19 deletion or the L858R amino acid substitution in exon 21) and race (Asian or non-Asian).
Patients were randomly assigned to treatment with either oral osimertinib 80 mg daily or an EGFR TKI, either oral gefitinib 250 mg or erlotinib 150 mg daily.
The patients were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) every 6 weeks until objective disease progression.
Patients assigned to the standard-of-care arm who had central confirmation of progression and T790M positivity were allowed to cross over to open-label osimertinib.
PFS, the primary endpoint, was also significantly better with osimertinib than with either of the comparator TKIs in patients with and without central nervous system metastases at study entry (HR, 0.47; P = .0009 for patients with CNS metastases; HR, 0.46; P less than .0001 for patients with no CNS metastases).
“For clinicians, for patients, and also for our health authorities, the results in terms of overall survival are really relevant, and this is why this study is so important, knowing this secondary endpoint from a statistical point of view. The study is statistically significant and clinically relevant,” commented Pilar Garrido, MD, from the department of medical oncology, Hospital Universitario Ramón y Cajal in Madrid, the invited discussant at a briefing where Dr. Ramalingam outlined the study findings prior to his presentation of the data in a symposium.
“What’s the future of EGFR mutant lung cancer? Well, I think we should be done with single-agent EGFR-TKI comparisons: We have a clear agent that’s associated with an improvement in survival. I think our focus needs to shift to building on or adding to osimertinib,” commented Pasi A Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute in Boston, the invited discussant at the symposium.
He said that the challenge for clinicians will be to identify high- and low-risk EGFR-mutant NSCLC, and to determine which patients could be treated with a single agent, and which may require a combination therapy approach.
FLAURA was sponsored by AstraZeneca. Dr. Ramalingam disclosed honoraria, an advisory or consulting role, and research funding from that company and others. Dr. Garrido disclosed a speaker and advisory role for AstraZeneca and others. Dr. Jänne disclosed prior consulting for AstraZeneca.
SOURCE: Ramalingam S et al. ESMO 2019. Abstract LBA5_PR.
BARCELONA – In patients with , compared with other agents targeted against NSCLC with epidermal growth factor–receptor (EGFR) mutations, investigators for the FLAURA trial reported.
After median follow-up ranging from 27 to 35.8 months, the median overall survival was 38.6 months for patients randomized to osimertinib, compared with 31.8 months for patients assigned to either of two comparator tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) or erlotinib (Tarceva).
The hazard ratio for death with osimertinib was 0.799 (P = .0462), reported Suresh Ramalingam, MD, director of the lung cancer program at Winship Cancer Institute of Emory University, Atlanta.
“I’m excited that the new milestone accomplished with osimertinib in this trial will serve as the platform to build on in our efforts to improve the lives of patients with lung cancer,” he said at the European Society for Medical Oncology Congress.
Osimertinib is the first TKI to show improvement in overall survival over another TKI in the treatment of advanced stage cancers, he noted.
Overall survival was a secondary endpoint of the FLAURA trial. As previously reported, FLAURA met its primary endpoint of improvement in progression-free survival (PFS) in an interim analysis presented at ESMO 2017. In that analysis, osimertinib cut the risk of disease progression by 54%, compared with gefitinib or erlotinib.
Among 279 patients with EGFR-mutated locally advanced or metastatic NSCLC treated with osimertinib, the median PFS was 18.9 months, compared with 10.2 months for 277 patients treated with the standard of care, which translated into a HR of 0.46 (P less than .0001).
The FLAURA results supported Food and Drug Administration approval of osimertinib in April 2018 for first-line treatment of patients with metastatic NSCLC with EGFR mutations as detected by an FDA-approved test.
The current overall survival analysis, although not powered to show differences among patient subgroups, showed trends favoring osimertinib over a comparator TKI among both men and women, older and younger patients, patients with central nervous system metastases at trial entry, and patients with the EGFR exon 19 deletion at randomization.
The 31.8 month median overall survival for the control (comparator-TKI) arm is among the highest reported for patients with EGFR-mutated NSCLC, Dr. Ramalingam noted.
“That is because a lot of patients crossed over from the control group to receive osimertinib on progression,” he said, adding that the magnitude of benefit from osimertinib was greater among non-Asian patients, compared with Asians.
FLAURA details
In the phase 3 FLAURA trial, investigators stratified patients with previously untreated NSCLC positive for EGFR resistance mutations according to mutation status (exon 19 deletion or the L858R amino acid substitution in exon 21) and race (Asian or non-Asian).
Patients were randomly assigned to treatment with either oral osimertinib 80 mg daily or an EGFR TKI, either oral gefitinib 250 mg or erlotinib 150 mg daily.
The patients were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) every 6 weeks until objective disease progression.
Patients assigned to the standard-of-care arm who had central confirmation of progression and T790M positivity were allowed to cross over to open-label osimertinib.
PFS, the primary endpoint, was also significantly better with osimertinib than with either of the comparator TKIs in patients with and without central nervous system metastases at study entry (HR, 0.47; P = .0009 for patients with CNS metastases; HR, 0.46; P less than .0001 for patients with no CNS metastases).
“For clinicians, for patients, and also for our health authorities, the results in terms of overall survival are really relevant, and this is why this study is so important, knowing this secondary endpoint from a statistical point of view. The study is statistically significant and clinically relevant,” commented Pilar Garrido, MD, from the department of medical oncology, Hospital Universitario Ramón y Cajal in Madrid, the invited discussant at a briefing where Dr. Ramalingam outlined the study findings prior to his presentation of the data in a symposium.
