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2015 American Society of Clinical Oncology annual meeting
News
2015 American Society of Clinical Oncology annual meeting
Nick Ledger/JAI/Corbis
Nivolumab for lung cancer
Published Online June 11, 2015 http://dx.doi.org/10.1016/ S2213-2600(15)00244-1 The 51st annual meeting of the American Society of Clinical Oncology was held in Chicago, IL, USA, on May 29 to June 2, 2015 For the phase 1 study of pembrolizumab for NSCLC see N Engl J Med 2015; 372: 2018–28 For more about the phase 1 study of pembrolizumab see News Lancet Respir Med 2015; 3: 429
516
Immunotherapeutic drugs featured heavily at this year’s American Society of Clinical Oncology (ASCO) annual meeting, with positive results reported for several indications, including lung cancer. Nivolumab is one such drug. It blocks PD-1, a negative regulator of T-cell activation, thereby enabling the immune system to attack and destroy tumours. The results of two phase 3 trials of nivolumab were presented. David Spigel and colleagues (Tennessee Oncology, Nashville, TN, USA) presented the results of CheckMate 017, which compared nivolumab (3 mg/kg every 2 weeks) with docetaxel (75 mg/m2 every 3 weeks) in 272 patients with previously treated, advanced or metastatic squamous-cell non-small-cell lung cancer (NSCLC). The outlook for patients who have failed platinumbased chemotherapy is very poor, so the results were met warmly by clinicians; the primary outcome of median overall survival was 9·2 months for nivolumab versus 6·0 months for docetaxel (hazard ratio [HR] 0·59, 95% CI 0·44–0·79; p=0·00025). Safety was also much better with nivolumab than with docetaxel, with grade 3–4 adverse events in nine (7%) of 131 patients in the nivolumab group versus 71 (55%) of 129 patients in the docetaxel group. The trial was stopped early and the findings led to the drug’s approval in the USA earlier this year. Edward Garon (UCLA Medical Center, Los Angeles, CA, USA) hailed nivolumab as the new “standard of care for second-line treatment”. CheckMate 057 was a trial of nivolumab versus docetaxel for patients with non-squamous-cell NSCLC—the more common form of the disease. Luis Paz-Ares and colleagues (Hospital Universitario Virgen Del Rocio, Sevilla, Spain) randomly assigned patients who had progressed after platinum-based doublet chemotherapy to nivolumab or docetaxel. Similar to squamous-cell disease, median overall survival was
much improved, from 9·4 months (95% CI 8·0–10·7) in the docetaxel group to 12·2 months (9·7–15·0) in the nivolumab group (HR 0·73, 96% CI 0·59–0·89). Safety was also better in the nivolumab group than the docetaxel group (30 [10%] of 287 patients had drug-related grade 3–4 adverse events vs 144 [54%] of 268). These findings should change practice in this setting. “This is the first phase 3 study to show that immunotherapy is effective against non-squamous-cell NSCLC”, said Paz-Ares. “It is also far easier on patients compared to the standard secondline treatment, docetaxel.” Gregory Masters (Thomas Jefferson University Medical School, Philadelphia, PA, USA), who was not involved in the study, agreed: “Even 5 years ago, an effective immunotherapy for lung cancer was largely considered impossible. Today, we have such a treatment, and it surpasses the standard therapy both in terms of efficacy and patient quality of life.” Nivolumab seemed to be more effective against tumours that express high levels of PD-L1. In non-squamous disease, the HR for overall survival was 0·43 in PD-L1-positive patients (≥5% of tumour cells expressing PD-L1 on the cell surface), compared with 1·01 for PD-L1-negative patients (<5% expression). This finding suggests that clinicians might have to select patients for treatment or, at least, said Garon, that more studies of the importance of PD-L1 expression levels are needed. “Patients with high levels of PD-L1 staining are seeing tremendous benefit. The role in patients without staining or low-level staining are still somewhat unclear. Efficacy appears no worse than docetaxel, but issues of quality of life, as well as value, will be particularly important in defining the role of these agents in this population.” Further results of nivolumab studies were presented in a phase 1/2 trial testing the addition of ipilimumab to nivolumab in recurrent small-cell lung cancer (SCLC). Scott Antonia
and colleagues (Moffitt Cancer Center, Tampa, FL, USA) gave 40 patients nivolumab (3 mg/kg every 2 weeks), and 35 patients nivolumab (1 mg/ kg) plus ipilimumab (3 mg/kg) every 3 weeks for four doses followed by nivolumab (3 mg/kg) every 2 weeks until disease progression, discontinuation for toxic effects, or the end of the study. Drug-related adverse events were similar in each group, and the efficacy results were promising: six (15%) of 40 assessable patients in the nivolumab only group had a response (all partial) versus five (25%) of 20 patients given ipilimumab and nivolumab (one complete response), and preliminary data show that overall survival was 4 months versus 8 months. These findings will have to be tested in larger trials before being applied to clinical practice.
