Pembro Plus Chemo: Practice-Changing for mNSCLC

Alexander M. Castellino, PhD

April 17, 2018

CHICAGO — Patients with nonsquamous metastatic non-small cell lung carcinoma (NSCLC) lived significantly longer and had a 48% reduced risk for disease progression if they received pembrolizumab (Keytruda, Merck) in addition to chemotherapy compared with those who received standard chemotherapy alone.  

These data for overall survival (OS) and progression-free survival (PFS) from the  KEYNOTE-189 were presented here at the American Association for Cancer Research (AACR) 2018 Annual Meeting and were simultaneously published online in the New England Journal of Medicine.

The combination of pembrolizumab with pemetrexed and carboplatin chemotherapy is already approved by the US Food and Drug Administration for first-line treatment in this patient population, based on results from a small phase 2 trial (KEYNOTE-021).

However, this approach has not been widely adopted, commented presenter Leena  Gandhi, MD, PhD, associate professor in the Department of Medicine and director of the Thoracic Medical Oncology Program at the Perlmutter Cancer Center at NYU Langone Health, New York City.

The approval was based on a small phase 2 trial that was conducted "only in the US and only in a small number of patients," Gandhi told Medscape Medical News.

"Although that phase 2 study led to approval for the first-line use of pembrolizumab in combination with pemetrexed and carboplatin-based chemotherapy, clinicians typically look for results from large randomized studies to inform clinical decisions," she added.

Now clinicians have data from a large, international phase 3 study.

"This phase 3 trial demonstrated an improvement in overall response rate [ORR], PFS, and OS across all groups of patients, irrespective of PD-L1 [programmed cell death-ligand-1] expression, halving the risk of death, which is an unprecedented effect of therapy in the first-line setting for advanced nonsquamous NSCLC without EGFR or ALK alterations," Gandhi said in an AACR news statement.

She told Medscape Medical News she believes that the new results from the phase 3 KEYNOTE-189 trial "are practice changing."

The discussant for the study agreed. Roy S. Herbst, MD, PhD, Ensign Professor of Medicine and director of the Thoracic Oncology Program at the Yale Cancer Center, New Haven, Connecticut, agreed that this combination of pembrolizumab with pemetrexed and platinum-based chemotherapy (carboplatin or cisplatin) represents a new standard of care.

"This randomized trial is positive for all the endpoints and sets a new standard for first-line metastatic NSCLC," he said. "The survival benefit is seen across all subpopulations, and the combination was well-tolerated, with only slightly increased adverse events," he added.

Study Details

KEYNOTE-189 enrolled 616 patients with stage IV NSCLC with no ALK or EGFR mutations who had received no prior therapy for metastatic disease. Patients were randomly assigned in a 2:1 ratio to receive the combination of pembrolizumab plus chemotherapy (n = 410) or chemotherapy alone (n = 206).

All patients received pemetrexed 500 mg/m2 and carboplatin with area under the curve of 5 or cisplatin 75 mg/m2 for four cycles every 3 weeks, and then received maintenance pemetrexed every 3 weeks.

Patients randomly assigned to immunotherapy also had four cycles of pembrolizumab 200 mg every 3 weeks followed by maintenance pembrolizumab for up to 31 cycles.

After a median follow-up of 10.5 months, Gandhi reported that twice as many patients in the pembrolizumab plus chemotherapy  group remained on therapy as in the chemotherapy group: 34% vs 18%.

Sixty-seven patients from the chemotherapy group crossed over to the pembrolizumab group, and 18 patients received anti-PD-(L)-1 therapy outside the study.

With a hazard ratio (HR) of 0.49, patients receiving pembrolizumab plus chemotherapy  had a 51% reduced risk for death (P < .00001) compared with patients receiving chemotherapy. Similarly, patients had a 48% reduced risk for disease progression (HR for PFS, 0.52; P < .00001).

