Lung Cancer

GENEVA – For lung lesion biopsy, electromagnetic navigation bronchoscopy (ENB) offers high navigational success with a relatively low rate of pneumothorax, according to European data from the international NAVIGATE study.

Will Pass/MDedge News

In addition to lung lesion biopsy, ENB can facilitate concurrent lymph node sampling and fiducial placement during a single anesthetic event, reported lead author Kelvin Lau, MD, chief of thoracic surgery at Barts Thorax Centre in London, and his colleagues. According to Dr. Lau, who presented at the European Lung Cancer Conference, the findings from this European cohort add weight to previously published data from the NAVIGATE trial, which aims to demonstrate real-world use of ENB.

“The outcomes show that [ENB] is very safe in terms of pneumothorax rate, despite the fact that many of these patients were challenging and actually were turned down by the percutaneous radiologist before they came to us,” Dr. Lau said at the meeting, presented by the European Society for Medical Oncology.

Out of 1,200 patients enrolled in the NAVIGATE trial in the United States and Europe, the present 1-month interim analysis showed experiences with 175 patients treated at eight European centers. Anyone undergoing navigational bronchoscopy was eligible. The primary outcome was pneumothorax rate and the secondary outcome was diagnostic yield.

Data analysis showed that lesions were most frequently in the upper lobe (62.6%) and in the peripheral third of the lung (72.7%), the latter of which is beyond the reach of a conventional bronchoscope. In two out of three patients (66.8%), a bronchus sign was present, which “means that the bronchoscope runs straight into the lesion, and theoretically means it’s easier to access,” Dr. Lau said. Almost all patients had ENB for lung biopsy (99.4%), while in a small minority (8.0%), ENB was used for fiducial marking. The median total procedure time was 43.5 minutes, of which 32.9 minutes were spent navigating and sampling with ENB.

The ENB-related pneumothorax rate was 7.4%, although a slightly lower percentage, 5.1%, required intervention or hospitalization. According to the ENB-related Common Terminology Criteria for Adverse Events, 2.3% of patients had grade 2 or higher bronchopulmonary hemorrhage and 0.6% of patients had grade 4 or higher respiratory failure. Although the secondary endpoint, diagnostic yield, was not met because of inadequate follow-up time, the navigational success rate, defined as access to the intended lung lesion, was 96.6%, which offers some sense of efficacy.

“The purpose of this study is to show that [ENB] is very safe,” Dr. Lau said in an interview. “And the numbers are significantly better than historic CT-guided biopsy data.”

Considering the choice between ENB and CT-guided biopsy, invited discussant Anne-Marie Dingemans, MD, of Maastricht University, the Netherlands, offered a different viewpoint.

Will Pass/MDedge News

“CT-guided biopsies are low cost ... and the sensitivity is very, very high,” Dr. Dingemans said. “In good hands, with a good radiologist, you have a high chance that you will have a good diagnosis of the nodules.” She also noted that a bronchus sign does not impact efficacy.

“I’m very into CT-guided biopsies,” Dr. Dingemans continued, noting that the radiologist at her treatment center takes biopsies with a 10-gauge large-core needle. With this technique, Dr. Dingemans reported a 5.7% pneumothorax rate, which is comparable with the present NAVIGATE data.

However, Dr. Lau contested this figure.

“The pneumothorax rates [for CT-guided biopsy] in larger studies have always been about 20% to 40%,” Dr. Lau said. “You can’t compare large overall practice in a pragmatic study capturing everyone versus one single center. The truth is, most centers will have a 20% pneumothorax rate.”

Dr. Lau added that patient experiences are likely to be better with ENB than with CT-guided percutaneous biopsy.

“To me, patient comfort for biopsy is essential,” Dr. Lau said. “Having a needle stuck into your chest – it’s very uncomfortable. I’ve had patients who’ve come to me after they had a percutaneous biopsy and who for some reason needed a re-biopsy ... those patients almost always wish they had navigational bronchoscopy the first time because there would be no pain for them.”

When asked about capital cost concerns surrounding ENB, Dr. Lau suggested that the benefits outweigh the costs.

“The most expensive procedure is the one you have to do again,” Dr. Lau said. “So what we do is put a brush in, and a needle, and a biopsy, and hopefully, one of those three, if not all three, gets tissue, and we can do that with navigational bronchoscopy because there is one channel down. You can’t repeatedly stick needles into patients. By definition, you can’t throw three needle jabs, because you will get a 90% pneumothorax rate. And that’s the beauty of navigational bronchoscopy as well, because in the NAVIGATE series, a number of patients, about 10%, had multiple lesions biopsied.” Furthermore, Dr. Lau noted, percutaneous biopsy is “almost never” performed bilaterally, for fear of collapsing both lungs, but this is not the case with ENB. “We’ve done it on patients who have one lung,” he said.

Dr. Lau predicted that costs of ENB will come down with time. “Because of the number of products increasing, the price will drop,” he said.

Concluding the interview, Dr. Lau offered a summarizing message: “If you want to give the patient the safe option, you should do [ENB], and when it becomes more popular, the price will fall,” he said.

Medtronic funded the study. The investigators reported financial relationships with Olympus, Ambu, PulmonX, Boston Scientific, and others.

SOURCE: Lau et al. ELCC 2019. Abstract 68O.

GENEVA – For lung lesion biopsy, electromagnetic navigation bronchoscopy (ENB) offers high navigational success with a relatively low rate of pneumothorax, according to European data from the international NAVIGATE study.

Will Pass/MDedge News

In addition to lung lesion biopsy, ENB can facilitate concurrent lymph node sampling and fiducial placement during a single anesthetic event, reported lead author Kelvin Lau, MD, chief of thoracic surgery at Barts Thorax Centre in London, and his colleagues. According to Dr. Lau, who presented at the European Lung Cancer Conference, the findings from this European cohort add weight to previously published data from the NAVIGATE trial, which aims to demonstrate real-world use of ENB.

“The outcomes show that [ENB] is very safe in terms of pneumothorax rate, despite the fact that many of these patients were challenging and actually were turned down by the percutaneous radiologist before they came to us,” Dr. Lau said at the meeting, presented by the European Society for Medical Oncology.

Out of 1,200 patients enrolled in the NAVIGATE trial in the United States and Europe, the present 1-month interim analysis showed experiences with 175 patients treated at eight European centers. Anyone undergoing navigational bronchoscopy was eligible. The primary outcome was pneumothorax rate and the secondary outcome was diagnostic yield.

Data analysis showed that lesions were most frequently in the upper lobe (62.6%) and in the peripheral third of the lung (72.7%), the latter of which is beyond the reach of a conventional bronchoscope. In two out of three patients (66.8%), a bronchus sign was present, which “means that the bronchoscope runs straight into the lesion, and theoretically means it’s easier to access,” Dr. Lau said. Almost all patients had ENB for lung biopsy (99.4%), while in a small minority (8.0%), ENB was used for fiducial marking. The median total procedure time was 43.5 minutes, of which 32.9 minutes were spent navigating and sampling with ENB.

The ENB-related pneumothorax rate was 7.4%, although a slightly lower percentage, 5.1%, required intervention or hospitalization. According to the ENB-related Common Terminology Criteria for Adverse Events, 2.3% of patients had grade 2 or higher bronchopulmonary hemorrhage and 0.6% of patients had grade 4 or higher respiratory failure. Although the secondary endpoint, diagnostic yield, was not met because of inadequate follow-up time, the navigational success rate, defined as access to the intended lung lesion, was 96.6%, which offers some sense of efficacy.

“The purpose of this study is to show that [ENB] is very safe,” Dr. Lau said in an interview. “And the numbers are significantly better than historic CT-guided biopsy data.”

Considering the choice between ENB and CT-guided biopsy, invited discussant Anne-Marie Dingemans, MD, of Maastricht University, the Netherlands, offered a different viewpoint.

Will Pass/MDedge News

“CT-guided biopsies are low cost ... and the sensitivity is very, very high,” Dr. Dingemans said. “In good hands, with a good radiologist, you have a high chance that you will have a good diagnosis of the nodules.” She also noted that a bronchus sign does not impact efficacy.

“I’m very into CT-guided biopsies,” Dr. Dingemans continued, noting that the radiologist at her treatment center takes biopsies with a 10-gauge large-core needle. With this technique, Dr. Dingemans reported a 5.7% pneumothorax rate, which is comparable with the present NAVIGATE data.

However, Dr. Lau contested this figure.

“The pneumothorax rates [for CT-guided biopsy] in larger studies have always been about 20% to 40%,” Dr. Lau said. “You can’t compare large overall practice in a pragmatic study capturing everyone versus one single center. The truth is, most centers will have a 20% pneumothorax rate.”

Dr. Lau added that patient experiences are likely to be better with ENB than with CT-guided percutaneous biopsy.

“To me, patient comfort for biopsy is essential,” Dr. Lau said. “Having a needle stuck into your chest – it’s very uncomfortable. I’ve had patients who’ve come to me after they had a percutaneous biopsy and who for some reason needed a re-biopsy ... those patients almost always wish they had navigational bronchoscopy the first time because there would be no pain for them.”

When asked about capital cost concerns surrounding ENB, Dr. Lau suggested that the benefits outweigh the costs.

“The most expensive procedure is the one you have to do again,” Dr. Lau said. “So what we do is put a brush in, and a needle, and a biopsy, and hopefully, one of those three, if not all three, gets tissue, and we can do that with navigational bronchoscopy because there is one channel down. You can’t repeatedly stick needles into patients. By definition, you can’t throw three needle jabs, because you will get a 90% pneumothorax rate. And that’s the beauty of navigational bronchoscopy as well, because in the NAVIGATE series, a number of patients, about 10%, had multiple lesions biopsied.” Furthermore, Dr. Lau noted, percutaneous biopsy is “almost never” performed bilaterally, for fear of collapsing both lungs, but this is not the case with ENB. “We’ve done it on patients who have one lung,” he said.

Dr. Lau predicted that costs of ENB will come down with time. “Because of the number of products increasing, the price will drop,” he said.

Concluding the interview, Dr. Lau offered a summarizing message: “If you want to give the patient the safe option, you should do [ENB], and when it becomes more popular, the price will fall,” he said.

Medtronic funded the study. The investigators reported financial relationships with Olympus, Ambu, PulmonX, Boston Scientific, and others.

SOURCE: Lau et al. ELCC 2019. Abstract 68O.

GENEVA – For lung lesion biopsy, electromagnetic navigation bronchoscopy (ENB) offers high navigational success with a relatively low rate of pneumothorax, according to European data from the international NAVIGATE study.

Will Pass/MDedge News

In addition to lung lesion biopsy, ENB can facilitate concurrent lymph node sampling and fiducial placement during a single anesthetic event, reported lead author Kelvin Lau, MD, chief of thoracic surgery at Barts Thorax Centre in London, and his colleagues. According to Dr. Lau, who presented at the European Lung Cancer Conference, the findings from this European cohort add weight to previously published data from the NAVIGATE trial, which aims to demonstrate real-world use of ENB.

“The outcomes show that [ENB] is very safe in terms of pneumothorax rate, despite the fact that many of these patients were challenging and actually were turned down by the percutaneous radiologist before they came to us,” Dr. Lau said at the meeting, presented by the European Society for Medical Oncology.

Out of 1,200 patients enrolled in the NAVIGATE trial in the United States and Europe, the present 1-month interim analysis showed experiences with 175 patients treated at eight European centers. Anyone undergoing navigational bronchoscopy was eligible. The primary outcome was pneumothorax rate and the secondary outcome was diagnostic yield.