Pembrolizumab for SCLC Promising findings were also presented for pembrolizumab, another antiPD-1 antibody. Impressive results of a phase 1 study of pembrolizumab for NSCLC were published in May in the New England Journal of Medicine. Meanwhile, Patrick Ott and colleagues (Dana-Farber Cancer Institute, Boston, MA, USA) are studying pembrolizumab treatment for patients with PD-L1positive SCLC. The phase 1 study is ongoing, but preliminary results show that, of 16 enrolled patients, nine (56%) had a drug-related adverse event, one of which was grade 3–4. Four (25%) patients had a partial response, and one had stable disease. However, Natasha Leighl, of the Princess Margaret Cancer Centre (Toronto, ON, Canada), sounded a note of caution about the shortcomings of selecting patients on the basis of PD-L1 expression. Most of the screened patients were excluded because their tumours were deemed PD-L1 negative—only 37 (27%) of patients screened had PD-L1-positive tumours—but, said Leighl, “PD-L1 expression is challenging even in www.thelancet.com/respiratory Vol 3 July 2015
News
NSCLC…It’s a dynamic biomarker, there’s a lot of heterogeneity, it can change with different treatments. In SCLC, it’s been estimated that it may be even more difficult to measure, potentially less common in terms of positivity than in NSCLC, and there may be less concordance among pathologists.”
Alectinib for adenocarcinoma The importance of patient selection was further shown in two other studies. ALK rearrangements are present in roughly 5% of patients with lung adenocarcinoma. Crizotinib is approved for such patients, but progression usually recurs within 12 months, very often with CNS metastases. Leena Gandhi and colleagues (Dana-Farber Cancer Institute, Boston, MA, USA) presented favourable results of a phase 2 trial testing another ALK inhibitor—alectinib—in ALKpositive patients who progressed after crizotinib treatment. Of 69 assessable patients, 47·7% (95% CI 35·6–60·2) had an overall response. For the 16 patients with measurable CNS disease at baseline, the CNS response rate was 68·8% (41·3–89·0), including two complete responses.
Dabrafenib and trametinib David Planchard and co-workers (Gustave Roussy, Villejuif, France) discussed interim findings from a phase 2 study of the BRAF inhibitor, dabrafenib, combined with the MEK inhibitor, trametinib, for patients with BRAF Val600Glu-mutated metastatic NSCLC in whom chemotherapy has failed. 1–2% of patients have this mutation, which is associated with more aggressive disease that is less sensitive to platinum-based chemotherapy. Suresh Ramalingam (Emory University, Atlanta, GA, USA) praised the study, saying that “though the sample size of the study [24] is relatively small, the observed response rate of 63%, and the durability of the responses is exciting”. The most common adverse events were pyrexia, diarrhoea, and nausea. These findings pave the way for further studies in this setting. www.thelancet.com/respiratory Vol 3 July 2015
Testing erlotinib Erlotinib has been approved by the US Food and Drug Administration for second-line and third-line treatment of NSCLC, but its use was tested in two trials. MET amplification is a mechanism of resistance in EGFR-mutant NSCLC and cabozantinib is a tyrosine kinase inhibitor that inhibits MET, and has activity alone in NSCLC. In a phase 2 study in this setting, Joel Neal and colleagues (Stanford University School of Medicine, Stanford, CA, USA) showed that median progression-free survival was significantly greater for cabozantinib alone (3·9 months) than for erlotinib alone (1·9 months; HR 0·33, 80% CI 0·22–0·49; p=0·0002). The combination of carbozantinib and erlotinib also faired better than erlotinib alone (median 4·1 months; HR 0·31, 0·21–0·46; p=0·0002), with erlotinib having seemingly little effect. Garon was fairly damning in his interpretation: “If I had a patient in clinic who I knew to be EGFR mutation-negative and…the only options I had were giving them erlotinib or giving them chocolate cake, my bias would be in favour of the cake.” Results from the Lux-Lung 8 study showed that afatinib, an ErbB inhibitor, significantly improved progressionfree survival compared with erlotinib in patients with squamous-cell carcinoma. At ASCO this year, updated efficacy data were presented, reinforcing this finding: median overall survival was 7·9 months with afatinib versus 6·8 months for erlotinib (HR 0·81, 95% CI 0·69–0·95; p=0·0077). Patient-reported outcome data that favoured afatinib were also presented (improvement in global health status 36·4% vs 27·1%; p=0·026), suggesting that afatinib should be the EGFR tyrosine kinase inhibitor of choice this setting. Ramalingam told The Lancet Respiratory Medicine that the study “adds to increasing lines of evidence that erlotinib has relatively modest effects in patients with wild-type EGFR. Erlotinib cannot be considered as the preferred agent
for this subset of lung cancer patients, given the availability of more effective therapeutic options.”
