Immunotherapy Combos Rapidly Evolving for Lung Cancer

Silas Inman @silasinman
Published: Friday, Jul 27, 2018

Corey J. Langer, MD

Corey J. Langer, MD

The past year has witnessed an explosion in immunotherapy combinations for patients with lung cancer, accompanied by a growing knowledge of biomarkers such as PD-L1 and tumor mutation burden (TMB); however, an exact standard of care remains elusive, according to a presentation by Corey Langer, MD, at the 19th International Lung Cancer Congress (ILCC).

In May 2017, the FDA approved pembrolizumab (Keytruda) in combination with pemetrexed (Alimta) and carboplatin for the treatment of patients with previously untreated metastatic non-squamous non–small cell lung cancer (NSCLC), based on findings from the open-label phase II KEYNOTE-021 cohort G study. The lack of long-term data at the time rendered this a controversial approval; however, in just a little over a year, multiple phase III trials have reported their findings showing a significant advantage for immunotherapy plus chemotherapy over chemotherapy alone.

"This was a highly controversial conditional approval just 1 year ago for this triplet in non-squamous lung cancer, independent of PD-L1," said Langer, professor of medicine at the Hospital of the University of Pennsylvania. "In the absence of the results of a validated phase III, there was tremendous backlash at the time, but time and circumstances have been kind to cohort G."

In updated long-term findings from the KEYNOTE-021 cohort G trial,1 median overall survival (OS) with the immunotherapy combination was not reached (95% CI, 24.5-NR) compared with 21.1 months (95% CI, 14.9-NR) for carboplatin and pemetrexed alone. The 2-year OS rate was 67% with pembrolizumab compared with 48% in the control arm, representing a 44% reduction in the risk of death with the immunotherapy combination (HR, 0.56; 95% CI, 0.32-0.95).

Findings from the KEYNOTE-189 trial,2 which were published in the New England Journal of Medicine, further confirmed the efficacy of the combination of immunotherapy with chemotherapy. The estimated 12-month 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 <.001).

The median progression-free survival (PFS) in the pembrolizumab group was 8.8 months (95% CI, 7.6-9.2) versus 4.9 months (95% CI, 4.7-5.5) in the control arm (HR, 0.52; 95% CI, 0.43-0.64; P <.001). Median OS was not reached with pembrolizumab versus 11.3 months (95% CI, 8.7-15.1) in the control arm.

With these combination data available, the question is now whether to utilize pembrolizumab as a single-agent or in combination with chemotherapy, Langer noted. For this, he looked to data for the single-agent PD-1 inhibitor from the KEYNOTE-042 trial, which was presented at the 2018 ASCO Annual Meeting.

In this phase III trial,3 OS correlated with greater levels of PD-L1 expression, with those having a tumor proportion score (TPS) ≥50% having the best outcomes. The median OS was 20 months with pembrolizumab versus 12.2 months with chemotherapy (HR, 0.69; 95% CI, 0.56-0.85; P = .0003). However, in an exploratory analysis of patients with PD-L1 TPS of 1% to 49%, the median OS was 13.4 months with pembrolizumab compared with 12.1 months for chemotherapy (HR, 0.92; 95% CI, 0.77-1.11).

Based on these findings, Langer recommended using the combination for most patients with PD-L1 expression between 1% and 49%. In those with PD-L1 expression ≥50%, he considered single-agent pembrolizumab, particularly for those who were older, with a low metastatic burden, and significant comorbidities. However, in younger patients, with high metastatic burden and aggressive tumors, Langer felt the combination was best.

"KEYNOTE-189 showed a clear advantage for the triplet compared with standard chemo. There's an improvement in OS, PFS, and response rate, validating the cohort G data," he said. "However, single-agent pembrolizumab is still arguably a standard. There's less toxicity and lower costs for single-agent pembrolizumab, it also doesn't preclude the option of going to pemetrexed and carboplatin at the time of progression."

The phase III INSIGNA trial is being planned, which will compare first-line pembrolizumab alone with the agent in combination with chemotherapy for patients with advanced nonsquamous NSCLC. However, the trial will include patients with PD-L1 expression of 1% of higher, which caused Langer consternation. He felt this question was less relevant than a comparison in those with ≥50% expression.

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