Data analysis showed that lesions were most frequently in the upper lobe (62.6%) and in the peripheral third of the lung (72.7%), the latter of which is beyond the reach of a conventional bronchoscope. In two out of three patients (66.8%), a bronchus sign was present, which “means that the bronchoscope runs straight into the lesion, and theoretically means it’s easier to access,” Dr. Lau said. Almost all patients had ENB for lung biopsy (99.4%), while in a small minority (8.0%), ENB was used for fiducial marking. The median total procedure time was 43.5 minutes, of which 32.9 minutes were spent navigating and sampling with ENB.

The ENB-related pneumothorax rate was 7.4%, although a slightly lower percentage, 5.1%, required intervention or hospitalization. According to the ENB-related Common Terminology Criteria for Adverse Events, 2.3% of patients had grade 2 or higher bronchopulmonary hemorrhage and 0.6% of patients had grade 4 or higher respiratory failure. Although the secondary endpoint, diagnostic yield, was not met because of inadequate follow-up time, the navigational success rate, defined as access to the intended lung lesion, was 96.6%, which offers some sense of efficacy.

“The purpose of this study is to show that [ENB] is very safe,” Dr. Lau said in an interview. “And the numbers are significantly better than historic CT-guided biopsy data.”

Considering the choice between ENB and CT-guided biopsy, invited discussant Anne-Marie Dingemans, MD, of Maastricht University, the Netherlands, offered a different viewpoint.

Will Pass/MDedge News

“CT-guided biopsies are low cost ... and the sensitivity is very, very high,” Dr. Dingemans said. “In good hands, with a good radiologist, you have a high chance that you will have a good diagnosis of the nodules.” She also noted that a bronchus sign does not impact efficacy.

“I’m very into CT-guided biopsies,” Dr. Dingemans continued, noting that the radiologist at her treatment center takes biopsies with a 10-gauge large-core needle. With this technique, Dr. Dingemans reported a 5.7% pneumothorax rate, which is comparable with the present NAVIGATE data.

However, Dr. Lau contested this figure.

“The pneumothorax rates [for CT-guided biopsy] in larger studies have always been about 20% to 40%,” Dr. Lau said. “You can’t compare large overall practice in a pragmatic study capturing everyone versus one single center. The truth is, most centers will have a 20% pneumothorax rate.”

Dr. Lau added that patient experiences are likely to be better with ENB than with CT-guided percutaneous biopsy.

“To me, patient comfort for biopsy is essential,” Dr. Lau said. “Having a needle stuck into your chest – it’s very uncomfortable. I’ve had patients who’ve come to me after they had a percutaneous biopsy and who for some reason needed a re-biopsy ... those patients almost always wish they had navigational bronchoscopy the first time because there would be no pain for them.”

When asked about capital cost concerns surrounding ENB, Dr. Lau suggested that the benefits outweigh the costs.

“The most expensive procedure is the one you have to do again,” Dr. Lau said. “So what we do is put a brush in, and a needle, and a biopsy, and hopefully, one of those three, if not all three, gets tissue, and we can do that with navigational bronchoscopy because there is one channel down. You can’t repeatedly stick needles into patients. By definition, you can’t throw three needle jabs, because you will get a 90% pneumothorax rate. And that’s the beauty of navigational bronchoscopy as well, because in the NAVIGATE series, a number of patients, about 10%, had multiple lesions biopsied.” Furthermore, Dr. Lau noted, percutaneous biopsy is “almost never” performed bilaterally, for fear of collapsing both lungs, but this is not the case with ENB. “We’ve done it on patients who have one lung,” he said.

Dr. Lau predicted that costs of ENB will come down with time. “Because of the number of products increasing, the price will drop,” he said.

Concluding the interview, Dr. Lau offered a summarizing message: “If you want to give the patient the safe option, you should do [ENB], and when it becomes more popular, the price will fall,” he said.

Medtronic funded the study. The investigators reported financial relationships with Olympus, Ambu, PulmonX, Boston Scientific, and others.

SOURCE: Lau et al. ELCC 2019. Abstract 68O.

ATLANTA – A combination of the epidermal growth factor receptor–targeted agent osimertinib (Tagrisso) with selumetinib, an investigational inhibitor of MEK1/2, was safe and associated with partial responses in about one-third of patients with non–small cell lung cancer in the phase 1b TATTON trial.

Neil Osterweil/MDedge News

In the dose-finding phase of the trial, the objective response rate was 42% for 36 patients treated with the combination either as a second- or third-line therapy, or following prior therapy for the epidermal growth factor receptor (EGFR) T70M mutation. In the dose-expansion phase of the trial, the ORR was 34% for 47 patients treated regardless of mutational status, reported Suresh S. Ramalingam, MD, from the Winship Cancer Institute at Emory University, Atlanta.

“We conclude that combining osimertinib with intermittent selumetinib is feasible with manageable toxicity and has already demonstrated promising preliminary anticancer activity,” he said at the annual meeting of the American Association for Cancer Research.

The EGFR T790M mutation is the most common cause of resistance in patients with non–small cell lung cancer (NSCLC) bearing EGFR mutations who are treated with first- or second-generation, EGFR-targeted tyrosine kinase inhibitors (TKI). Up-regulation of the RAS/RAF/MEK/ERK signaling pathway has also been implicated in NSCLC resistance to EGFR-targeted TKIs.

Selumetinib is an oral, potent, and selective inhibitor of MEK1/2 with a short half-life.

In the phase 3 SELECT-1 trial, selumetinib in combination with docetaxel did not significantly improve progression-free survival, compared with docetaxel alone as second-line therapy for patients with KRAS-mutated NSCLC.

Therapeutic rationale

Invited discussant Roy S. Herbst, MD, PhD, chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Conn., said that there is sound rationale for combining osimertinib and selumetinib in EGFR-mutant NSCLC.

Neil Osterweil/MDedge News

In addition to the up-regulation of the RAS/RAF/MEK/ERK pathway noted before, resistance to osimertinib has been shown in models of EGFR-mutant NSCLC to develop from aberrant ERK signaling mediation in part by MEK1 amplification, and MEK kinase inhibitors can restore sensitivity to osimertinib in resistant cells, he said.

As previously reported, the TATTON investigators are evaluating in separate cohorts combinations of osimertinib with savolitinib, an investigational MET inhibitor for safety and activity against MET-driven NSCLC in patients with disease that has progressed on one or more prior EGFR-targeted agents, or with selumetinib for patients with advanced EGFR-mutated NSCLC that had progressed on prior therapy, including EGFR-targeted TKIs, irrespective of T790M or KRAS status.

In part A, the dose-finding phase, patients received osimertinib 80 mg daily plus intermittent or continuous selumetinib. Asian patients received continuous selumetinib 25/50 mg twice daily, while other patients received continuous selumetinib 50/75 mg twice daily, or intermittent selumetinib 75 mg twice daily 4 days on, 3 days off or on days 1 and 4 of each week of treatment.

In part B, the dose-expansion phase, patients received osimertinib plus intermittent selumetinib 75 mg twice daily on the 4 days on/3 days off schedule.

An analysis of preliminary antitumor activity in part A showed an ORR in 15 of 36 patients (42%); all were partial responses (PR). In addition, 14 patients (39%) had stable disease at 6 weeks, 3 had progressive disease, 2 died, and 2 were not evaluable. The median duration of response was 16.6 months; 77% of the patients had responses lasting at least 12 months.

In part B, 16 of 47 patients enrolled (34%) had confirmed PR, and 16 had stable disease. Of the remaining patients, 11 had disease progression, 2 died, and 2 were not evaluable. The median duration of response in this group was 9.1 months, and 31% of patients remained in response at 12 months.

The most common treatment-related adverse events in the dose-finding phase were diarrhea in 75% of patients, nausea in 39% and fatigue in 33%. Dose-limiting toxicities occurred in six patients, all of whom had been treated with continuous selumetinib. These toxicities, all grade 3, include liver enzyme increases, diarrhea, asthenia, dizziness, nausea, and pneumonitis.

The most common treatment-related adverse events in the dose-expansion phase were diarrhea in 81%, stomatitis in 32%, and paronychia in 30% of patients.

Results ‘okay’

In his discussion, Dr. Herbst commented that the part A results “look okay, until you realize that the most of the activity is in those patients who are T790M-positive, who have not been exposed in this cohort to a third-generation T790M inhibitor.” Patients with the mutation who are treated with third-generation inhibitors would be expected to have a 78% response rate.

Part B included a few more patients with responses who were negative for T790M. “My thought here is that perhaps there is a biomarker” for selecting patients most likely to benefit from the combination, he said.

For MET-negative patients, the combination appears to have manageable toxicities with noncontinuous dosing of selumetinib, and there may be benefit to using it in the first-line setting in select patients, but that will require further trials and identification of suitable biomarkers, Dr. Herbst summarized.

TATTON was sponsored by AstraZeneca. Dr. Ramalingam reported receiving research support from the company and consulting/contracting with others. Dr. Herbst reported receiving research support from AstraZeneca, Eli Lilly, and Merck, and serving as a consultant for AstraZeneca, Eli Lilly, Genentech/Roche, Merck, NextCure, and Pfizer.

SOURCE: Ramalingam SS et al. AACR 2019, Abstract CT034.

ATLANTA – A combination of the epidermal growth factor receptor–targeted agent osimertinib (Tagrisso) with selumetinib, an investigational inhibitor of MEK1/2, was safe and associated with partial responses in about one-third of patients with non–small cell lung cancer in the phase 1b TATTON trial.

Neil Osterweil/MDedge News

In the dose-finding phase of the trial, the objective response rate was 42% for 36 patients treated with the combination either as a second- or third-line therapy, or following prior therapy for the epidermal growth factor receptor (EGFR) T70M mutation. In the dose-expansion phase of the trial, the ORR was 34% for 47 patients treated regardless of mutational status, reported Suresh S. Ramalingam, MD, from the Winship Cancer Institute at Emory University, Atlanta.

“We conclude that combining osimertinib with intermittent selumetinib is feasible with manageable toxicity and has already demonstrated promising preliminary anticancer activity,” he said at the annual meeting of the American Association for Cancer Research.

The EGFR T790M mutation is the most common cause of resistance in patients with non–small cell lung cancer (NSCLC) bearing EGFR mutations who are treated with first- or second-generation, EGFR-targeted tyrosine kinase inhibitors (TKI). Up-regulation of the RAS/RAF/MEK/ERK signaling pathway has also been implicated in NSCLC resistance to EGFR-targeted TKIs.

Selumetinib is an oral, potent, and selective inhibitor of MEK1/2 with a short half-life.

In the phase 3 SELECT-1 trial, selumetinib in combination with docetaxel did not significantly improve progression-free survival, compared with docetaxel alone as second-line therapy for patients with KRAS-mutated NSCLC.

Therapeutic rationale

Invited discussant Roy S. Herbst, MD, PhD, chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Conn., said that there is sound rationale for combining osimertinib and selumetinib in EGFR-mutant NSCLC.

Neil Osterweil/MDedge News

In addition to the up-regulation of the RAS/RAF/MEK/ERK pathway noted before, resistance to osimertinib has been shown in models of EGFR-mutant NSCLC to develop from aberrant ERK signaling mediation in part by MEK1 amplification, and MEK kinase inhibitors can restore sensitivity to osimertinib in resistant cells, he said.

As previously reported, the TATTON investigators are evaluating in separate cohorts combinations of osimertinib with savolitinib, an investigational MET inhibitor for safety and activity against MET-driven NSCLC in patients with disease that has progressed on one or more prior EGFR-targeted agents, or with selumetinib for patients with advanced EGFR-mutated NSCLC that had progressed on prior therapy, including EGFR-targeted TKIs, irrespective of T790M or KRAS status.

In part A, the dose-finding phase, patients received osimertinib 80 mg daily plus intermittent or continuous selumetinib. Asian patients received continuous selumetinib 25/50 mg twice daily, while other patients received continuous selumetinib 50/75 mg twice daily, or intermittent selumetinib 75 mg twice daily 4 days on, 3 days off or on days 1 and 4 of each week of treatment.

