Adding Pembrolizumab to Chemotherapy as First-Line Treatment Significantly Improves Outcomes in Patients with Advanced NSCLC

Charles Bankhead

November 2016, Vol 7, No 10 - Lung Cancer


Copenhagen, Denmark—Immunotherapy for advanced non–small-cell lung cancer (NSCLC) took a step toward first-line indication as results from a randomized clinical trial showed that patients who received pembrolizumab (Keytruda) plus chemotherapy had a significantly higher response rate compared with patients who received chemotherapy alone, reported Corey J. Langer, MD, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, at the 2016 European Society for Medical Oncology (ESMO) Congress. The clinical trial results (KEYNOTE-021) were also published in Lancet Oncology, and are available online (Langer CJ, et al. Lancet Oncol. 2016 Oct 9. Epub ahead of print).

The objective response rate (ORR) was 55% with pembrolizumab plus chemotherapy versus 29% with chemotherapy alone. The median time to response was cut nearly in half with the addition of pembrolizumab.

Tumors with and without PD-L1 expression were equally likely to respond to pembrolizumab plus chemotherapy.

“Pembrolizumab, in combination with carboplatin and pemetrexed, is superior to carbo-pemetrexed alone as first-line therapy for advanced, nonsquamous non–small-cell lung cancer,” said Dr Langer. “The response rate is nearly doubled by adding pembrolizu­mab to chemotherapy, and the risk for progression or death is nearly halved. There is no difference in overall survival, but these data are very early.”

“This combination could be an effective treatment option for patients with chemotherapy-naïve, advanced, nonsquamous non–small-cell lung cancer,” he added.

The improvement in response rate is indisputable, said invited discussant Jean-Charles Soria, MD, Gustave Roussy Institute, Villejuif, France. “We have a clear progression-free survival [PFS] benefit and no overall survival advantage.”

Despite the clear advantages demonstrated by the addition of pembroliz­umab, Dr Soria cautioned attendees in the interpretation and extrapolation of the results.

“We have all been sitting in rooms just like this one, listening to very positive phase 2 trials like this one, with no guarantee of a positive phase 3 trial. This has happened many times,” he added.

This phase 2 clinical trial was 1 of 2 studies of first-line pembrolizumab therapy reported at ESMO. The other clinical trial (KEYNOTE-024) (see Pembrolizumab Succeeds, Nivolumab Fails, as First-Line Therapy for Advanced NSCLC) was a phase 3 evaluation of pembrolizumab monotherapy that showed a significant improvement in PFS compared with conventional platinum-based chemotherapy. (Based on those results, the FDA approved pembrolizumab as first-line treatment for NSCLC; see Keytruda Receives New FDA Indication for First-Line Treatment of Metastatic NSCLC.) Dr Soria noted that the phase 2 clinical trial of pembrolizumab plus chemotherapy yielded an even larger difference in PFS than the phase 3 study, although the PFS was assessed at different time points in the 2 studies.

A sound biologic rationale supports the evaluation of combined chemoimmunotherapy in NSCLC, said Dr Langer. Several lines of evidence have suggested that chemotherapy may have multiple immunologic effects. More specifically, evidence has demonstrated that chemotherapy can induce PD-L1 expression on tumor cells.

The KEYNOTE-021 Clinical Trial

At ESMO 2016 Dr Langer reported findings from cohort G of the KEYNOTE-021 clinical trial.

The study included 123 patients with treatment-naïve stage IIIB/IV nonsquamous NSCLC. Patients with EGFR or ALK mutations were excluded, and all patients consented to be assessed for PD-L1 expression, although patients were not selected on the basis of tumor PD-L1 status. PD-L1 positivity was defined as ≥1% expression.

All patients received 4 cycles of carboplatin plus pemetrexed chemotherapy and were randomized to pembroliz­umab 200 mg every 3 weeks, continued for as long as 2 years, or to chemotherapy alone. The primary end point was the ORR. The main secondary end points included PFS, overall survival, and safety. Dr Langer reported data from a median follow-up of 10.6 months.

In addition to a 26% absolute difference in the ORR (P = .0016), the median time to response was 1.5 months with pembrolizumab plus chemotherapy versus 2.7 months with chemotherapy alone. The ORR in the pembro­lizumab group included 33 partial responses, and 20 patients had stable disease. Only 2 patients in the pembrolizumab group had progressive disease as best response compared with 11 patients who received chemotherapy alone, Dr Langer reported.

The median PFS was 13 months with pembrolizumab plus chemotherapy versus 8.9 months with chemotherapy alone, which translated into a 47% reduction in the hazard for disease progression or death (P = .0102). Furthermore, the 6-month PFS was 77% with pembrolizumab plus chemotherapy versus 63% with chemotherapy alone.

Analysis by PD-L1 status showed nearly identical response rates in patients with PD-L1–expressing tumors (54%) and those without PD-L1 expression (57%).

Grade 3 or 4 adverse events were more frequent with pembrolizumab plus chemotherapy (39%) compared with chemotherapy alone (26%), but discontinuation secondary to adverse events occurred at a similar rate with the combination (10%) versus chemotherapy alone (13%). Adverse events (any grade) that occurred more often with the addition of pembrolizumab included fatigue, nausea, rash, vomiting, diarrhea, increased aspartate aminotransferase, and constipation.