Median OS was not reached for patients receiving the combination of pembrolizumab plus chemotherapy and was 11.3 months for patients receiving chemotherapy alone; correspondingly, median PFS was 8.8 and 4.9 months, respectively.

In addition, Gandhi showed that OS and PFS benefits were seen across all subgroups of patients regardless of PD-L1 expression levels; however, OS and PFS benefits were numerically higher for patients with higher PD-L1 levels.

"Despite a 50% crossover rate, there was still a very clear survival benefit, suggesting that combination therapy upfront may be better than if PD-1/PD-L1 inhibitors are given later in the course of illness," Gandhi said in an AACR news statement.

ORR was 47.6% for patients receiving pembrolizumab plus chemotherapy and 18.9% for patients receiving chemotherapy alone. Again, ORR benefit was seen across all patient subgroups, regardless of PD-L1 levels.

The combination of pembrolizumab plus chemotherapy was associated with more adverse events (AEs) than was chemotherapy alone, such as AEs leading to discontinuation of any treatment (27.7% for combination therapy vs 14.9% for chemotherapy alone), AEs leading to discontinuation of all treatment (13.8% vs 7.9%), and death (6.7% vs 5.9%).

Immune-related AEs occurred in twice as many patients in the pembrolizumab group as in the chemotherapy group: 22.7% vs 11.9%. Three patients in the pembrolizumab group died of immune-mediated AEs.

"Immune-related grade 3 to 5 adverse events were similar to those seen with pembrolizumab monotherapy," Gandhi said.

She also highlighted acute kidney injury, which was seen in 5.2% of patients in the pembrolizumab plus chemotherapy  group vs 0.5% of patients in the chemotherapy-only group. "Each agent is independently associated with renal toxicity," she pointed out. Two patients in the pembrolizumab group died of acute kidney injury. "Most events occurred in the setting of acute illness and were likely multifactorial," Gandhi said.

Gandhi noted that a limitation of the study is that it was not designed to assess whether patients with high PD-L1 expression benefited from pembrolizumab alone vs pembrolizumab plus chemotherapy. In addition, she said, "The control arm did not perform as well as some historical controls, but this was a rigorous randomized study which did show a clear difference between the two arms."

Pembrolizumab is also approved for use alone in the first-line use setting in NSCLC, but the KEYNOTE-024 study for that approval was conducted in patients with a high PD-L1 expression, which requires biopsy testing for PD-L1 levels.

This testing is still required, Gandhi told Medscape Medical News, and in nonsquamous NSCLC, testing for PD-L1 is now routine. A subgroup of patients still benefit from pembrolizumab alone, which requires PD-L1 testing, she emphasized.

In his discussion, Herbst also noted the need for PD-1 biomarker assay for patient selection. "The ORR, PFS, and OS appear to track with PD-L1 status, which remains important."

He also pointed out that patients with a PD-L1 tumor proportion score less than 1% and between 1% and 49% should receive the combination of pembrolizumab and chemotherapy, but patients with the highest level of PD-L1 (tumor protection score ≥ 50%) now have the option of pembrolizumab alone or pembrolizumab and chemotherapy depending on clinical circumstances and toxicity concerns.

However, Herbst also noted that other biomarkers, such as tumor mutational burden, should also be explored.

"Despite the remarkable results, only 34% of patients remain progression free at 1 year," Herbst noted. Longer follow-up is needed to fully understand the effects of combination immunotherapy, he concluded.   

The study was supported by Merck. Gandhi has served on scientific advisory boards for Merck, Genentech/Roche, Syndax, Ignyta, and AstraZeneca and has obtained research funding from Merck. Herbst reported consulting with Astra-Zeneca, Lilly, Roche/Genentech, and Pfizer.

American Association for Cancer Research (AACR) 2018 Annual Meeting. Abstract CT075. Presented April 16, 2018.

N Engl J Med. Published online April 16, 2018. Full text

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