In part B, the dose-expansion phase, patients received osimertinib plus intermittent selumetinib 75 mg twice daily on the 4 days on/3 days off schedule.

An analysis of preliminary antitumor activity in part A showed an ORR in 15 of 36 patients (42%); all were partial responses (PR). In addition, 14 patients (39%) had stable disease at 6 weeks, 3 had progressive disease, 2 died, and 2 were not evaluable. The median duration of response was 16.6 months; 77% of the patients had responses lasting at least 12 months.

In part B, 16 of 47 patients enrolled (34%) had confirmed PR, and 16 had stable disease. Of the remaining patients, 11 had disease progression, 2 died, and 2 were not evaluable. The median duration of response in this group was 9.1 months, and 31% of patients remained in response at 12 months.

The most common treatment-related adverse events in the dose-finding phase were diarrhea in 75% of patients, nausea in 39% and fatigue in 33%. Dose-limiting toxicities occurred in six patients, all of whom had been treated with continuous selumetinib. These toxicities, all grade 3, include liver enzyme increases, diarrhea, asthenia, dizziness, nausea, and pneumonitis.

The most common treatment-related adverse events in the dose-expansion phase were diarrhea in 81%, stomatitis in 32%, and paronychia in 30% of patients.

Results ‘okay’

In his discussion, Dr. Herbst commented that the part A results “look okay, until you realize that the most of the activity is in those patients who are T790M-positive, who have not been exposed in this cohort to a third-generation T790M inhibitor.” Patients with the mutation who are treated with third-generation inhibitors would be expected to have a 78% response rate.

Part B included a few more patients with responses who were negative for T790M. “My thought here is that perhaps there is a biomarker” for selecting patients most likely to benefit from the combination, he said.

For MET-negative patients, the combination appears to have manageable toxicities with noncontinuous dosing of selumetinib, and there may be benefit to using it in the first-line setting in select patients, but that will require further trials and identification of suitable biomarkers, Dr. Herbst summarized.

TATTON was sponsored by AstraZeneca. Dr. Ramalingam reported receiving research support from the company and consulting/contracting with others. Dr. Herbst reported receiving research support from AstraZeneca, Eli Lilly, and Merck, and serving as a consultant for AstraZeneca, Eli Lilly, Genentech/Roche, Merck, NextCure, and Pfizer.

SOURCE: Ramalingam SS et al. AACR 2019, Abstract CT034.

ATLANTA – A combination of the epidermal growth factor receptor–targeted agent osimertinib (Tagrisso) with selumetinib, an investigational inhibitor of MEK1/2, was safe and associated with partial responses in about one-third of patients with non–small cell lung cancer in the phase 1b TATTON trial.

Neil Osterweil/MDedge News

In the dose-finding phase of the trial, the objective response rate was 42% for 36 patients treated with the combination either as a second- or third-line therapy, or following prior therapy for the epidermal growth factor receptor (EGFR) T70M mutation. In the dose-expansion phase of the trial, the ORR was 34% for 47 patients treated regardless of mutational status, reported Suresh S. Ramalingam, MD, from the Winship Cancer Institute at Emory University, Atlanta.

“We conclude that combining osimertinib with intermittent selumetinib is feasible with manageable toxicity and has already demonstrated promising preliminary anticancer activity,” he said at the annual meeting of the American Association for Cancer Research.

The EGFR T790M mutation is the most common cause of resistance in patients with non–small cell lung cancer (NSCLC) bearing EGFR mutations who are treated with first- or second-generation, EGFR-targeted tyrosine kinase inhibitors (TKI). Up-regulation of the RAS/RAF/MEK/ERK signaling pathway has also been implicated in NSCLC resistance to EGFR-targeted TKIs.

Selumetinib is an oral, potent, and selective inhibitor of MEK1/2 with a short half-life.

In the phase 3 SELECT-1 trial, selumetinib in combination with docetaxel did not significantly improve progression-free survival, compared with docetaxel alone as second-line therapy for patients with KRAS-mutated NSCLC.

Therapeutic rationale

Invited discussant Roy S. Herbst, MD, PhD, chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Conn., said that there is sound rationale for combining osimertinib and selumetinib in EGFR-mutant NSCLC.

Neil Osterweil/MDedge News

In addition to the up-regulation of the RAS/RAF/MEK/ERK pathway noted before, resistance to osimertinib has been shown in models of EGFR-mutant NSCLC to develop from aberrant ERK signaling mediation in part by MEK1 amplification, and MEK kinase inhibitors can restore sensitivity to osimertinib in resistant cells, he said.

As previously reported, the TATTON investigators are evaluating in separate cohorts combinations of osimertinib with savolitinib, an investigational MET inhibitor for safety and activity against MET-driven NSCLC in patients with disease that has progressed on one or more prior EGFR-targeted agents, or with selumetinib for patients with advanced EGFR-mutated NSCLC that had progressed on prior therapy, including EGFR-targeted TKIs, irrespective of T790M or KRAS status.

In part A, the dose-finding phase, patients received osimertinib 80 mg daily plus intermittent or continuous selumetinib. Asian patients received continuous selumetinib 25/50 mg twice daily, while other patients received continuous selumetinib 50/75 mg twice daily, or intermittent selumetinib 75 mg twice daily 4 days on, 3 days off or on days 1 and 4 of each week of treatment.

In part B, the dose-expansion phase, patients received osimertinib plus intermittent selumetinib 75 mg twice daily on the 4 days on/3 days off schedule.

An analysis of preliminary antitumor activity in part A showed an ORR in 15 of 36 patients (42%); all were partial responses (PR). In addition, 14 patients (39%) had stable disease at 6 weeks, 3 had progressive disease, 2 died, and 2 were not evaluable. The median duration of response was 16.6 months; 77% of the patients had responses lasting at least 12 months.

In part B, 16 of 47 patients enrolled (34%) had confirmed PR, and 16 had stable disease. Of the remaining patients, 11 had disease progression, 2 died, and 2 were not evaluable. The median duration of response in this group was 9.1 months, and 31% of patients remained in response at 12 months.

The most common treatment-related adverse events in the dose-finding phase were diarrhea in 75% of patients, nausea in 39% and fatigue in 33%. Dose-limiting toxicities occurred in six patients, all of whom had been treated with continuous selumetinib. These toxicities, all grade 3, include liver enzyme increases, diarrhea, asthenia, dizziness, nausea, and pneumonitis.

The most common treatment-related adverse events in the dose-expansion phase were diarrhea in 81%, stomatitis in 32%, and paronychia in 30% of patients.

Results ‘okay’

In his discussion, Dr. Herbst commented that the part A results “look okay, until you realize that the most of the activity is in those patients who are T790M-positive, who have not been exposed in this cohort to a third-generation T790M inhibitor.” Patients with the mutation who are treated with third-generation inhibitors would be expected to have a 78% response rate.

Part B included a few more patients with responses who were negative for T790M. “My thought here is that perhaps there is a biomarker” for selecting patients most likely to benefit from the combination, he said.

For MET-negative patients, the combination appears to have manageable toxicities with noncontinuous dosing of selumetinib, and there may be benefit to using it in the first-line setting in select patients, but that will require further trials and identification of suitable biomarkers, Dr. Herbst summarized.

TATTON was sponsored by AstraZeneca. Dr. Ramalingam reported receiving research support from the company and consulting/contracting with others. Dr. Herbst reported receiving research support from AstraZeneca, Eli Lilly, and Merck, and serving as a consultant for AstraZeneca, Eli Lilly, Genentech/Roche, Merck, NextCure, and Pfizer.

SOURCE: Ramalingam SS et al. AACR 2019, Abstract CT034.

For patients with centrally located lung cancers in a multicenter phase 1/2 trial, a specific five-fraction radiotherapy schedule was well tolerated and linked to fairly low rates of treatment-related toxicity, investigators say.

The 12-Gy/fraction schedule of stereotactic body radiotherapy (SBRT) had a 7.2% rate of dose-limiting toxicities and a high tumor-control rate in the NRG Oncology/RTOG 0813 trial, which enrolled 120 patients with medically inoperable stage T1/2 N0M0 non–small cell lung cancers at 43 centers in the United States and Canada.

This is an important study that has implications for clinical practice, according to the investigators, led by Andrea Bezjak, MD, of Princess Margaret Cancer Centre in Toronto.

“The ability to treat patients with centrally located node-negative tumors in multiple institutions across the United States and Canada while maintaining plan qualities and achieving good patient outcomes and relatively modest rates of toxicity is an important achievement,” Dr. Bezjak and coinvestigators said in the Journal of Clinical Oncology.

These patients are frequently at increased risk from surgery, because of advanced age and the comorbidities that come with it, they added.

The 12-Gy/fraction dose level was the highest of nine dose levels included in the study protocol. Doses were delivered in five fractions over the course of 1.5-2 weeks. Investigators sought to determine the maximum tolerated dose of SRBT, defined as the level at which the probability of dose-limiting toxicities (grade 3 or greater) within the first year was as close to 20% as possible, without going over.

Thus, the 7.2% rate of dose-limiting toxicities at this highest-allowed dose level was “well below” that protocol-specified threshold, investigators said, commenting on results of the study.

The rate of local control at 2 years was 89.4% for the 12-Gy/fraction dose level. The 2-year overall survival was 70%, which compared favorably to what has been seen previously with use of SBRT in similar patients with peripheral tumors, according to Dr. Bezjak and colleagues.

Most deaths in the study were attributable to causes other than lung cancer, according to investigators, who noted that all accrued patients were deemed medically inoperable by an experienced thoracic surgeon.

“Thus, this study provides robust data about the safety and efficacy of a five-fraction SBRT schedule that is well tolerated and associated with relatively low rates of serious treatment-related toxicity,” they concluded.

Dr. Bezjak reported disclosures related to AstraZeneca and Abbvie. Coauthors provided disclosures related to Varian Medical Systems, Elekta, Accuray, Seattle Genetics, Celgene, Exelixis, Gilead Sciences, Illumina, Ions Pharmaceuticals, and EMD Serono, among others.

SOURCE: Bezjak A et al. J Clin Oncol. 2019 Apr 3. doi: 10.1200/JCO.18.00622.

For patients with centrally located lung cancers in a multicenter phase 1/2 trial, a specific five-fraction radiotherapy schedule was well tolerated and linked to fairly low rates of treatment-related toxicity, investigators say.

The 12-Gy/fraction schedule of stereotactic body radiotherapy (SBRT) had a 7.2% rate of dose-limiting toxicities and a high tumor-control rate in the NRG Oncology/RTOG 0813 trial, which enrolled 120 patients with medically inoperable stage T1/2 N0M0 non–small cell lung cancers at 43 centers in the United States and Canada.

This is an important study that has implications for clinical practice, according to the investigators, led by Andrea Bezjak, MD, of Princess Margaret Cancer Centre in Toronto.

“The ability to treat patients with centrally located node-negative tumors in multiple institutions across the United States and Canada while maintaining plan qualities and achieving good patient outcomes and relatively modest rates of toxicity is an important achievement,” Dr. Bezjak and coinvestigators said in the Journal of Clinical Oncology.

These patients are frequently at increased risk from surgery, because of advanced age and the comorbidities that come with it, they added.

The 12-Gy/fraction dose level was the highest of nine dose levels included in the study protocol. Doses were delivered in five fractions over the course of 1.5-2 weeks. Investigators sought to determine the maximum tolerated dose of SRBT, defined as the level at which the probability of dose-limiting toxicities (grade 3 or greater) within the first year was as close to 20% as possible, without going over.

Thus, the 7.2% rate of dose-limiting toxicities at this highest-allowed dose level was “well below” that protocol-specified threshold, investigators said, commenting on results of the study.

The rate of local control at 2 years was 89.4% for the 12-Gy/fraction dose level. The 2-year overall survival was 70%, which compared favorably to what has been seen previously with use of SBRT in similar patients with peripheral tumors, according to Dr. Bezjak and colleagues.

