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Add-On Keytruda Boosts OS in Advanced Squamous Lung Cancer

— Benefit seen across all subgroups, PD-L1 expression levels

Ƶ MedicalToday

TORONTO -- Adding the PD-1 inhibitor pembrolizumab (Keytruda) to a standard chemotherapy backbone improved survival outcomes in patients with squamous non-small cell lung cancer (NSCLC), the phase III KEYNOTE-407 trial found.

Median overall survival (OS) was 15.9 months in patients treated with pembrolizumab plus carboplatin and either paclitaxel or nab-paclitaxel compared with 11.3 months in those treated with chemotherapy plus placebo, at a median follow-up of 7.8 months (HR 0.64, 95% CI 0.49-0.85, P<0.001), reported Balazs Halmos, MD, of Montefiore Medical Center-Albert Einstein College of Medicine in New York City, at the World Conference on Lung Cancer (WCLC). The results were also simultaneously published in the .

At 6.4 versus 4.8 months, median progression-free survival (PFS) was also higher in the pembrolizumab group (HR 0.56, 95% CI 0.45-0.70, P<0.001). And PFS favored the PD-1 inhibitor-treated group in all pre-specified subgroups -- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, sex, age, type of chemotherapy, and PD-L1 expression levels.

"It represents a new standard of care for physicians, and more important, it provides a new hope for patients," co-investigator Luis Paz‑Ares, MD, of Hospital Universitario 12 de Octubre in Madrid, told Ƶ, noting that the 36% reduction in mortality risk came with a reasonable trade-off in added side effects.

OS results were consistent across most pre-specified subgroups, including PD-L1 expression level:

  • <1%: HR 0.61 (95% CI 0.38-0.98)
  • ≥1%: HR 0.65 (95% CI 0.45-0.92)
  • 1% to 49%: HR 0.57 (95% CI 0.36-0.90)
  • ≥50%: HR 0.64 (95% CI 0.37-1.10)

The results complement the KEYNOTE-189 trial, said Paz-Ares. That trial, presented at the 2018 American Association for Cancer Research (AACR) meeting, showed that 1-year survival improved dramatically in advanced non-squamous NSCLC patients who received pembrolizumab in addition to chemotherapy as initial therapy.

In his WCLC presentation, Halmos presented data on an exploratory analysis of KEYNOTE-407 based on investigator's choice of chemotherapy -- 60.1% of patients in the study received paclitaxel and 39.9% received nab-paclitaxel. The overall survival HRs for pembrolizumab-treated patients were 0.67 with paclitaxel (95% CI 0.48-0.93) and 0.59 with nab-paclitaxel (95% CI 0.36-0.98), respectively.

The rate of overall response was similar between the two (57.4% vs 58.7%, respectively), but grade ≥3 adverse events (AEs) were slightly less frequent with paclitaxel (63.9% vs 78.9%).

While cautioning that "cross trial comparisons are fraught with potential problems," Paul Bunn Jr., MD, of the University of Colorado in Denver, told Ƶ that KEYNOTE-407 and past trials provide evidence as to which patients are most appropriate for, or might benefit most from, immunotherapy alone or concurrently with chemotherapy.

For those with PD-L1 tumor proportion scores >49%, pembrolizumab alone appears to be the best option, he said. But for those who are very sick and need a rapid response, pembrolizumab with chemotherapy might be a better option as a higher overall response rate was reported with the combination.

For those with a PD-L1 score <49%, pembrolizumab seems to be more effective than atezolizumab (Tecentriq) when paired with chemotherapy, according to Bunn, adding that if these patients aren't eligible for chemotherapy -- e.g., those with ECOG performance status of 2-3 -- pembrolizumab alone is acceptable as it "tied chemo" in those with PD-L1 scores <49%.

KEYNOTE-407 was a double-blind, multicenter trial that randomized 559 patients with metastatic, previously untreated squamous NSCLC (1:1) to treatment with four cycles of carboplatin and either paclitaxel or nab-paclitaxel plus 200-mg pembrolizumab or placebo for up to 35 cycles.

Overall, AEs were similar between the two treatment arms, with grade ≥3 AEs occurring in 69.8% of the pembrolizumab group versus 68.2% of the placebo group.

But immune-related AEs and infusion reactions were more frequent in those treated with pembrolizumab (28.8% versus 8.6% with placebo), as were grade ≥3 events (10.8% vs 3.2%, respectively). And in the pembrolizumab group, there were nearly twice as many AEs leading to treatment discontinuation of either all drugs (12.2% vs 6.4%) or one of the therapies (19.4% vs 10.4%). Deaths related to treatment occurred in 3.6% and 2.1%, respectively.

The most common grade 3/4 AEs (≥5% of patients) in the pembrolizumab and placebo groups, respectively, were anemia (15.5% vs 20.4%), neutropenia (22.7% vs 24.6%), and thrombocytopenia (6.8% vs 6.4%).

Disclosures

The study was funded by Merck Sharp & Dohme.

Halmos disclosed multiple relevant relationships with industry including Merck Sharp & Dohme, Bristol-Myers Squibb (BMS), Genentech, Lilly, AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, Ignyta, and Takeda.

Paz-Ares disclosed relevant relationships with Merck Sharp & Dohme, BMS, AstraZeneca, Lilly, Pfizer, Roche, Amgen, Takeda, and Incyte.

Primary Source

New England Journal of Medicine

Paz-Ares L, et al "Pembrolizumab plus chemotherapy for squamous non–small-cell lung cancer" N Engl J Med 2018; DOI:10.1056/NEJMoa1810865.