“What’s the future of EGFR mutant lung cancer? Well, I think we should be done with single-agent EGFR-TKI comparisons: We have a clear agent that’s associated with an improvement in survival. I think our focus needs to shift to building on or adding to osimertinib,” commented Pasi A Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute in Boston, the invited discussant at the symposium.
He said that the challenge for clinicians will be to identify high- and low-risk EGFR-mutant NSCLC, and to determine which patients could be treated with a single agent, and which may require a combination therapy approach.
FLAURA was sponsored by AstraZeneca. Dr. Ramalingam disclosed honoraria, an advisory or consulting role, and research funding from that company and others. Dr. Garrido disclosed a speaker and advisory role for AstraZeneca and others. Dr. Jänne disclosed prior consulting for AstraZeneca.
SOURCE: Ramalingam S et al. ESMO 2019. Abstract LBA5_PR.
BARCELONA – In patients with , compared with other agents targeted against NSCLC with epidermal growth factor–receptor (EGFR) mutations, investigators for the FLAURA trial reported.
After median follow-up ranging from 27 to 35.8 months, the median overall survival was 38.6 months for patients randomized to osimertinib, compared with 31.8 months for patients assigned to either of two comparator tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) or erlotinib (Tarceva).
The hazard ratio for death with osimertinib was 0.799 (P = .0462), reported Suresh Ramalingam, MD, director of the lung cancer program at Winship Cancer Institute of Emory University, Atlanta.
“I’m excited that the new milestone accomplished with osimertinib in this trial will serve as the platform to build on in our efforts to improve the lives of patients with lung cancer,” he said at the European Society for Medical Oncology Congress.
Osimertinib is the first TKI to show improvement in overall survival over another TKI in the treatment of advanced stage cancers, he noted.
Overall survival was a secondary endpoint of the FLAURA trial. As previously reported, FLAURA met its primary endpoint of improvement in progression-free survival (PFS) in an interim analysis presented at ESMO 2017. In that analysis, osimertinib cut the risk of disease progression by 54%, compared with gefitinib or erlotinib.
Among 279 patients with EGFR-mutated locally advanced or metastatic NSCLC treated with osimertinib, the median PFS was 18.9 months, compared with 10.2 months for 277 patients treated with the standard of care, which translated into a HR of 0.46 (P less than .0001).
The FLAURA results supported Food and Drug Administration approval of osimertinib in April 2018 for first-line treatment of patients with metastatic NSCLC with EGFR mutations as detected by an FDA-approved test.
The current overall survival analysis, although not powered to show differences among patient subgroups, showed trends favoring osimertinib over a comparator TKI among both men and women, older and younger patients, patients with central nervous system metastases at trial entry, and patients with the EGFR exon 19 deletion at randomization.
The 31.8 month median overall survival for the control (comparator-TKI) arm is among the highest reported for patients with EGFR-mutated NSCLC, Dr. Ramalingam noted.
“That is because a lot of patients crossed over from the control group to receive osimertinib on progression,” he said, adding that the magnitude of benefit from osimertinib was greater among non-Asian patients, compared with Asians.
FLAURA details
In the phase 3 FLAURA trial, investigators stratified patients with previously untreated NSCLC positive for EGFR resistance mutations according to mutation status (exon 19 deletion or the L858R amino acid substitution in exon 21) and race (Asian or non-Asian).
Patients were randomly assigned to treatment with either oral osimertinib 80 mg daily or an EGFR TKI, either oral gefitinib 250 mg or erlotinib 150 mg daily.
The patients were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) every 6 weeks until objective disease progression.
Patients assigned to the standard-of-care arm who had central confirmation of progression and T790M positivity were allowed to cross over to open-label osimertinib.
PFS, the primary endpoint, was also significantly better with osimertinib than with either of the comparator TKIs in patients with and without central nervous system metastases at study entry (HR, 0.47; P = .0009 for patients with CNS metastases; HR, 0.46; P less than .0001 for patients with no CNS metastases).
“For clinicians, for patients, and also for our health authorities, the results in terms of overall survival are really relevant, and this is why this study is so important, knowing this secondary endpoint from a statistical point of view. The study is statistically significant and clinically relevant,” commented Pilar Garrido, MD, from the department of medical oncology, Hospital Universitario Ramón y Cajal in Madrid, the invited discussant at a briefing where Dr. Ramalingam outlined the study findings prior to his presentation of the data in a symposium.
“What’s the future of EGFR mutant lung cancer? Well, I think we should be done with single-agent EGFR-TKI comparisons: We have a clear agent that’s associated with an improvement in survival. I think our focus needs to shift to building on or adding to osimertinib,” commented Pasi A Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute in Boston, the invited discussant at the symposium.
He said that the challenge for clinicians will be to identify high- and low-risk EGFR-mutant NSCLC, and to determine which patients could be treated with a single agent, and which may require a combination therapy approach.
FLAURA was sponsored by AstraZeneca. Dr. Ramalingam disclosed honoraria, an advisory or consulting role, and research funding from that company and others. Dr. Garrido disclosed a speaker and advisory role for AstraZeneca and others. Dr. Jänne disclosed prior consulting for AstraZeneca.
SOURCE: Ramalingam S et al. ESMO 2019. Abstract LBA5_PR.
REPORTING FROM ESMO 2019