Most deaths in the study were attributable to causes other than lung cancer, according to investigators, who noted that all accrued patients were deemed medically inoperable by an experienced thoracic surgeon.

“Thus, this study provides robust data about the safety and efficacy of a five-fraction SBRT schedule that is well tolerated and associated with relatively low rates of serious treatment-related toxicity,” they concluded.

Dr. Bezjak reported disclosures related to AstraZeneca and Abbvie. Coauthors provided disclosures related to Varian Medical Systems, Elekta, Accuray, Seattle Genetics, Celgene, Exelixis, Gilead Sciences, Illumina, Ions Pharmaceuticals, and EMD Serono, among others.

SOURCE: Bezjak A et al. J Clin Oncol. 2019 Apr 3. doi: 10.1200/JCO.18.00622.

For patients with centrally located lung cancers in a multicenter phase 1/2 trial, a specific five-fraction radiotherapy schedule was well tolerated and linked to fairly low rates of treatment-related toxicity, investigators say.

The 12-Gy/fraction schedule of stereotactic body radiotherapy (SBRT) had a 7.2% rate of dose-limiting toxicities and a high tumor-control rate in the NRG Oncology/RTOG 0813 trial, which enrolled 120 patients with medically inoperable stage T1/2 N0M0 non–small cell lung cancers at 43 centers in the United States and Canada.

This is an important study that has implications for clinical practice, according to the investigators, led by Andrea Bezjak, MD, of Princess Margaret Cancer Centre in Toronto.

“The ability to treat patients with centrally located node-negative tumors in multiple institutions across the United States and Canada while maintaining plan qualities and achieving good patient outcomes and relatively modest rates of toxicity is an important achievement,” Dr. Bezjak and coinvestigators said in the Journal of Clinical Oncology.

These patients are frequently at increased risk from surgery, because of advanced age and the comorbidities that come with it, they added.

The 12-Gy/fraction dose level was the highest of nine dose levels included in the study protocol. Doses were delivered in five fractions over the course of 1.5-2 weeks. Investigators sought to determine the maximum tolerated dose of SRBT, defined as the level at which the probability of dose-limiting toxicities (grade 3 or greater) within the first year was as close to 20% as possible, without going over.

Thus, the 7.2% rate of dose-limiting toxicities at this highest-allowed dose level was “well below” that protocol-specified threshold, investigators said, commenting on results of the study.

The rate of local control at 2 years was 89.4% for the 12-Gy/fraction dose level. The 2-year overall survival was 70%, which compared favorably to what has been seen previously with use of SBRT in similar patients with peripheral tumors, according to Dr. Bezjak and colleagues.

Most deaths in the study were attributable to causes other than lung cancer, according to investigators, who noted that all accrued patients were deemed medically inoperable by an experienced thoracic surgeon.

“Thus, this study provides robust data about the safety and efficacy of a five-fraction SBRT schedule that is well tolerated and associated with relatively low rates of serious treatment-related toxicity,” they concluded.

Dr. Bezjak reported disclosures related to AstraZeneca and Abbvie. Coauthors provided disclosures related to Varian Medical Systems, Elekta, Accuray, Seattle Genetics, Celgene, Exelixis, Gilead Sciences, Illumina, Ions Pharmaceuticals, and EMD Serono, among others.

SOURCE: Bezjak A et al. J Clin Oncol. 2019 Apr 3. doi: 10.1200/JCO.18.00622.

ATLANTA – About 10%-25% of patients with epithelial growth factor receptor–(EGFR) mutant non–small cell lung cancer (NSCLC) have tumors with either MET amplification or another MET-based mechanism that leads to drug resistance.

In the TATTON trial, investigators are evaluating a combination of the EGFR-targeted tyrosine kinase inhibitor (TKI) osimertinib (Tagrisso) with savolitinib, an investigational MET inhibitor, for safety and activity against MET-driven NSCLC in patients with disease that has progressed on one or more prior EGFR-targeted agents.

In a video interview at the annual meeting of the American Association for Cancer Research, Lecia Sequist, MD, from the Massachusetts General Hospital Cancer Center in Boston, discusses early results with the osimertinib/savolitinib combination in patients with disease progression after a first and/or second-generation EGFR TKI, or after a third-generation agent.

Dr. Sequist said results of TATTON suggest that it may be possible to overcome MET-driven drug-resistance mechanisms.

The TATTON trial is sponsored by AstraZeneca. Dr. Sequist reported serving as an advisory board member and receiving research support and honoraria from the company.

ATLANTA – About 10%-25% of patients with epithelial growth factor receptor–(EGFR) mutant non–small cell lung cancer (NSCLC) have tumors with either MET amplification or another MET-based mechanism that leads to drug resistance.

In the TATTON trial, investigators are evaluating a combination of the EGFR-targeted tyrosine kinase inhibitor (TKI) osimertinib (Tagrisso) with savolitinib, an investigational MET inhibitor, for safety and activity against MET-driven NSCLC in patients with disease that has progressed on one or more prior EGFR-targeted agents.

In a video interview at the annual meeting of the American Association for Cancer Research, Lecia Sequist, MD, from the Massachusetts General Hospital Cancer Center in Boston, discusses early results with the osimertinib/savolitinib combination in patients with disease progression after a first and/or second-generation EGFR TKI, or after a third-generation agent.

Dr. Sequist said results of TATTON suggest that it may be possible to overcome MET-driven drug-resistance mechanisms.

The TATTON trial is sponsored by AstraZeneca. Dr. Sequist reported serving as an advisory board member and receiving research support and honoraria from the company.

ATLANTA – About 10%-25% of patients with epithelial growth factor receptor–(EGFR) mutant non–small cell lung cancer (NSCLC) have tumors with either MET amplification or another MET-based mechanism that leads to drug resistance.

In the TATTON trial, investigators are evaluating a combination of the EGFR-targeted tyrosine kinase inhibitor (TKI) osimertinib (Tagrisso) with savolitinib, an investigational MET inhibitor, for safety and activity against MET-driven NSCLC in patients with disease that has progressed on one or more prior EGFR-targeted agents.

In a video interview at the annual meeting of the American Association for Cancer Research, Lecia Sequist, MD, from the Massachusetts General Hospital Cancer Center in Boston, discusses early results with the osimertinib/savolitinib combination in patients with disease progression after a first and/or second-generation EGFR TKI, or after a third-generation agent.

Dr. Sequist said results of TATTON suggest that it may be possible to overcome MET-driven drug-resistance mechanisms.

The TATTON trial is sponsored by AstraZeneca. Dr. Sequist reported serving as an advisory board member and receiving research support and honoraria from the company.

Taking a deep dive into plasma cell-free DNA in patients with advanced non–small cell lung cancer may reveal targetable mutations and cancer resistance mechanisms in tumors, even when tissue biopsy samples are not adequate for genotyping, investigators say,

Noninvasive tumor genotyping of plasma cell-free DNA (cfDNA) with ultra-deep next generation sequencing (NGS) in plasma samples from 127 patients identified known oncogenic drivers with a sensitivity of 75% and ruled out the presence of driver mutations with a specificity of 100% in patients with tissue samples indicating no mutations, reported Bob T. Li, MD, MPH, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, and his colleagues.

“These results reveal the potential utility of NGS assays that use cfDNA as input for detecting actionable driver alterations and both de novo and emergent resistance mechanisms in the clinical setting,” they wrote. The report is in Annals of Oncology.

Although the researchers did not directly assess clinical utility, the results suggest that NGS-based analysis of cfDNA may help guide treatment selection, they added.

Ultra-deep NGS is a kind of obsessive-compulsive form of sequencing in which the same genomic region is read repeatedly – in this study, 50,000 times over – with filtering of somatic mutations attributable to clonal hematopoiesis. The technique allows for detection of rare genetic alterations that can be missed by other methods.

“More recent studies employing plasma cfDNA NGS have shown promise in detecting a broader variety of genetic alterations with similar sensitivity to that of digital PCR, with potential to change clinical practice,” Dr. Li and his colleagues wrote.

They conducted a systematic study of a novel cfDNA assay in patients whose cancers had oncogenic driver mutations, those who were driver negative on tissue-based NGS, and those whose tumors had unknown mutational status.

A total of 127 patients from three centers (MSKCC, the Dana-Farber Cancer Center in Boston, and the University of Texas MD Anderson Cancer Center in Houston) were available for assessment.

Ultra-deep NGS was performed on cfDNA and matched white blood cells using a hybrid capture panel covering 37 lung cancer-related genes sequenced to 50,000 times raw-target coverage filtering somatic mutations attributable to clonal hematopoiesis.

Plasma NGS was able to detect driver mutations with variant allele frequencies ranging from as low as 0.14% to as high as 52%.

In 21 of 22 patients, plasma digital drop polymerase chain reaction (ddPCR) results for EGFR or KRAS mutations were nearly identical to those of NGS, with high concordance for variant allele frequencies (r = .98).

In analyses blinded to tissue genotyping results in 91 patients, plasma NGS detected de novo known oncogenic driver alterations in 68 samples, for a sensitivity of 75%, and in 19 of 19 patients who were driver negative by tissue sequencing, plasma NGS also showed an absence of mutations, for a specificity of 100%.

Furthermore, plasma NGS identified four KRAS mutations in plasma from 17 patients for whom tissues samples were not adequate for genotyping, and the plasma-based technique was able to identify potential resistance mutations in samples from 23 patients with EGFR mutations whose tumors had required resistance to targeted therapy.

“The sensitivity of detection by NGS was comparable to that of established ddPCR methods. Its high concordance with tissue genotyping and the detection of drivers in settings where tissue biopsy had failed or was not feasible lend credence to the potential clinical use of plasma cfDNA NGS and the development of cfDNA-guided intervention studies,” the investigators wrote.

The study was supported by Illumina. Authors from MSKCC and MD Anderson were supported by National Institutes of Health grants. Dr. Li received consulting/advisory board fees from Genentech, Thermo-Fisher Scientific, and Guardant Health outside of the submitted work. Multiple coauthors reported similar relationships, and eight coauthors were current or former employees of Illumina.

SOURCE: Source: Li BT et al. Ann Oncol. doi: 10.1093/annonc/mdz046.

Taking a deep dive into plasma cell-free DNA in patients with advanced non–small cell lung cancer may reveal targetable mutations and cancer resistance mechanisms in tumors, even when tissue biopsy samples are not adequate for genotyping, investigators say,

Noninvasive tumor genotyping of plasma cell-free DNA (cfDNA) with ultra-deep next generation sequencing (NGS) in plasma samples from 127 patients identified known oncogenic drivers with a sensitivity of 75% and ruled out the presence of driver mutations with a specificity of 100% in patients with tissue samples indicating no mutations, reported Bob T. Li, MD, MPH, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, and his colleagues.

“These results reveal the potential utility of NGS assays that use cfDNA as input for detecting actionable driver alterations and both de novo and emergent resistance mechanisms in the clinical setting,” they wrote. The report is in Annals of Oncology.

Although the researchers did not directly assess clinical utility, the results suggest that NGS-based analysis of cfDNA may help guide treatment selection, they added.

Ultra-deep NGS is a kind of obsessive-compulsive form of sequencing in which the same genomic region is read repeatedly – in this study, 50,000 times over – with filtering of somatic mutations attributable to clonal hematopoiesis. The technique allows for detection of rare genetic alterations that can be missed by other methods.

“More recent studies employing plasma cfDNA NGS have shown promise in detecting a broader variety of genetic alterations with similar sensitivity to that of digital PCR, with potential to change clinical practice,” Dr. Li and his colleagues wrote.

They conducted a systematic study of a novel cfDNA assay in patients whose cancers had oncogenic driver mutations, those who were driver negative on tissue-based NGS, and those whose tumors had unknown mutational status.

