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Atezolizumab prolongs OS in advanced NSCLC
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Atezolizumab extended survival compared with standard-of-care docetaxel in patients with advanced non–small cell lung cancer regardless of their PD-L1 expression, according to results of a randomized, open-label, phase 3 clinical trial published in The Lancet.
Atezolizumab (Tecentriq, Genentech) also demonstrated a favorable safety profile.
“Recently, important advances in the treatment of lung cancer have come from immunotherapies that target programmed death-ligand 1 and programmed death-1 pathway,” Achim Rittmeyer, MD, of University Göttingen in Germany, said in a press release. “Atezolizumab reinvigorates patients’ immune systems against cancer and our trial has shown that this has significant results for their survival.”
Docetaxel has been the standard of care for second- or third-line treatment of NSCLC, but its efficacy has been offset by substantial toxic effects.
The development of antibodies like atezolizumab that target PD-L1 and PD-1 represents an important advance in the management of metastatic NSCLC, Rittmeyer and colleagues wrote.
Researchers examined the efficacy and safety of atezolizumab compared with docetaxel in patients with locally advanced or metastatic, previously treated NSCLC.
The analysis included 1,125 adults from 194 academic or community oncology centers in 31 countries who were enrolled from March 11, 2014, to April 29, 2015. Patients had received one or two previous cytotoxic chemotherapy regimens — including one or more platinum-based combination therapies — for stage IIIB or IV NSCLC. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel were excluded.
In total, 425 patients (61% male; median age, 63 years) were randomly assigned to receive 1,200 mg IV atezolizumab and 425 patients (61% male; median age, 64 years) received 75 mg/m2 docetaxel every 3 weeks.
OS in the intention-to-treat and PD-L1–expressing populations — defined as TC1/2/3 or IC1/2/3, or PD-L1 expression on at least 1% of tumor cells or tumor-infiltrating immune cells (atezolizumab, n = 241; docetaxel, n = 222) — served as primary endpoints.
Patients in the intention-to-treat population assigned atezolizumab showed significantly longer OS compared with those assigned docetaxel (13.8 months vs. 9.6 months; HR = 0.73, 95% CI, 0.62-0.87).
The TC1/2/3 or IC1/2/3 population also had improved OS with atezolizumab over docetaxel (15.7 months vs. 10.3 months; HR = 0.74; 95% CI, 0.58-0.93).
Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved OS with atezolizumab (12.6 months vs. 8.9 months; HR = 0.75; 95% CI, 0.59-0.96).
OS also was similarly improved in patients with squamous (HR = 0.73; 95% CI, 0.54-0.96) or nonsquamous (HR = 0.73; 95% CI, 0.6-9-0.89) histology.
Rittmeyer and colleagues reported fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (15%) than with docetaxel (43%). There was one treatment-related death from a respiratory tract infection in the docetaxel group.
“This is the first phase 3 trial of a PD-L1–directed immunotherapy in lung cancer,” researcher David Gandara, MD, director of thoracic oncology at UC Davis Comprehensive Cancer Center, said in the release. “The fact that it improves survival in patients with all categories of PD-L1 expression is highly encouraging and adds to the already known benefits of immunotherapy in lung cancer.”
In an accompanying editorial, Charlotte LeDuc, MD, and Elisabeth Quoix, MD, of the department of pneumology at University Hospital in Strasbourg, France, point out that the limited predictive value of assessing PD-L1 positivity, as well as the absence of homogenization between assays, represent major limitations for routine clinical use of assessing PD-L1 positivity on immune cells or tumor cells.
“In this study authors have chosen to assess PD-L1 expression both in immune cells and tumor cells with four expression levels, which appears a tiresome task in clinical practice,” LeDuc and Quoix wrote. “The fact that even patients with low or undetectable PD-L1 expression in their tumors might benefit from atezolizumab confirms the imperfection of this biomarker.”
However, the time when chemotherapy will no longer be the mainstay of treatment for metastatic NSCLC is perhaps not so far away, LeDuc and Quoix added.