For the Lux-Lung 8 study see http://bit.ly/1FGI5kb
Bevacizumab for mesothelioma Positive findings were also reported for malignant pleural mesothelioma. The disease is rare, being mainly associated with asbestos exposure, and the current first-line treatment of pemetrexed and cisplatin provides a median overall survival of just over 1 year. These cancers highly express VEGF and VEGF receptors, so Gerard Zalcman and colleagues (Caen University Hospital, Caen, France) assessed the effect of adding bevacizumab, a VEGF-A inhibitor, to chemotherapy. They assigned 225 patients to standard chemotherapy and 223 to bevacizumab (15 mg/kg every 21 days), and showed that overall survival was longer in the bevacizumab group (median 18·8 months, 95% CI 15·9–22·6) than in the chemotherapy only group (16·1, 14·0–17·9; HR 0·76, 95% CI 0·61–0·96; p=0·0127). Addition of bevacizumab also improved progression-free survival. Global quality-of-life was much the same in each group, although data for symptom-specific quality of life were unavailable, and grade 3–4 adverse events were more common in the bevacizumab group (71%) than in the chemotherapy only group (62%). Leighl was positive about the findings, saying that “in my opinion, I think we can change practice on the basis of this trial”, but she cautioned that the cost of bevacizumab could be a stumbling block. A treatment course with bevacizumab costs tens of thousands of dollars, and many health-care systems have deemed it not cost-effective enough. Anna Nowak (University of Western Australia, Crawley, WA, Australia) agreed, saying that whether the regimen will be adopted as a standard of care in this setting will depend on costeffectiveness and whether health-care systems are willing to pay for it.
Sean Cleghorn 517
2015 American Society of Clinical Oncology annual meeting
Nick Ledger/JAI/Corbis
Nivolumab for lung cancer
Published Online June 11, 2015 http://dx.doi.org/10.1016/ S2213-2600(15)00244-1 The 51st annual meeting of the American Society of Clinical Oncology was held in Chicago, IL, USA, on May 29 to June 2, 2015 For the phase 1 study of pembrolizumab for NSCLC see N Engl J Med 2015; 372: 2018–28 For more about the phase 1 study of pembrolizumab see News Lancet Respir Med 2015; 3: 429
516
Immunotherapeutic drugs featured heavily at this year’s American Society of Clinical Oncology (ASCO) annual meeting, with positive results reported for several indications, including lung cancer. Nivolumab is one such drug. It blocks PD-1, a negative regulator of T-cell activation, thereby enabling the immune system to attack and destroy tumours. The results of two phase 3 trials of nivolumab were presented. David Spigel and colleagues (Tennessee Oncology, Nashville, TN, USA) presented the results of CheckMate 017, which compared nivolumab (3 mg/kg every 2 weeks) with docetaxel (75 mg/m2 every 3 weeks) in 272 patients with previously treated, advanced or metastatic squamous-cell non-small-cell lung cancer (NSCLC). The outlook for patients who have failed platinumbased chemotherapy is very poor, so the results were met warmly by clinicians; the primary outcome of median overall survival was 9·2 months for nivolumab versus 6·0 months for docetaxel (hazard ratio [HR] 0·59, 95% CI 0·44–0·79; p=0·00025). Safety was also much better with nivolumab than with docetaxel, with grade 3–4 adverse events in nine (7%) of 131 patients in the nivolumab group versus 71 (55%) of 129 patients in the docetaxel group. The trial was stopped early and the findings led to the drug’s approval in the USA earlier this year. Edward Garon (UCLA Medical Center, Los Angeles, CA, USA) hailed nivolumab as the new “standard of care for second-line treatment”. CheckMate 057 was a trial of nivolumab versus docetaxel for patients with non-squamous-cell NSCLC—the more common form of the disease. Luis Paz-Ares and colleagues (Hospital Universitario Virgen Del Rocio, Sevilla, Spain) randomly assigned patients who had progressed after platinum-based doublet chemotherapy to nivolumab or docetaxel. Similar to squamous-cell disease, median overall survival was