A total of 127 patients from three centers (MSKCC, the Dana-Farber Cancer Center in Boston, and the University of Texas MD Anderson Cancer Center in Houston) were available for assessment.

Ultra-deep NGS was performed on cfDNA and matched white blood cells using a hybrid capture panel covering 37 lung cancer-related genes sequenced to 50,000 times raw-target coverage filtering somatic mutations attributable to clonal hematopoiesis.

Plasma NGS was able to detect driver mutations with variant allele frequencies ranging from as low as 0.14% to as high as 52%.

In 21 of 22 patients, plasma digital drop polymerase chain reaction (ddPCR) results for EGFR or KRAS mutations were nearly identical to those of NGS, with high concordance for variant allele frequencies (r = .98).

In analyses blinded to tissue genotyping results in 91 patients, plasma NGS detected de novo known oncogenic driver alterations in 68 samples, for a sensitivity of 75%, and in 19 of 19 patients who were driver negative by tissue sequencing, plasma NGS also showed an absence of mutations, for a specificity of 100%.

Furthermore, plasma NGS identified four KRAS mutations in plasma from 17 patients for whom tissues samples were not adequate for genotyping, and the plasma-based technique was able to identify potential resistance mutations in samples from 23 patients with EGFR mutations whose tumors had required resistance to targeted therapy.

“The sensitivity of detection by NGS was comparable to that of established ddPCR methods. Its high concordance with tissue genotyping and the detection of drivers in settings where tissue biopsy had failed or was not feasible lend credence to the potential clinical use of plasma cfDNA NGS and the development of cfDNA-guided intervention studies,” the investigators wrote.

The study was supported by Illumina. Authors from MSKCC and MD Anderson were supported by National Institutes of Health grants. Dr. Li received consulting/advisory board fees from Genentech, Thermo-Fisher Scientific, and Guardant Health outside of the submitted work. Multiple coauthors reported similar relationships, and eight coauthors were current or former employees of Illumina.

SOURCE: Source: Li BT et al. Ann Oncol. doi: 10.1093/annonc/mdz046.

Taking a deep dive into plasma cell-free DNA in patients with advanced non–small cell lung cancer may reveal targetable mutations and cancer resistance mechanisms in tumors, even when tissue biopsy samples are not adequate for genotyping, investigators say,

Noninvasive tumor genotyping of plasma cell-free DNA (cfDNA) with ultra-deep next generation sequencing (NGS) in plasma samples from 127 patients identified known oncogenic drivers with a sensitivity of 75% and ruled out the presence of driver mutations with a specificity of 100% in patients with tissue samples indicating no mutations, reported Bob T. Li, MD, MPH, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, and his colleagues.

“These results reveal the potential utility of NGS assays that use cfDNA as input for detecting actionable driver alterations and both de novo and emergent resistance mechanisms in the clinical setting,” they wrote. The report is in Annals of Oncology.

Although the researchers did not directly assess clinical utility, the results suggest that NGS-based analysis of cfDNA may help guide treatment selection, they added.

Ultra-deep NGS is a kind of obsessive-compulsive form of sequencing in which the same genomic region is read repeatedly – in this study, 50,000 times over – with filtering of somatic mutations attributable to clonal hematopoiesis. The technique allows for detection of rare genetic alterations that can be missed by other methods.

“More recent studies employing plasma cfDNA NGS have shown promise in detecting a broader variety of genetic alterations with similar sensitivity to that of digital PCR, with potential to change clinical practice,” Dr. Li and his colleagues wrote.

They conducted a systematic study of a novel cfDNA assay in patients whose cancers had oncogenic driver mutations, those who were driver negative on tissue-based NGS, and those whose tumors had unknown mutational status.

A total of 127 patients from three centers (MSKCC, the Dana-Farber Cancer Center in Boston, and the University of Texas MD Anderson Cancer Center in Houston) were available for assessment.

Ultra-deep NGS was performed on cfDNA and matched white blood cells using a hybrid capture panel covering 37 lung cancer-related genes sequenced to 50,000 times raw-target coverage filtering somatic mutations attributable to clonal hematopoiesis.

Plasma NGS was able to detect driver mutations with variant allele frequencies ranging from as low as 0.14% to as high as 52%.

In 21 of 22 patients, plasma digital drop polymerase chain reaction (ddPCR) results for EGFR or KRAS mutations were nearly identical to those of NGS, with high concordance for variant allele frequencies (r = .98).

In analyses blinded to tissue genotyping results in 91 patients, plasma NGS detected de novo known oncogenic driver alterations in 68 samples, for a sensitivity of 75%, and in 19 of 19 patients who were driver negative by tissue sequencing, plasma NGS also showed an absence of mutations, for a specificity of 100%.

Furthermore, plasma NGS identified four KRAS mutations in plasma from 17 patients for whom tissues samples were not adequate for genotyping, and the plasma-based technique was able to identify potential resistance mutations in samples from 23 patients with EGFR mutations whose tumors had required resistance to targeted therapy.

“The sensitivity of detection by NGS was comparable to that of established ddPCR methods. Its high concordance with tissue genotyping and the detection of drivers in settings where tissue biopsy had failed or was not feasible lend credence to the potential clinical use of plasma cfDNA NGS and the development of cfDNA-guided intervention studies,” the investigators wrote.

The study was supported by Illumina. Authors from MSKCC and MD Anderson were supported by National Institutes of Health grants. Dr. Li received consulting/advisory board fees from Genentech, Thermo-Fisher Scientific, and Guardant Health outside of the submitted work. Multiple coauthors reported similar relationships, and eight coauthors were current or former employees of Illumina.

SOURCE: Source: Li BT et al. Ann Oncol. doi: 10.1093/annonc/mdz046.

The Food and Drug Administration has approved atezolizumab (Tecentriq), in combination with carboplatin and etoposide, for the first-line treatment of adults with extensive-stage small cell lung cancer (ES-SCLC).

Approval was based on results from the phase 3 IMpower133 study, in which 403 treatment-naive patients with ES-SCLC received atezolizumab at 1,200 mg with carboplatin at 5 mg/mL per minute on day 1 and etoposide 100 mg/m² on days 1, 2, and 3 of a 21-day cycle for four cycles, followed by atezolizumab at 1,200 mg once every 3 weeks until disease progression or unacceptable toxicity; or received placebo with the same dosage of carboplatin and etoposide for a similar duration.

Overall survival was significantly better in patients who received atezolizumab, compared with placebo (12.3 vs. 10.3 months; hazard ratio, 0.70; 95% confidence interval, 0.54-0.91; P = .0069), as was progression-free survival (5.2 vs. 4.3 months; HR, 0.77; 95% CI, 0.62-0.96; P = .017).

The most common adverse events associated with atezolizumab in the study were fatigue/asthenia, nausea, alopecia, constipation, and decreased appetite.

According to the FDA, the recommended dose is 1,200 mg IV over 60 minutes every 3 weeks. When administered on the same day as chemotherapy, atezolizumab should be given first. If the first infusion is tolerated, all subsequent infusions can be delivered over 30 minutes.

Find the full press release on the FDA website.

lfranki@mdedge.com

The Food and Drug Administration has approved atezolizumab (Tecentriq), in combination with carboplatin and etoposide, for the first-line treatment of adults with extensive-stage small cell lung cancer (ES-SCLC).

Approval was based on results from the phase 3 IMpower133 study, in which 403 treatment-naive patients with ES-SCLC received atezolizumab at 1,200 mg with carboplatin at 5 mg/mL per minute on day 1 and etoposide 100 mg/m² on days 1, 2, and 3 of a 21-day cycle for four cycles, followed by atezolizumab at 1,200 mg once every 3 weeks until disease progression or unacceptable toxicity; or received placebo with the same dosage of carboplatin and etoposide for a similar duration.

Overall survival was significantly better in patients who received atezolizumab, compared with placebo (12.3 vs. 10.3 months; hazard ratio, 0.70; 95% confidence interval, 0.54-0.91; P = .0069), as was progression-free survival (5.2 vs. 4.3 months; HR, 0.77; 95% CI, 0.62-0.96; P = .017).

The most common adverse events associated with atezolizumab in the study were fatigue/asthenia, nausea, alopecia, constipation, and decreased appetite.

According to the FDA, the recommended dose is 1,200 mg IV over 60 minutes every 3 weeks. When administered on the same day as chemotherapy, atezolizumab should be given first. If the first infusion is tolerated, all subsequent infusions can be delivered over 30 minutes.

Find the full press release on the FDA website.

lfranki@mdedge.com

The Food and Drug Administration has approved atezolizumab (Tecentriq), in combination with carboplatin and etoposide, for the first-line treatment of adults with extensive-stage small cell lung cancer (ES-SCLC).

Approval was based on results from the phase 3 IMpower133 study, in which 403 treatment-naive patients with ES-SCLC received atezolizumab at 1,200 mg with carboplatin at 5 mg/mL per minute on day 1 and etoposide 100 mg/m² on days 1, 2, and 3 of a 21-day cycle for four cycles, followed by atezolizumab at 1,200 mg once every 3 weeks until disease progression or unacceptable toxicity; or received placebo with the same dosage of carboplatin and etoposide for a similar duration.

Overall survival was significantly better in patients who received atezolizumab, compared with placebo (12.3 vs. 10.3 months; hazard ratio, 0.70; 95% confidence interval, 0.54-0.91; P = .0069), as was progression-free survival (5.2 vs. 4.3 months; HR, 0.77; 95% CI, 0.62-0.96; P = .017).

The most common adverse events associated with atezolizumab in the study were fatigue/asthenia, nausea, alopecia, constipation, and decreased appetite.

According to the FDA, the recommended dose is 1,200 mg IV over 60 minutes every 3 weeks. When administered on the same day as chemotherapy, atezolizumab should be given first. If the first infusion is tolerated, all subsequent infusions can be delivered over 30 minutes.

Find the full press release on the FDA website.

lfranki@mdedge.com

SAN FRANCISCO – Antibiotic exposure in the month before cancer immunotherapy starts may hamper the efficacy of immune checkpoint inhibitors, investigators caution.

Neil Osterweil/MDedge News

A prospective study of 196 patients treated with immune checkpoint inhibitors for various cancers showed that the 29 patients who received antibiotics within 30 days of starting immunotherapy had significantly worse overall survival than patients without antibiotic exposure; this effect was seen across cancer types, reported David James Pinato, MD, PhD, from Imperial College London.

In contrast, concurrent antibiotic and checkpoint inhibitor use was not significantly associated with overall survival differences, he said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

“I think these data are quite interesting in showing an independent detrimental effect, both on response and survival, in unselected patients treated with immune checkpoint inhibitors in routine clinical practice,” Dr. Pinato said.

The data also suggest “the timing of antibiotic exposure is crucial,” he added. Antibiotic treatment concurrent with immunotherapy did not appear to affect prognosis. Alternatively, prior antibiotic therapy appeared to have “a sort of a priming effect towards the immune system.”

Broad-spectrum antibiotics can affect the diversity of the gut microbiome, which influences mucosal immunity, dendritic cell function, and antigen presentation. Alternatively, enrichment of the microbiome with several bacterial species can enhance the potency of checkpoint inhibitors by facilitating the process of tumor rejection, Dr. Pinato explained.

To see whether antibiotic disruption, or “dysbiosis” of the gut microbiome, could hinder responsiveness to checkpoint inhibitors regardless of the tumor site and whether there were time-dependent effects of antibiotic exposure on response to checkpoint inhibitors, the investigators conducted a prospective, observational study in 196 patients treated with checkpoint inhibitors for non–small cell lung cancer (NSCLC), melanoma, renal cell carcinoma, head and neck cancer, transitional cell carcinoma of the bladder, and other cancers.

