Pembrolizumab Plus Chemotherapy Improves Outcomes Over Chemotherapy Alone in Advanced NSCLC


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Combining immunotherapy with a standard chemotherapy doublet appears to be an attractive option for the front-line treatment of advanced nonsquamous non–small cell lung cancer (NSCLC), according to the results of a phase II study presented at the 2016 European Society for Medical Oncology (ESMO) Congress.1 Experts agreed that a confirmatory phase III trial is needed before this treatment can be viewed as a valid first-line approach, and in fact, a phase III trial is underway.

Pembrolizumab (Keytruda) plus carboplatin/pemetrexed (Alimta) almost doubled overall response rates compared with the chemotherapy doublet alone: 59% vs 29%, respectively. Although not the primary endpoint, the pembrolizumab/chemotherapy arm extended progression-free survival compared with chemotherapy: median progression-free survival was not yet reached in the pembrolizumab-containing arm vs 13 months in the chemotherapy arm.

Pembrolizumab is approved by the U.S. Food and Drug Administration (FDA) for programmed cell death ligand 1 (PD-L1)–expressing NSCLC that has progressed on one or more prior therapy.


The addition of pembrolizumab to platinum-doublet chemotherapy could help a greater number of patients experience durable response more rapidly compared with standard platinum-based chemotherapy alone and may be an effective option for patients with chemotherapy-naive, advanced nonsquamous NSCLC.
— Corey J. Langer, MD

Lead investigator Corey J. Langer, MD, of Abramson Cancer Center of the University of Pennsylvania, Philadelphia, was enthusiastic about these findings, which were published in The Lancet Oncology2 to coincide with the presentation at the ESMO Congress.

“To the best of our knowledge, these data constitute the first published report of a randomized controlled clinical trial in NSCLC to prospectively evaluate the benefit of combining a PD-1 [programmed cell death protein 1] inhibitor and chemotherapy in the first-line setting. These data suggest that the addition of pembrolizumab to platinum-doublet chemotherapy could help a greater number of patients experience durable response compared with standard platinum-based chemotherapy alone and may be an effective option for patients with chemotherapy-naive, advanced nonsquamous NSCLC,” Dr. Langer stated.

Study Details

At the ESMO Congress, Dr. Langer reported on cohort G, comprising patients with NSCLC as part of the KEYNOTE-021 phase II prospective, randomized, open-label study conducted at 26 centers in the United States and Taiwan.

All patients were tested and stratified for PD-L1 expression, but PD-L1 expression was not an inclusion criterion, he explained. The study enrolled 123 patients with chemotherapy-naive stage IIIB or IV nonsquamous NSCLC without targetable EGFR or ALK mutations.

Patients were randomized 1:1 to receive 4 cycles of pembrolizumab at 200 mg plus carboplatin/pemetrexed every 3 weeks followed by pembrolizumab for 24 months and pemetrexed maintenance therapy vs 4 cycles of carboplatin/pemetrexed followed by pemetrexed maintenance therapy. Patients in the control arm (chemotherapy) could cross over to pembrolizumab monotherapy at disease progression, and 51% crossed over or received subsequent immunotherapy.

At a median follow-up of 10.6 months, 47% of patients in the investigational arm and 31% on the control arm remained on therapy.

Response and Survival

For the primary endpoint, the objective response rate was 55% for the pembrolizumab-containing arm vs 29% for chemotherapy alone, significantly favoring the addition of immunotherapy to chemotherapy (P = .0016).

Progression-free survival was also significantly superior in the combined immunotherapy-chemotherapy arm: 13 months vs 8.9 months for chemotherapy alone. At data cutoff, the rate of progression-free survival was 77% vs 63%, respectively.

“This makes KEYNOTE-021 one of the first randomized, controlled trials of first-line therapy for advanced NSCLC in which median [progression-free survival] exceeded 1 year,” he noted.

Immunotherapy Plus Chemotherapy in Advanced Lung Cancer

  • The first randomized trial to evaluate the combination of pembrolizumab plus standard chemotherapy as front-line treatment of advanced NSCLC showed improved response rates and progression-free survival for this approach when compared with standard chemotherapy alone.
  • Response rates were almost double in the overall study population, and the combination led to a 4-month gain in progression-free survival.
  • Patients with PD-L1 expression of 50% or greater did even better on the combination, but numbers were too small to draw a definitive conclusion.

Patients were able to stay on the investigational arm almost twice as long: a median of 8 months vs 4.9 months for chemotherapy alone (P = .010).

Response rates appeared to be similar in patients with PD-L1 expression < 1% and those with higher levels of PD-L1 expression. Using a cutoff score of 50% or greater, a higher proportion of responders were observed, Dr. Langer said. However, the small sample size of the individual PD-L1 subgroups does not allow for a conclusive determination of the relationship between PD-L1 expression and responses in patients treated with pembrolizumab plus chemotherapy.

With early follow-up, there was no difference in overall survival between the two treatment arms: 92% were alive at data cutoff.

Toxicity

The most common treatment-related events of any grade were fatigue (59% in the investigational arm vs 15% in the control arm) and alopecia (14% vs 2%, respectively).

Rates of grades 3 and 4 toxicity were higher in the pembrolizumab-containing arm: 39% vs 26%. They included anemia, decreased neutrophil count, thrombocytopenia, and decreased lymphocyte count. The most common immune-mediated events of any grade in the pembrolizumab-containing arm were hypothyroidism (15%), hyperthyroidism (8%), and pneumonitis (5%).

“There were no major surprises in adverse events. These toxicities did not translate into more deaths,” Dr. Langer noted.

Awaiting Phase III Data

Ongoing phase III studies are evaluating pembrolizumab added to chemotherapy in chemotherapy-naive patients. They include KEYNOTE-189 (carboplatin or cisplatin and pemetrexed plus or minus pembrolizumab) and KEYNOTE-407 (carboplatin and paclitaxel or nab-paclitaxel [nanoparticle albumin-bound paclitaxel, Abraxane) plus or minus pembrolizumab for squamous histology).

“Once this drug is approved, PD-L1 assessment should be part of the standard workup of every patient. Patients cannot afford to wait for these results,” Dr. Langer explained. “PD-L1 is a dynamic marker, and it is not the end of the story. Patients should be rebiopsied at the time of progression,” he added.

Stefan Zimmermann, MD

Stefan Zimmermann, MD

“The combination of pembrolizumab plus standard chemotherapy improves progression-free survival on an already performant control arm, and the response rates are absolutely unheard of in the first-line setting, declared Stefan Zimmermann, MD, of Fribourg Hospital, Switzerland, who moderated a press conference where Dr. Langer presented these data. “However, we have to wait for phase III data before recommending [this approach].” ■

Disclosure: Dr. Zimmermann reported no potential conflicts of interest.

References

1. Langer C, Gadgeel S, Borghaei H, et al: Randomized, phase 2 study of carboplatin and pemetrexed with or without pembrolizumab as first-line therapy for advanced NSCLC: KEYNOTE-021 cohort G. 2016 ESMO Congress. LBA 2949_PR. Presented October 10, 2016.

2. Langer C, Gadgeel S, Borghaei H, et al: Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous, non-small-cell lung cancer. The Lancet Oncology. October 9, 2016 (early release online).


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