Corey Langer, MD
Less than 3 years after the first checkpoint blockade immunotherapies were introduced for non–small cell lung cancer (NSCLC), the treatment paradigm is poised for dramatic changes in frontline care for patients with metastatic disease.
The FDA has granted priority reviews for 2 applications for first-line regimens for patients with metastatic nonsquamous disease: pembrolizumab (Keytruda) in combination with standard chemotherapy and atezolizumab (Tecentriq) plus bevacizumab (Avastin), carboplatin, and paclitaxel. Adding to the interest are recent study results for the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) in patients with squamous or nonsquamous histology with high tumor mutational burden (TMB), an emerging biomarker.
The flurry of research developments is noteworthy even amid the rapid advancements in the lung cancer field that have occurred in less than a decade. The emerging combinations, if approved, would expand the use of the PD-1 immune checkpoint inhibitors pembrolizumab and nivolumab and the PD-L1 inhibitor atezolizumab, which already have lung cancer indications. Ipilimumab, which targets the CTLA-4 checkpoint, currently is approved only in melanoma settings.
The potential for expanding the use of these agents in NSCLC was showcased at this year’s American Association for Cancer Research (AACR) Annual Meeting in April (Table). Additional results for atezolizumab were reported at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in June. The study findings pave the way for greater opportunities to personalize care for patients, according to several experts who put the findings into perspective in interviews with OncologyLive®
Table. Key Findings in Frontline Lung Cancer Studies
In the KEYNOTE-189 trial, investigators found that pembrolizumab with pemetrexed (Alimta) and either cisplatin or carboplatin showed a much greater benefit than chemotherapy alone, reducing the risk of death by over 50% in patients with nonsquamous NSCLC without EGFR
At a median follow-up of 10.5 months, the estimated 12-month overall survival (OS) rate was 69.2% (95% CI, 64.1%-73.8%) in the pembrolizumab arm compared with 49.4% (95% CI, 42.1%-56.2%) in the control group (HR, 0.49; 95% CI, 0.38-0.64; P
The HR of 0.49, indicating the reduced risk of death in the pembrolizumab arm, is “absolutely astounding,” said Corey J. Langer, MD, director of thoracic oncology at the Hospital of the University of Pennsylvania Abramson Cancer Center in Philadelphia. In patients with a PD-L1 expression score of 50% or greater (% of tumor cells with membranous staining), the HR was even lower at 0.42. “In more than 30 years of being a clinical researcher I have never seen results like that in thoracic oncology. I’ve just never seen that profound a benefit, ever,” he said. “In my mind this really makes that triplet regimen, if not the standard care, certainly a strong standard care.”
Langer was the lead investigator on the KEYNOTE-021 cohort G trial, which showed significant increases in objective response rate (ORR) and progression-free survival (PFS) with the pembrolizumab triplet, and he said his practice has been using the treatment since it received FDA accelerated approval a year ago.3
The new results, which now form the basis of the application for permanent approval in this setting, cement the change and may compel skeptics to use the combination, he said.
Jessica R. Bauman, MD, a thoracic oncologist at Fox Chase Cancer Center in Philadelphia, said she held off changing her practice after the small KEYNOTE- 021 study (N = 123) came out but is now starting to administer the triplet therapy. She said KEYNOTE-189 (N = 616) shows there is “clear synergy” of immunotherapy with chemotherapy, with “vast improvement” at all endpoints including ORR and PFS, as well as benefit to patients in all PD-L1 expression level groups. She said physicians must now consider when to use the triplet for patients with high-PD-L1–expression and when to stick with pembrolizumab monotherapy. The latter which has been a standard frontline treatment for patients without EGFR
mutations or ALK
translocations since the KEYNOTE-024 trial results were published in 2016.4