The researchers defined prior antibiotic exposure as more than 30 days before the start of checkpoint inhibitor therapy and concurrent exposure as antibiotics begun on the first day of the first cycle of checkpoint inhibitor dosing.

Of the 196 patients, 29 had previously received antibiotics, and 68 received them concurrently. The most frequently prescribed antibiotics were beta-lactam agents given in a single, short course. Other classes of drugs, used in eight or fewer patients each, included quinolones, macrolides, sulfonamides, tetracyclines, aminoglycosides, and nitroimidazole.

Median overall survival for the entire cohort, one of two primary outcomes, was 2 months for patients who had received prior antibiotics and 26 months for patients with no prior exposure. This difference was similar for patients with NSCLC (2.5 vs. 26 months), melanoma (3.9 vs. 14 months), and other cancers combined (1.1 vs. 11.0 months; log-rank P less than .01 for all comparisons).

In multivariate analysis, only response to checkpoints inhibitors (complete vs. partial response, stable disease, or progression) and prior antibiotic exposure were significantly associated with survival. The hazard ratio for survival for patients who had not previously received antibiotics was 3.5 (P less than .001).

In contrast, concurrent antibiotic and checkpoint inhibitor use did not have a significant effect on survival.

An analysis of radiologic responses also showed that patients with prior antibiotic exposure had a significantly higher probability of primary disease progression than those without (81% vs. 44%; P less than .001). There were no associations, however, between specific classes of antibiotics or corticosteroid use.

The findings indicate that “certainly, mechanistic studies are required here, not just to investigate the prognostic role of antibiotic-mediated dysbiosis, but perhaps transform this into an actual driver of antitumor immunity,” Dr. Pinato concluded.

The study was internally supported. Dr. Pinato reported receiving grant funding from Merck and Bristol-Myers Squibb unrelated to the study, as well as honoraria from ViiV Healthcare.

SOURCE: Pinato DJ et al. ASCO-SITC, Abstract 147.

SAN FRANCISCO – Antibiotic exposure in the month before cancer immunotherapy starts may hamper the efficacy of immune checkpoint inhibitors, investigators caution.

Neil Osterweil/MDedge News

A prospective study of 196 patients treated with immune checkpoint inhibitors for various cancers showed that the 29 patients who received antibiotics within 30 days of starting immunotherapy had significantly worse overall survival than patients without antibiotic exposure; this effect was seen across cancer types, reported David James Pinato, MD, PhD, from Imperial College London.

In contrast, concurrent antibiotic and checkpoint inhibitor use was not significantly associated with overall survival differences, he said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

“I think these data are quite interesting in showing an independent detrimental effect, both on response and survival, in unselected patients treated with immune checkpoint inhibitors in routine clinical practice,” Dr. Pinato said.

The data also suggest “the timing of antibiotic exposure is crucial,” he added. Antibiotic treatment concurrent with immunotherapy did not appear to affect prognosis. Alternatively, prior antibiotic therapy appeared to have “a sort of a priming effect towards the immune system.”

Broad-spectrum antibiotics can affect the diversity of the gut microbiome, which influences mucosal immunity, dendritic cell function, and antigen presentation. Alternatively, enrichment of the microbiome with several bacterial species can enhance the potency of checkpoint inhibitors by facilitating the process of tumor rejection, Dr. Pinato explained.

To see whether antibiotic disruption, or “dysbiosis” of the gut microbiome, could hinder responsiveness to checkpoint inhibitors regardless of the tumor site and whether there were time-dependent effects of antibiotic exposure on response to checkpoint inhibitors, the investigators conducted a prospective, observational study in 196 patients treated with checkpoint inhibitors for non–small cell lung cancer (NSCLC), melanoma, renal cell carcinoma, head and neck cancer, transitional cell carcinoma of the bladder, and other cancers.

The researchers defined prior antibiotic exposure as more than 30 days before the start of checkpoint inhibitor therapy and concurrent exposure as antibiotics begun on the first day of the first cycle of checkpoint inhibitor dosing.

Of the 196 patients, 29 had previously received antibiotics, and 68 received them concurrently. The most frequently prescribed antibiotics were beta-lactam agents given in a single, short course. Other classes of drugs, used in eight or fewer patients each, included quinolones, macrolides, sulfonamides, tetracyclines, aminoglycosides, and nitroimidazole.

Median overall survival for the entire cohort, one of two primary outcomes, was 2 months for patients who had received prior antibiotics and 26 months for patients with no prior exposure. This difference was similar for patients with NSCLC (2.5 vs. 26 months), melanoma (3.9 vs. 14 months), and other cancers combined (1.1 vs. 11.0 months; log-rank P less than .01 for all comparisons).

In multivariate analysis, only response to checkpoints inhibitors (complete vs. partial response, stable disease, or progression) and prior antibiotic exposure were significantly associated with survival. The hazard ratio for survival for patients who had not previously received antibiotics was 3.5 (P less than .001).

In contrast, concurrent antibiotic and checkpoint inhibitor use did not have a significant effect on survival.

An analysis of radiologic responses also showed that patients with prior antibiotic exposure had a significantly higher probability of primary disease progression than those without (81% vs. 44%; P less than .001). There were no associations, however, between specific classes of antibiotics or corticosteroid use.

The findings indicate that “certainly, mechanistic studies are required here, not just to investigate the prognostic role of antibiotic-mediated dysbiosis, but perhaps transform this into an actual driver of antitumor immunity,” Dr. Pinato concluded.

The study was internally supported. Dr. Pinato reported receiving grant funding from Merck and Bristol-Myers Squibb unrelated to the study, as well as honoraria from ViiV Healthcare.

SOURCE: Pinato DJ et al. ASCO-SITC, Abstract 147.

SAN FRANCISCO – Antibiotic exposure in the month before cancer immunotherapy starts may hamper the efficacy of immune checkpoint inhibitors, investigators caution.

Neil Osterweil/MDedge News

A prospective study of 196 patients treated with immune checkpoint inhibitors for various cancers showed that the 29 patients who received antibiotics within 30 days of starting immunotherapy had significantly worse overall survival than patients without antibiotic exposure; this effect was seen across cancer types, reported David James Pinato, MD, PhD, from Imperial College London.

In contrast, concurrent antibiotic and checkpoint inhibitor use was not significantly associated with overall survival differences, he said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

“I think these data are quite interesting in showing an independent detrimental effect, both on response and survival, in unselected patients treated with immune checkpoint inhibitors in routine clinical practice,” Dr. Pinato said.

The data also suggest “the timing of antibiotic exposure is crucial,” he added. Antibiotic treatment concurrent with immunotherapy did not appear to affect prognosis. Alternatively, prior antibiotic therapy appeared to have “a sort of a priming effect towards the immune system.”

Broad-spectrum antibiotics can affect the diversity of the gut microbiome, which influences mucosal immunity, dendritic cell function, and antigen presentation. Alternatively, enrichment of the microbiome with several bacterial species can enhance the potency of checkpoint inhibitors by facilitating the process of tumor rejection, Dr. Pinato explained.

To see whether antibiotic disruption, or “dysbiosis” of the gut microbiome, could hinder responsiveness to checkpoint inhibitors regardless of the tumor site and whether there were time-dependent effects of antibiotic exposure on response to checkpoint inhibitors, the investigators conducted a prospective, observational study in 196 patients treated with checkpoint inhibitors for non–small cell lung cancer (NSCLC), melanoma, renal cell carcinoma, head and neck cancer, transitional cell carcinoma of the bladder, and other cancers.

The researchers defined prior antibiotic exposure as more than 30 days before the start of checkpoint inhibitor therapy and concurrent exposure as antibiotics begun on the first day of the first cycle of checkpoint inhibitor dosing.

Of the 196 patients, 29 had previously received antibiotics, and 68 received them concurrently. The most frequently prescribed antibiotics were beta-lactam agents given in a single, short course. Other classes of drugs, used in eight or fewer patients each, included quinolones, macrolides, sulfonamides, tetracyclines, aminoglycosides, and nitroimidazole.

Median overall survival for the entire cohort, one of two primary outcomes, was 2 months for patients who had received prior antibiotics and 26 months for patients with no prior exposure. This difference was similar for patients with NSCLC (2.5 vs. 26 months), melanoma (3.9 vs. 14 months), and other cancers combined (1.1 vs. 11.0 months; log-rank P less than .01 for all comparisons).

In multivariate analysis, only response to checkpoints inhibitors (complete vs. partial response, stable disease, or progression) and prior antibiotic exposure were significantly associated with survival. The hazard ratio for survival for patients who had not previously received antibiotics was 3.5 (P less than .001).

In contrast, concurrent antibiotic and checkpoint inhibitor use did not have a significant effect on survival.

An analysis of radiologic responses also showed that patients with prior antibiotic exposure had a significantly higher probability of primary disease progression than those without (81% vs. 44%; P less than .001). There were no associations, however, between specific classes of antibiotics or corticosteroid use.

The findings indicate that “certainly, mechanistic studies are required here, not just to investigate the prognostic role of antibiotic-mediated dysbiosis, but perhaps transform this into an actual driver of antitumor immunity,” Dr. Pinato concluded.

The study was internally supported. Dr. Pinato reported receiving grant funding from Merck and Bristol-Myers Squibb unrelated to the study, as well as honoraria from ViiV Healthcare.

SOURCE: Pinato DJ et al. ASCO-SITC, Abstract 147.

SAN FRANCISCO – For patients with advanced non–small cell lung cancer (NSCLC) who previously had disease control with the checkpoint inhibitor nivolumab (Opdivo), second-line nivolumab at a higher dose every 4 weeks appeared to be comparable in efficacy and safety with standard-dose nivolumab every 2 weeks.

The key word in that last sentence is “appeared,” because the Checkmate 384 trial that was designed to show noninferiority of the every-4-weeks regimen lacked the statistical muscle to get the job done, reported Edward B. Garon, MD, from the University of California, Los Angeles.

“In many respects, extending the dosing frequency of nivolumab fulfills some of the promise of immunotherapy: The idea that we would be able to decrease the medicalization of the lives of our patients. For some people this would lead to them being able to resume a more normal work schedule, and for other people it would allow them to do things for fun, like travel on trips that would take longer than a couple of weeks,” he said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

However, because of difficulties in recruitment, the investigators had to stop enrollment early and settle for a sample size of 363 patients, instead of the 600 planned that would be necessary to meet a 10% noninferiority margin and one-sided 95% confidence interval. Thus, the trial analysis can only be reported as descriptive rather than definitive, Dr. Garon acknowledged.

Nivolumab is approved at a fixed dose of 240 mg every 2 weeks for the treatment of multiple tumor types in several different nations, and in the United States and Canada it is approved at a dose of 480 mg every 4 weeks for the treatment of NSCLC.

The CheckMate 384 study enrolled patients with advanced or metastatic NSCLC who had received 3 mg/kg or 240 mg of nivolumab every 2 weeks for up to 1 year. The patients had to have had relatively good performance status (Eastern Cooperative Oncology Group 0-2) and two consecutive assessments of either complete response, partial response, or stable disease.

The patients were stratified by tumor histology (squamous or nonsquamous) and response to prior nivolumab therapy at randomization, and were then randomized to receive nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks until disease progression or unacceptable toxicity for up to 2 years.

Dr. Garon presented an interim analysis including data on 329 of the 363 patients; the final analysis will occur after all patients have had a minimum of 12 months of follow-up. Here, he reported on 6-month progression-free survival, a coprimary endpoint with 12-month PFS.

After a median follow-up of 9.5 months in the Q4-week group and 10.2 months in the Q2-week group, the 6-month PFS rates were identical between the two dosing strategies, at 72%. The median PFS was 12.1 months and 12.2 months, respectively.

“Although the study is no longer formally powered to show noninferiority, there’s certainly nothing in these curves that makes me concerned that this 480 mg every-4-week dose would be inferior,” Dr. Garon said.

There was a slightly higher rate of treatment-related adverse events of any grade in the lower, more frequent dose group: 48% in the Q4-week versus 61% in the Q2-week arm. The respective rates of grade 3 or 4 adverse events were 8% and 12%. Rates of serious adverse events and events leading to treatment discontinuation were similar between the group; there were no treatment-related deaths.

The investigators hypothesize that the higher rate of overall events in the lower-dose group may be attributable to more frequent visits and more opportunities to report adverse events, Dr. Garon said.

“Overall, the clinical data are in agreement with the pharmacokinetic modeling and give further evidence for this 480 mg every 4 week nivolumab dosing option,” he concluded.

The study was supported by Bristol-Myers Squibb. Dr. Garon reported receiving research support from Bristol-Myers Squibb and others and consulting fees from Dracen Pharmaceuticals.

SOURCE: Garon EB et al. ASCO-SITC, Abstract 100.

SAN FRANCISCO – For patients with advanced non–small cell lung cancer (NSCLC) who previously had disease control with the checkpoint inhibitor nivolumab (Opdivo), second-line nivolumab at a higher dose every 4 weeks appeared to be comparable in efficacy and safety with standard-dose nivolumab every 2 weeks.

The key word in that last sentence is “appeared,” because the Checkmate 384 trial that was designed to show noninferiority of the every-4-weeks regimen lacked the statistical muscle to get the job done, reported Edward B. Garon, MD, from the University of California, Los Angeles.

“In many respects, extending the dosing frequency of nivolumab fulfills some of the promise of immunotherapy: The idea that we would be able to decrease the medicalization of the lives of our patients. For some people this would lead to them being able to resume a more normal work schedule, and for other people it would allow them to do things for fun, like travel on trips that would take longer than a couple of weeks,” he said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

However, because of difficulties in recruitment, the investigators had to stop enrollment early and settle for a sample size of 363 patients, instead of the 600 planned that would be necessary to meet a 10% noninferiority margin and one-sided 95% confidence interval. Thus, the trial analysis can only be reported as descriptive rather than definitive, Dr. Garon acknowledged.

Nivolumab is approved at a fixed dose of 240 mg every 2 weeks for the treatment of multiple tumor types in several different nations, and in the United States and Canada it is approved at a dose of 480 mg every 4 weeks for the treatment of NSCLC.

The CheckMate 384 study enrolled patients with advanced or metastatic NSCLC who had received 3 mg/kg or 240 mg of nivolumab every 2 weeks for up to 1 year. The patients had to have had relatively good performance status (Eastern Cooperative Oncology Group 0-2) and two consecutive assessments of either complete response, partial response, or stable disease.

The patients were stratified by tumor histology (squamous or nonsquamous) and response to prior nivolumab therapy at randomization, and were then randomized to receive nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks until disease progression or unacceptable toxicity for up to 2 years.

Dr. Garon presented an interim analysis including data on 329 of the 363 patients; the final analysis will occur after all patients have had a minimum of 12 months of follow-up. Here, he reported on 6-month progression-free survival, a coprimary endpoint with 12-month PFS.

After a median follow-up of 9.5 months in the Q4-week group and 10.2 months in the Q2-week group, the 6-month PFS rates were identical between the two dosing strategies, at 72%. The median PFS was 12.1 months and 12.2 months, respectively.

“Although the study is no longer formally powered to show noninferiority, there’s certainly nothing in these curves that makes me concerned that this 480 mg every-4-week dose would be inferior,” Dr. Garon said.

There was a slightly higher rate of treatment-related adverse events of any grade in the lower, more frequent dose group: 48% in the Q4-week versus 61% in the Q2-week arm. The respective rates of grade 3 or 4 adverse events were 8% and 12%. Rates of serious adverse events and events leading to treatment discontinuation were similar between the group; there were no treatment-related deaths.

The investigators hypothesize that the higher rate of overall events in the lower-dose group may be attributable to more frequent visits and more opportunities to report adverse events, Dr. Garon said.

“Overall, the clinical data are in agreement with the pharmacokinetic modeling and give further evidence for this 480 mg every 4 week nivolumab dosing option,” he concluded.

The study was supported by Bristol-Myers Squibb. Dr. Garon reported receiving research support from Bristol-Myers Squibb and others and consulting fees from Dracen Pharmaceuticals.

SOURCE: Garon EB et al. ASCO-SITC, Abstract 100.

SAN FRANCISCO – For patients with advanced non–small cell lung cancer (NSCLC) who previously had disease control with the checkpoint inhibitor nivolumab (Opdivo), second-line nivolumab at a higher dose every 4 weeks appeared to be comparable in efficacy and safety with standard-dose nivolumab every 2 weeks.

The key word in that last sentence is “appeared,” because the Checkmate 384 trial that was designed to show noninferiority of the every-4-weeks regimen lacked the statistical muscle to get the job done, reported Edward B. Garon, MD, from the University of California, Los Angeles.

“In many respects, extending the dosing frequency of nivolumab fulfills some of the promise of immunotherapy: The idea that we would be able to decrease the medicalization of the lives of our patients. For some people this would lead to them being able to resume a more normal work schedule, and for other people it would allow them to do things for fun, like travel on trips that would take longer than a couple of weeks,” he said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

However, because of difficulties in recruitment, the investigators had to stop enrollment early and settle for a sample size of 363 patients, instead of the 600 planned that would be necessary to meet a 10% noninferiority margin and one-sided 95% confidence interval. Thus, the trial analysis can only be reported as descriptive rather than definitive, Dr. Garon acknowledged.

Nivolumab is approved at a fixed dose of 240 mg every 2 weeks for the treatment of multiple tumor types in several different nations, and in the United States and Canada it is approved at a dose of 480 mg every 4 weeks for the treatment of NSCLC.

The CheckMate 384 study enrolled patients with advanced or metastatic NSCLC who had received 3 mg/kg or 240 mg of nivolumab every 2 weeks for up to 1 year. The patients had to have had relatively good performance status (Eastern Cooperative Oncology Group 0-2) and two consecutive assessments of either complete response, partial response, or stable disease.

The patients were stratified by tumor histology (squamous or nonsquamous) and response to prior nivolumab therapy at randomization, and were then randomized to receive nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks until disease progression or unacceptable toxicity for up to 2 years.

Dr. Garon presented an interim analysis including data on 329 of the 363 patients; the final analysis will occur after all patients have had a minimum of 12 months of follow-up. Here, he reported on 6-month progression-free survival, a coprimary endpoint with 12-month PFS.

After a median follow-up of 9.5 months in the Q4-week group and 10.2 months in the Q2-week group, the 6-month PFS rates were identical between the two dosing strategies, at 72%. The median PFS was 12.1 months and 12.2 months, respectively.

“Although the study is no longer formally powered to show noninferiority, there’s certainly nothing in these curves that makes me concerned that this 480 mg every-4-week dose would be inferior,” Dr. Garon said.

There was a slightly higher rate of treatment-related adverse events of any grade in the lower, more frequent dose group: 48% in the Q4-week versus 61% in the Q2-week arm. The respective rates of grade 3 or 4 adverse events were 8% and 12%. Rates of serious adverse events and events leading to treatment discontinuation were similar between the group; there were no treatment-related deaths.

The investigators hypothesize that the higher rate of overall events in the lower-dose group may be attributable to more frequent visits and more opportunities to report adverse events, Dr. Garon said.

“Overall, the clinical data are in agreement with the pharmacokinetic modeling and give further evidence for this 480 mg every 4 week nivolumab dosing option,” he concluded.

The study was supported by Bristol-Myers Squibb. Dr. Garon reported receiving research support from Bristol-Myers Squibb and others and consulting fees from Dracen Pharmaceuticals.

SOURCE: Garon EB et al. ASCO-SITC, Abstract 100.

Single-patient use (SPU) of investigational therapies via the Food and Drug Administration’s Expanded Access program is an option worth considering for heavily pretreated cancer patients, according to a retrospective analysis of SPUs at Memorial Sloan Kettering Cancer Center.

Although approximately 2% of cancer cases at Kettering are pediatric, 34.1% of SPUs were for children, reported lead author Noah Z. Feit of Cornell University, New York, and his colleagues.

Therefore, “SPUs may provide an important means of pediatric drug access,” the investigators wrote in a JAMA Oncology letter.

The analysis involved 179 patients with 43 cancer types; these were more often solid tumors than hematologic malignancies (57.9% vs. 42.1%). The most common solid tumor type was neuroblastoma (15.3%), followed by lung (7.9%), primary brain (7.9%), and breast (5.9%). Sixty-six investigational products were given; the top three types were kinase inhibitors (28.8%), naked antibodies (12.5%), and allogeneic cell therapy (12.0%). Therapies were in various stages of development, including phase 3 (39.4%), phase 2 (36.1%), and phase 1 (18.8%). SPU approval was most often based on previous clinical experience (61.5%), although genomic data (38.0%) and preclinical evidence (30.8%) were also cited. The median number of prior treatments was four, suggesting a heavily pretreated patient population.

Analysis showed that the overall response rate to SPU agents was 20.1%, and patients with hematologic cancers responded more often than did those with solid tumors (30.4% vs. 12.2%). Median progression-free survival and overall survival were 3.9 months and 11.4 months, respectively. About one-third of patients (29.7%) had at least one serious treatment-related adverse event, with adults more often affected than children (35.3% vs. 19.1%). No treatment-related deaths occurred.

“In summary, our data provide an initial evidence basis to evaluate the FDA Expanded Access mechanism. We find its use is broad, involving a wide variety of patients and products, and clinical benefit was observed,” the investigators concluded. “Routine prospective collection of key safety and efficacy metrics should be considered moving forward.”

The study was funded by National Institutes of Health, the St. Baldrick’s Foundation, and the Nonna’s Garden Foundation Initiative in Precision Oncology. The investigators reported financial relationships with Mylan, Atara Biotherapeutics, Chugai Pharma, Boehringer Ingelheim, and others.

SOURCE: Feit et al. JAMA Onc. 2019 Feb 28. doi: 10.1001/jamaoncol.2018.7002.

Single-patient use (SPU) of investigational therapies via the Food and Drug Administration’s Expanded Access program is an option worth considering for heavily pretreated cancer patients, according to a retrospective analysis of SPUs at Memorial Sloan Kettering Cancer Center.

Although approximately 2% of cancer cases at Kettering are pediatric, 34.1% of SPUs were for children, reported lead author Noah Z. Feit of Cornell University, New York, and his colleagues.

Therefore, “SPUs may provide an important means of pediatric drug access,” the investigators wrote in a JAMA Oncology letter.

The analysis involved 179 patients with 43 cancer types; these were more often solid tumors than hematologic malignancies (57.9% vs. 42.1%). The most common solid tumor type was neuroblastoma (15.3%), followed by lung (7.9%), primary brain (7.9%), and breast (5.9%). Sixty-six investigational products were given; the top three types were kinase inhibitors (28.8%), naked antibodies (12.5%), and allogeneic cell therapy (12.0%). Therapies were in various stages of development, including phase 3 (39.4%), phase 2 (36.1%), and phase 1 (18.8%). SPU approval was most often based on previous clinical experience (61.5%), although genomic data (38.0%) and preclinical evidence (30.8%) were also cited. The median number of prior treatments was four, suggesting a heavily pretreated patient population.

Analysis showed that the overall response rate to SPU agents was 20.1%, and patients with hematologic cancers responded more often than did those with solid tumors (30.4% vs. 12.2%). Median progression-free survival and overall survival were 3.9 months and 11.4 months, respectively. About one-third of patients (29.7%) had at least one serious treatment-related adverse event, with adults more often affected than children (35.3% vs. 19.1%). No treatment-related deaths occurred.

“In summary, our data provide an initial evidence basis to evaluate the FDA Expanded Access mechanism. We find its use is broad, involving a wide variety of patients and products, and clinical benefit was observed,” the investigators concluded. “Routine prospective collection of key safety and efficacy metrics should be considered moving forward.”

