Adding PD-1 Inhibition to Chemotherapy Boosts Response in Untreated NSCLC

Corey J. Langer, MD

The addition of pembrolizumab (Keytruda) to frontline platinum-based chemotherapy for advanced non—small cell lung cancer (NSCLC) almost doubled the response rate compared with chemotherapy alone, a randomized trial showed.

The group that received the PD-1 inhibitor in addition to chemotherapy had an overall response rate (ORR) of 55%, whereas 29% patients responded to standard chemotherapy. The median time to response was 1.5 months with pembrolizumab and 2.7 months without.

Among patients receiving pembrolizumab, the risk of progression or death was almost cut in half, as reported at the 2016 ESMO Congress.

“Pembrolizumab, in combination with carboplatin and pemetrexed, is superior to carboplatin and pemetrexed alone as first-line therapy for advanced, nonsquamous non—small cell lung cancer,” said Corey J. Langer, MD, director of Thoracic Oncology at University of Pennsylvania. “The combination is tolerable and has a manageable safety profile.

“Pembrolizumab, in combination with carboplatin and pemetrexed, could be an effective treatment option for patients with chemotherapy-naïve, advanced, nonsquamous non—small cell lung cancer,” he added.

Conventional platinum-based chemotherapy is standard of care for untreated, advanced NSCLC that has no targetable genetic alterations. Pembrolizumab has demonstrated single-agent efficacy in advanced NSCLC and has approval in Europe for treatment of PD-L1—positive disease that has progressed after 1 or more prior chemotherapy regimens.

The rationale for combining chemotherapy and immunotherapy has its basis in chemotherapy’s potential immunologic effects, which include inhibition of suppressive immune cells, induction of immunogenic cell death, enhanced presentation of tumor antigens, induction of maturation and activation of dendritic cells, and enhancement of effector T-cell function.

Moreover, chemotherapy can induce PD-L1 expression on tumor cells, providing a strong rationale for specific use in combination with a PD-1 inhibitor, Langer noted.

In a prior phase I/II study, the addition of pembrolizumab to carboplatin/pemetrexed chemotherapy resulted in an ORR of 71%, with no difference according to tumor level of PD-L1 expression, as well as a median progression-free survival (PFS) of 10.2 months (ASCO 2016, Abstract 9016).

Continuing the evaluation of pembrolizumab with chemotherapy in untreated NSCLC, investigators in a multicenter phase II trial enrolled 123 patients with untreated nonsquamous stage IIIb/IV NSCLC that had no targetable mutations. The trial had no specific requirement for PD-L1 expression, although samples were obtained for PD-L1 assessment.

Patients were randomized 1:1 to receive carboplatin at 5 mg and pemetrexed at 500 mg/m2 every 3 weeks for 4 cycles, with or without pembrolizumab at 200 mg every 3 weeks for 2 years. Patients who received chemotherapy alone could cross over to pembrolizumab at disease progression. Most patients in both treatment groups received pemetrexed maintenance therapy.

The primary endpoint was overall response rate and the principal secondary endpoint was PFS. Data analysis comprised 123 randomized patients.

The pembrolizumab group was younger (median age 62.5 vs 66.0 in the control group). Women accounted for the majority of patients in both groups (~60%). More than 90% of patients had adenocarcinoma, and all but a few patients had stage IV disease. Levels of PD-L1 expression were evenly distributed across the cutoffs of <1%, 1% to 49%, and ≥50%.

The results showed that the addition of pembrolizumab to chemotherapy led to a 26% absolute difference in response rate (P = 0.0016). More than 5 times as many patients in the control group had progressive disease as best response (11 vs 2). At data cutoff, 88% of responses were ongoing in the pembrolizumab group as were 78% of responses in the control group.

Analysis of response by PD-L1 expression showed little variation in the pembrolizumab group. Patients with PD-L1 expression <1% had an ORR of 57% compared with 54% for patients with higher levels of PD-L1 expression. In the patients who received chemotherapy alone, the response rate was 13% in association with PD-L1 expression <1% and 38% for PD-L1 expression ≥1%.

After a median follow-up of 10.6 months, the addition of pembrolizumab was associated with a 47% reduction in the hazard for progression or death, as compared with chemotherapy alone (P = 0.0102). Pembrolizumab-treated patients had an estimated median PFS of 13.0 months as compared with 8.9 months in the control group (HR, 0.53; 95% CI, 0.31-0.91). The 6-month PFS was 77% with pembrolizumab and 63% without. Overall survival data remained immature, and no difference had emerged between the groups.

Grade 3/4 treatment-related adverse events occurred more often with pembrolizumab (39% vs 26%), but discontinuation secondary to adverse events occurred at a similar rate in the 2 treatment groups (10% with pembrolizumab, 13% without).

Langer CJ, Gadgeel SM, Borghaei H, et al. Randomized phase 2 study of carboplatin and pemetrexed + pembrolizumab as first-line therapy for advanced NSCLC: KEYNOTE-021 cohort G. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark.