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Pembrolizumab plus chemotherapy prolongs OS, PFS for metastatic lung cancer
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The addition of pembrolizumab to chemotherapy extended OS and PFS compared with chemotherapy alone among patients with metastatic, squamous, non-small-cell lung cancer, according to results of the randomized phase 3 KEYNOTE-407 trial presented at International Association for the Study of Lung Cancer’s World Conference on Lung Cancer.
The double-blind study included 559 treatment-naive patients with metastatic, squamous NSCLC. Patients who had symptomatic central nervous system metastases, a history of noninfectious pneumonitis that required the use of glucocorticoids, active autoimmune disease or who were receiving systemic immunosuppressive treatment were excluded.
Luis Paz-Ares, MD, chair of the department of medical oncology at Hospital Doce de Octubre, associate professor at Universidad Complutense, and head of the lung cancer unit at the National Oncology Research Center in Madrid, Spain, and colleagues assigned patients to 200 mg pembrolizumab (Keytruda, Merck) or saline placebo on day 1 for up to 35 cycles. All patients also received carboplatin on day 1 and either 200 mg/m2 paclitaxel on day 1 or 100 mg/m2 nanoparticle albumin-bound (nab)-paclitaxel (Abraxane, Celgene) on days 1, 8, and 15, for the first four cycles.
OS and PFS served as primary endpoints.
Median follow-up was 7.8 months.
Results — published simultaneously in The New England Journal of Medicine — showed a consistent OS benefit, regardless of PD-L1 expression. Median OS was 15.9 months (95% CI, 13.2 to not reached) in the pembrolizumab combination arm and 11.3 months (95% CI, 9.5-14.8) in the placebo arm (HR for death = 0.64; 95% CI, 0.49-0.85).
Median PFS was 6.4 months (95% CI, 6.2-8.3) in the pembrolizumab combination arm and 4.8 months (95% CI, 4.3 to 5.7) in the placebo arm (HR for disease progression or death = 0.56; 95% CI, 0.45-0.7).
The response rate was 57.9% (95% CI, 51.9-63.8) in the pembrolizumab group and 38.4% (95% CI,32.7-44.4) in the placebo group.
In PD-L1 tumor proportion score subgroups, the response rates appeared higher among patients who received pembrolizumab compared with placebo (score < 1%, 63.2% vs. 40.4%; score of 1%-49%, 49.5% vs. 41.3%; score 50%, 60.3% vs. 32.9%).
Although differences in grade 3 or higher adverse events were not significant between the two arms (pembrolizumab, 69.8% vs. placebo, 68.2%), treatment discontinuation due to adverse events was more common among those in the pembrolizumab arm (13.3% vs. 6.4%).
The trial is being continued to evaluate long-term efficacy and safety, according to the researchers. – by Jennifer Southall
References:
Paz-Ares, et al. Abstract MA10.08. Presented at: International Association for the Study of Lung Cancer’s World Conference on Lung Cancer; Sept. 23-26, 2018; Toronto, Canada.
Paz-Ares, et al. N Eng J Med. 2018;doi:10.1056/NEJMoa1810865.
Disclosures: The study was funded by Merck Sharp & Dohme. Paz-Ares reports grants from Merck during the conduct of the study, and personal fees from Amgen, AstraZeneca, BMS, Incyte, Lilly, Merck-Serono, Merck, Pfizer, Roche and Takeda outside the submitted work. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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KEYNOTE-407 is practice changing for the treatment of metastatic, squamous NSCLC. There is now clear evidence to support first-line pembrolizumab plus chemotherapy in all histologic subtypes of metastatic NSCLC.
NSCLC — representing 20% to 30% of all lung cancers — has been associated with shorter survival compared with the nonsquamous subtype and, with rare actionable mutations, treatment options beyond cytotoxic chemotherapy have been limited.
Immunotherapy has transformed the landscape of lung cancer treatment. Several checkpoint inhibitors have been FDA approved. PD-L1 has helped define who may receive single-agent pembrolizumab in the first-line setting, but combination therapy has also yielded impressive results. KEYNOTE-189 demonstrated benefit in OS at 12 months (69.2% vs. 49%; HR = 0.49) and median PFS (8.8 months vs. 4.9 months; HR = 0.52) among patients with nonsquamous NSCLC. Additional trials, such as IMpower150 and IMpower131, have also shown efficacy of combination chemotherapy and immunotherapy in nonsquamous and squamous NSCLC. KEYNOTE-407 has now redefined the initial treatment paradigm for patients with squamous lung cancer.
Researchers of KEYNOTE-407 evaluated pembrolizumab plus chemotherapy vs. placebo plus chemotherapy in first-line treatment of advanced, squamous NSCLC with OS and PFS as dual primary endpoints, both of which were statistically positive, despite a crossover rate of 31.7% in the intention-to-treat population. This benefit occurred regardless of PD-L1 status.
Researchers stratified randomization by choice of taxane (paclitaxel vs. nab-paclitaxel) in combination with carboplatin chemotherapy. Paclitaxel was the preferred taxane, representing 60% of patients. Although more than 70% of those who received paclitaxel received all four cycles, about 20% of those who received nab-paclitaxel received all 12 doses, but more than 60% received five to 11 doses and dosing was similar regardless of receiving pembrolizumab or placebo. Regardless, improvements in OS and PFS were confirmed with either taxane.
A recent retrospective study revealed baseline steroid use of prednisone (> 10 mg) was associated with poorer outcomes (ORR, PFS and OS) among patients with NSCLC treated with PD-L1 blockade therapy. Although further research is required, these findings are intriguing when considering choice of taxane, possibly adding support to nab-paclitaxel.
More than 65% of patients in KEYNOTE-407 are considered elderly and most vulnerable to increased toxicities. A study comparing paclitaxel plus carboplatin with nab-paclitaxel plus carboplatin showed that in the elderly subgroup (older than 70 years), median OS was better with nab-paclitaxel plus carboplatin at 19.9 months vs. 10.4 months.
Most recently, the phase 4 ABOUND.70+ study prospectively evaluated nab-paclitaxel plus carboplatin in standard regimen cycled every 21 days compared with adding a 1-week break cycled every 28 days. Results favored the 1-week-break arm in terms of PFS and response rate, with comparable OS and adverse events, suggesting that the regimen is both efficacious and safe in the elderly population.
Now with the addition of pembrolizumab to this regimen, it remains important to reassess these elements in those considered elderly. A comprehensive geriatric assessment in this patient subgroup provides detailed information, potentially mitigating treatment discontinuation and possibly improving outcomes.
References:
Arbour KC, et al. J Clin Oncol. 2018;doi:10.1200/JCO.2018.79.0006.
Gandhi L, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1801005.
Langer CJ, et al. Front Oncol. 2018;doi:10.3389/fonc.2018.00262.
Socinski MA, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1716948.
Socinski MA, et al. Ann Oncol. 2013;doi:10.1093/annonc/mds461.
Kathryn Finch Mileham, MD, FACP
Raghava R. Induru, MD
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