The study was funded by National Institutes of Health, the St. Baldrick’s Foundation, and the Nonna’s Garden Foundation Initiative in Precision Oncology. The investigators reported financial relationships with Mylan, Atara Biotherapeutics, Chugai Pharma, Boehringer Ingelheim, and others.

SOURCE: Feit et al. JAMA Onc. 2019 Feb 28. doi: 10.1001/jamaoncol.2018.7002.

Single-patient use (SPU) of investigational therapies via the Food and Drug Administration’s Expanded Access program is an option worth considering for heavily pretreated cancer patients, according to a retrospective analysis of SPUs at Memorial Sloan Kettering Cancer Center.

Although approximately 2% of cancer cases at Kettering are pediatric, 34.1% of SPUs were for children, reported lead author Noah Z. Feit of Cornell University, New York, and his colleagues.

Therefore, “SPUs may provide an important means of pediatric drug access,” the investigators wrote in a JAMA Oncology letter.

The analysis involved 179 patients with 43 cancer types; these were more often solid tumors than hematologic malignancies (57.9% vs. 42.1%). The most common solid tumor type was neuroblastoma (15.3%), followed by lung (7.9%), primary brain (7.9%), and breast (5.9%). Sixty-six investigational products were given; the top three types were kinase inhibitors (28.8%), naked antibodies (12.5%), and allogeneic cell therapy (12.0%). Therapies were in various stages of development, including phase 3 (39.4%), phase 2 (36.1%), and phase 1 (18.8%). SPU approval was most often based on previous clinical experience (61.5%), although genomic data (38.0%) and preclinical evidence (30.8%) were also cited. The median number of prior treatments was four, suggesting a heavily pretreated patient population.

Analysis showed that the overall response rate to SPU agents was 20.1%, and patients with hematologic cancers responded more often than did those with solid tumors (30.4% vs. 12.2%). Median progression-free survival and overall survival were 3.9 months and 11.4 months, respectively. About one-third of patients (29.7%) had at least one serious treatment-related adverse event, with adults more often affected than children (35.3% vs. 19.1%). No treatment-related deaths occurred.

“In summary, our data provide an initial evidence basis to evaluate the FDA Expanded Access mechanism. We find its use is broad, involving a wide variety of patients and products, and clinical benefit was observed,” the investigators concluded. “Routine prospective collection of key safety and efficacy metrics should be considered moving forward.”

The study was funded by National Institutes of Health, the St. Baldrick’s Foundation, and the Nonna’s Garden Foundation Initiative in Precision Oncology. The investigators reported financial relationships with Mylan, Atara Biotherapeutics, Chugai Pharma, Boehringer Ingelheim, and others.

SOURCE: Feit et al. JAMA Onc. 2019 Feb 28. doi: 10.1001/jamaoncol.2018.7002.

SAN FRANCISCO – The immune checkpoint inhibitor pembrolizumab (Keytruda) was associated in a small case series with remarkable overall and progression-free survival of patients with pulmonary sarcomatoid carcinoma (PSC), a rare variant of non–small cell lung cancer (NSCLC) with a grim prognosis.

Among five patients with PSC, three of whom were treatment naive, none experienced disease progression on pembrolizumab after a median follow-up of 13 months – although one died from a fungal infection unrelated to therapy – with the longest overall survival to date out to 33 months.

In contrast, patients with PSC treated before the advent of immunotherapy had a median progression-free survival of just 2 months and median overall survival a brief 4-6 months, reported Vineeth Sukrithan, MD, and his colleagues at the Albert Einstein College of Medicine, New York.

“It’s a uniquely enriched population of patients with lung cancer that have the best prognosis in terms of benefits from checkpoint inhibitors,” he said in an interview at the ASCO-SITC Clinical Immuno-Oncology Symposium.

PSC, a poorly differentiated subtype of NSCLC, accounts for about 0.3%-1.3% of all cases of lung cancer. It is closely associated with a history of heavy cigarette smoking and is rapidly fatal, with a poor response to conventional chemotherapy, although approximately 20% of patients with PSC have MET exon 14–skipping mutations that are “exquisitely” sensitive to crizotinib (Xalkori), Dr. Sukrithan explained.

PSC tumors are also unique in that they have extraordinarily high levels of programmed death-ligand 1 (PD-L1), the target of immune checkpoint inhibitors, with tumor proportion scores exceeding 90% in some cases.

Additionally, up to 43% of PSC tumors have been found to have a high mutational burden, with more than 10 mutations per megabase, suggesting that these tumors may be especially attractive targets for checkpoint inhibitor therapy, he said.

The investigators retrospectively studied surgical pathology and treatment records for all patients with advanced PSC diagnosed at their center from June 2015 to June 2018 who received pembrolizumab. They performed immunohistochemistry testing on tissue samples from the patients to quantify PD-L1 expression.

They compared the results with a cohort of patients with advanced PSC diagnosed from June 2012 to June 2015, prior to the clinical availability of anti-PD-1/PD-L1 checkpoint inhibitors.

The PD-L1-treated cohort included two men and three women, ranging from 48 to 67 years, with smoking pack-years ranging from 24 to 50. Two of the patients had received prior chemotherapy followed by pembrolizumab, and the remaining three received pembrolizumab monotherapy.

Tumor proportion scores ranged from more than 75% of tumor cells examined in one patient to 100% of cells in another.

The objective response rate to pembrolizumab was 80% consisting of one complete response and three partial responses. The fifth patient continued to have stable disease out to more than 17 months.

“This highly treatment-refractory disease now should be carefully assessed for immuno-oncologic and molecularly targeted options, which are associated with significant improvement in outcomes,” the investigators wrote in a poster presentation.

The study was internally funded. Dr. Sukrithan reported having no disclosures.

SOURCE: Sukrithan V et al. ASCO-SITC, Abstract 115.

SAN FRANCISCO – The immune checkpoint inhibitor pembrolizumab (Keytruda) was associated in a small case series with remarkable overall and progression-free survival of patients with pulmonary sarcomatoid carcinoma (PSC), a rare variant of non–small cell lung cancer (NSCLC) with a grim prognosis.

Among five patients with PSC, three of whom were treatment naive, none experienced disease progression on pembrolizumab after a median follow-up of 13 months – although one died from a fungal infection unrelated to therapy – with the longest overall survival to date out to 33 months.

In contrast, patients with PSC treated before the advent of immunotherapy had a median progression-free survival of just 2 months and median overall survival a brief 4-6 months, reported Vineeth Sukrithan, MD, and his colleagues at the Albert Einstein College of Medicine, New York.

“It’s a uniquely enriched population of patients with lung cancer that have the best prognosis in terms of benefits from checkpoint inhibitors,” he said in an interview at the ASCO-SITC Clinical Immuno-Oncology Symposium.

PSC, a poorly differentiated subtype of NSCLC, accounts for about 0.3%-1.3% of all cases of lung cancer. It is closely associated with a history of heavy cigarette smoking and is rapidly fatal, with a poor response to conventional chemotherapy, although approximately 20% of patients with PSC have MET exon 14–skipping mutations that are “exquisitely” sensitive to crizotinib (Xalkori), Dr. Sukrithan explained.

PSC tumors are also unique in that they have extraordinarily high levels of programmed death-ligand 1 (PD-L1), the target of immune checkpoint inhibitors, with tumor proportion scores exceeding 90% in some cases.

Additionally, up to 43% of PSC tumors have been found to have a high mutational burden, with more than 10 mutations per megabase, suggesting that these tumors may be especially attractive targets for checkpoint inhibitor therapy, he said.

The investigators retrospectively studied surgical pathology and treatment records for all patients with advanced PSC diagnosed at their center from June 2015 to June 2018 who received pembrolizumab. They performed immunohistochemistry testing on tissue samples from the patients to quantify PD-L1 expression.

They compared the results with a cohort of patients with advanced PSC diagnosed from June 2012 to June 2015, prior to the clinical availability of anti-PD-1/PD-L1 checkpoint inhibitors.

The PD-L1-treated cohort included two men and three women, ranging from 48 to 67 years, with smoking pack-years ranging from 24 to 50. Two of the patients had received prior chemotherapy followed by pembrolizumab, and the remaining three received pembrolizumab monotherapy.

Tumor proportion scores ranged from more than 75% of tumor cells examined in one patient to 100% of cells in another.

The objective response rate to pembrolizumab was 80% consisting of one complete response and three partial responses. The fifth patient continued to have stable disease out to more than 17 months.

“This highly treatment-refractory disease now should be carefully assessed for immuno-oncologic and molecularly targeted options, which are associated with significant improvement in outcomes,” the investigators wrote in a poster presentation.

The study was internally funded. Dr. Sukrithan reported having no disclosures.

SOURCE: Sukrithan V et al. ASCO-SITC, Abstract 115.

SAN FRANCISCO – The immune checkpoint inhibitor pembrolizumab (Keytruda) was associated in a small case series with remarkable overall and progression-free survival of patients with pulmonary sarcomatoid carcinoma (PSC), a rare variant of non–small cell lung cancer (NSCLC) with a grim prognosis.

Among five patients with PSC, three of whom were treatment naive, none experienced disease progression on pembrolizumab after a median follow-up of 13 months – although one died from a fungal infection unrelated to therapy – with the longest overall survival to date out to 33 months.

In contrast, patients with PSC treated before the advent of immunotherapy had a median progression-free survival of just 2 months and median overall survival a brief 4-6 months, reported Vineeth Sukrithan, MD, and his colleagues at the Albert Einstein College of Medicine, New York.

“It’s a uniquely enriched population of patients with lung cancer that have the best prognosis in terms of benefits from checkpoint inhibitors,” he said in an interview at the ASCO-SITC Clinical Immuno-Oncology Symposium.

PSC, a poorly differentiated subtype of NSCLC, accounts for about 0.3%-1.3% of all cases of lung cancer. It is closely associated with a history of heavy cigarette smoking and is rapidly fatal, with a poor response to conventional chemotherapy, although approximately 20% of patients with PSC have MET exon 14–skipping mutations that are “exquisitely” sensitive to crizotinib (Xalkori), Dr. Sukrithan explained.

PSC tumors are also unique in that they have extraordinarily high levels of programmed death-ligand 1 (PD-L1), the target of immune checkpoint inhibitors, with tumor proportion scores exceeding 90% in some cases.

Additionally, up to 43% of PSC tumors have been found to have a high mutational burden, with more than 10 mutations per megabase, suggesting that these tumors may be especially attractive targets for checkpoint inhibitor therapy, he said.

The investigators retrospectively studied surgical pathology and treatment records for all patients with advanced PSC diagnosed at their center from June 2015 to June 2018 who received pembrolizumab. They performed immunohistochemistry testing on tissue samples from the patients to quantify PD-L1 expression.

They compared the results with a cohort of patients with advanced PSC diagnosed from June 2012 to June 2015, prior to the clinical availability of anti-PD-1/PD-L1 checkpoint inhibitors.

The PD-L1-treated cohort included two men and three women, ranging from 48 to 67 years, with smoking pack-years ranging from 24 to 50. Two of the patients had received prior chemotherapy followed by pembrolizumab, and the remaining three received pembrolizumab monotherapy.

Tumor proportion scores ranged from more than 75% of tumor cells examined in one patient to 100% of cells in another.

The objective response rate to pembrolizumab was 80% consisting of one complete response and three partial responses. The fifth patient continued to have stable disease out to more than 17 months.

“This highly treatment-refractory disease now should be carefully assessed for immuno-oncologic and molecularly targeted options, which are associated with significant improvement in outcomes,” the investigators wrote in a poster presentation.

The study was internally funded. Dr. Sukrithan reported having no disclosures.

SOURCE: Sukrithan V et al. ASCO-SITC, Abstract 115.