much improved, from 9·4 months (95% CI 8·0–10·7) in the docetaxel group to 12·2 months (9·7–15·0) in the nivolumab group (HR 0·73, 96% CI 0·59–0·89). Safety was also better in the nivolumab group than the docetaxel group (30 [10%] of 287 patients had drug-related grade 3–4 adverse events vs 144 [54%] of 268). These findings should change practice in this setting. “This is the first phase 3 study to show that immunotherapy is effective against non-squamous-cell NSCLC”, said Paz-Ares. “It is also far easier on patients compared to the standard secondline treatment, docetaxel.” Gregory Masters (Thomas Jefferson University Medical School, Philadelphia, PA, USA), who was not involved in the study, agreed: “Even 5 years ago, an effective immunotherapy for lung cancer was largely considered impossible. Today, we have such a treatment, and it surpasses the standard therapy both in terms of efficacy and patient quality of life.” Nivolumab seemed to be more effective against tumours that express high levels of PD-L1. In non-squamous disease, the HR for overall survival was 0·43 in PD-L1-positive patients (≥5% of tumour cells expressing PD-L1 on the cell surface), compared with 1·01 for PD-L1-negative patients (<5% expression). This finding suggests that clinicians might have to select patients for treatment or, at least, said Garon, that more studies of the importance of PD-L1 expression levels are needed. “Patients with high levels of PD-L1 staining are seeing tremendous benefit. The role in patients without staining or low-level staining are still somewhat unclear. Efficacy appears no worse than docetaxel, but issues of quality of life, as well as value, will be particularly important in defining the role of these agents in this population.” Further results of nivolumab studies were presented in a phase 1/2 trial testing the addition of ipilimumab to nivolumab in recurrent small-cell lung cancer (SCLC). Scott Antonia
and colleagues (Moffitt Cancer Center, Tampa, FL, USA) gave 40 patients nivolumab (3 mg/kg every 2 weeks), and 35 patients nivolumab (1 mg/ kg) plus ipilimumab (3 mg/kg) every 3 weeks for four doses followed by nivolumab (3 mg/kg) every 2 weeks until disease progression, discontinuation for toxic effects, or the end of the study. Drug-related adverse events were similar in each group, and the efficacy results were promising: six (15%) of 40 assessable patients in the nivolumab only group had a response (all partial) versus five (25%) of 20 patients given ipilimumab and nivolumab (one complete response), and preliminary data show that overall survival was 4 months versus 8 months. These findings will have to be tested in larger trials before being applied to clinical practice.
Pembrolizumab for SCLC Promising findings were also presented for pembrolizumab, another antiPD-1 antibody. Impressive results of a phase 1 study of pembrolizumab for NSCLC were published in May in the New England Journal of Medicine. Meanwhile, Patrick Ott and colleagues (Dana-Farber Cancer Institute, Boston, MA, USA) are studying pembrolizumab treatment for patients with PD-L1positive SCLC. The phase 1 study is ongoing, but preliminary results show that, of 16 enrolled patients, nine (56%) had a drug-related adverse event, one of which was grade 3–4. Four (25%) patients had a partial response, and one had stable disease. However, Natasha Leighl, of the Princess Margaret Cancer Centre (Toronto, ON, Canada), sounded a note of caution about the shortcomings of selecting patients on the basis of PD-L1 expression. Most of the screened patients were excluded because their tumours were deemed PD-L1 negative—only 37 (27%) of patients screened had PD-L1-positive tumours—but, said Leighl, “PD-L1 expression is challenging even in www.thelancet.com/respiratory Vol 3 July 2015
News
NSCLC…It’s a dynamic biomarker, there’s a lot of heterogeneity, it can change with different treatments. In SCLC, it’s been estimated that it may be even more difficult to measure, potentially less common in terms of positivity than in NSCLC, and there may be less concordance among pathologists.”
Alectinib for adenocarcinoma The importance of patient selection was further shown in two other studies. ALK rearrangements are present in roughly 5% of patients with lung adenocarcinoma. Crizotinib is approved for such patients, but progression usually recurs within 12 months, very often with CNS metastases. Leena Gandhi and colleagues (Dana-Farber Cancer Institute, Boston, MA, USA) presented favourable results of a phase 2 trial testing another ALK inhibitor—alectinib—in ALKpositive patients who progressed after crizotinib treatment. Of 69 assessable patients, 47·7% (95% CI 35·6–60·2) had an overall response. For the 16 patients with measurable CNS disease at baseline, the CNS response rate was 68·8% (41·3–89·0), including two complete responses.