“It would be unthinkable and unethical to deprive these patients of immunotherapy, even if the OS rate and the survival benefit are lower than for patients with higher PD-L1 expression,” they wrote. “More investigations are needed to find a more specific and powerful predictive biomarker, especially in patients with low or undetectable PD-L1 expression.” – by Chuck Gormley
Disclosure: Gandara reports grants from and consultant roles with Bristol-Myers Squibb, Genentech and Merck. Rittmeyer reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Roche and Pfizer. Please see the full study for a list of all other researchers’ financial disclosures. Quoix reports an investigator role in an immune checkpoint trial unrelated to this study for AstraZeneca, Bristol-Myers Squibb and Merck. Quoix also reports a coinvestigator role in the BIRCH trial conducted by Roche, the first phase 2 trial of atezolizumab. Leduc reports no relevant financial disclosures.
Perspective
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ECOG 1594 compared three different platinum doublets to a comparator arm of paclitaxel and cisplatin. It showed no difference in outcomes and a modest benefit at best for all regimens. Since the study’s publication, it became abundantly clear that a plateau has been reached with chemotherapy in the treatment of non–small cell lung cancer.
Further, docetaxel — which was approved for second-line treatment in 1999 — has remained the mainstay of treatment for the past 15 years. The addition of the antiangiogenics bevacizumab (Avastin, Genentech) in the font-line and ramucirumab (Cyramza, Eli Lilly) in the second-line setting has provided some, albeit modest, improvement. It was clear that a different approach for the treatment of NSCLC was needed.
Identification of oncogenic drivers — starting with EGFR mutations and EML-ALK translocations — represented a breakthrough. Tyrosine kinase inhibitors have provided significant improvement in outcome and changed the natural history of cancer harboring these alterations.
Patients with actionable oncogenic drivers, collectively, represent only approximately 25% of patients with lung cancer. For the remaining 75% of patients, chemotherapy had remained the only option until checkpoint inhibitors provided an alternative approach.
Based on results of the KEYNOTE-024 trial, pembrolizumab (Keytruda, Merck) — a PD-1 monoclonal antibody — replaced chemotherapy as the standard first-line choice for the subset of patients with PD-L1 expression greater than 50%. In that trial, such patients were randomly assigned to receive either pembrolizumab or an investigator’s choice platinum doublet. Despite allowance of crossover, pembrolizumab demonstrated superior OS compared with chemotherapy (median OS, not reached vs. 9.4 months; HR = 0.6, 95% CI, 0.41-0.89). This subset represents roughly 30% of patients with NSCLC.
In the second line, checkpoint inhibitors also replaced chemotherapy as a preferred option based on the CheckMate 017 and 057 randomized clinical trials of nivolumab (Opdivo, Bristol-Myers Squibb) and KEYNOTE-010 study of pembrolizumab compared with docetaxel. In the OAK study by Rittmeyer and colleagues, atezolizumab (Tecentriq, Genentech) was the first monoclonal antibody that targets PD-L1 to demonstrate improved survival compared with docetaxel in patients who had received one or more lines of treatment.
The KEYNOTE-010 trial of pembrolizumab enrolled patients with more than 1% PD-L1 expression, whereas in the nivolumab and atezolizumab studies, all patients were included. In Checkmate 017, which enrolled patients with squamous histology, survival in the nivolumab arm was superior to docetaxel regardless of PD-L1 expression. In Checkmate 057, enrolling patients with nonsquamous histology, survival was improved in patients with PD-L1–positive expression, and was at least equivalent to docetaxel in patients with PD-L1–negative tumors. In the OAK study, the benefit was demonstrated regardless of PD-L1 status.
Thus, the importance of PD-L1 expression remains a major question. PD-L1 expression should remain a positive predictive factor for response, but patients with negative PD-L1 expression may still sustain benefit from checkpoint inhibitors.
Future research should focus on at least two questions: how to increase the percent of patients who respond to checkpoint inhibitors and how to further prolong the duration of response.
Combination trials with chemotherapy, CTLA-4 inhibitors and other novel agents are ongoing and may help answer these questions.
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Brahmer J, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1504627.
Herbst RS, et al. Lancet. 2015;doi:10.1016/S0140-6736(15)01281-7.
Reck M, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1606774.
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