Dabrafenib and trametinib David Planchard and co-workers (Gustave Roussy, Villejuif, France) discussed interim findings from a phase 2 study of the BRAF inhibitor, dabrafenib, combined with the MEK inhibitor, trametinib, for patients with BRAF Val600Glu-mutated metastatic NSCLC in whom chemotherapy has failed. 1–2% of patients have this mutation, which is associated with more aggressive disease that is less sensitive to platinum-based chemotherapy. Suresh Ramalingam (Emory University, Atlanta, GA, USA) praised the study, saying that “though the sample size of the study [24] is relatively small, the observed response rate of 63%, and the durability of the responses is exciting”. The most common adverse events were pyrexia, diarrhoea, and nausea. These findings pave the way for further studies in this setting. www.thelancet.com/respiratory Vol 3 July 2015
Testing erlotinib Erlotinib has been approved by the US Food and Drug Administration for second-line and third-line treatment of NSCLC, but its use was tested in two trials. MET amplification is a mechanism of resistance in EGFR-mutant NSCLC and cabozantinib is a tyrosine kinase inhibitor that inhibits MET, and has activity alone in NSCLC. In a phase 2 study in this setting, Joel Neal and colleagues (Stanford University School of Medicine, Stanford, CA, USA) showed that median progression-free survival was significantly greater for cabozantinib alone (3·9 months) than for erlotinib alone (1·9 months; HR 0·33, 80% CI 0·22–0·49; p=0·0002). The combination of carbozantinib and erlotinib also faired better than erlotinib alone (median 4·1 months; HR 0·31, 0·21–0·46; p=0·0002), with erlotinib having seemingly little effect. Garon was fairly damning in his interpretation: “If I had a patient in clinic who I knew to be EGFR mutation-negative and…the only options I had were giving them erlotinib or giving them chocolate cake, my bias would be in favour of the cake.” Results from the Lux-Lung 8 study showed that afatinib, an ErbB inhibitor, significantly improved progressionfree survival compared with erlotinib in patients with squamous-cell carcinoma. At ASCO this year, updated efficacy data were presented, reinforcing this finding: median overall survival was 7·9 months with afatinib versus 6·8 months for erlotinib (HR 0·81, 95% CI 0·69–0·95; p=0·0077). Patient-reported outcome data that favoured afatinib were also presented (improvement in global health status 36·4% vs 27·1%; p=0·026), suggesting that afatinib should be the EGFR tyrosine kinase inhibitor of choice this setting. Ramalingam told The Lancet Respiratory Medicine that the study “adds to increasing lines of evidence that erlotinib has relatively modest effects in patients with wild-type EGFR. Erlotinib cannot be considered as the preferred agent
for this subset of lung cancer patients, given the availability of more effective therapeutic options.”
For the Lux-Lung 8 study see http://bit.ly/1FGI5kb
Bevacizumab for mesothelioma Positive findings were also reported for malignant pleural mesothelioma. The disease is rare, being mainly associated with asbestos exposure, and the current first-line treatment of pemetrexed and cisplatin provides a median overall survival of just over 1 year. These cancers highly express VEGF and VEGF receptors, so Gerard Zalcman and colleagues (Caen University Hospital, Caen, France) assessed the effect of adding bevacizumab, a VEGF-A inhibitor, to chemotherapy. They assigned 225 patients to standard chemotherapy and 223 to bevacizumab (15 mg/kg every 21 days), and showed that overall survival was longer in the bevacizumab group (median 18·8 months, 95% CI 15·9–22·6) than in the chemotherapy only group (16·1, 14·0–17·9; HR 0·76, 95% CI 0·61–0·96; p=0·0127). Addition of bevacizumab also improved progression-free survival. Global quality-of-life was much the same in each group, although data for symptom-specific quality of life were unavailable, and grade 3–4 adverse events were more common in the bevacizumab group (71%) than in the chemotherapy only group (62%). Leighl was positive about the findings, saying that “in my opinion, I think we can change practice on the basis of this trial”, but she cautioned that the cost of bevacizumab could be a stumbling block. A treatment course with bevacizumab costs tens of thousands of dollars, and many health-care systems have deemed it not cost-effective enough. Anna Nowak (University of Western Australia, Crawley, WA, Australia) agreed, saying that whether the regimen will be adopted as a standard of care in this setting will depend on costeffectiveness and whether health-care systems are willing to pay for it.
Sean Cleghorn 517