Pembrolizumab Plus Chemotherapy Elicits Intriguing Responses in Nonsquamous NSCLC

Delvys Rodriguez-Abreu, MD

In the phase 3 KEYNOTE-189 clinical trial (NCT02578680), the addition of pembrolizumab (Keytruda) to pemetrexed and platinum chemotherapy as treatment of patients with treatment-naïve metastatic nonsquamous non–small cell lung cancer (NSCLC) improved outcomes over pemetrexed and platinum therapy with placebo.

After a median follow-up of 31.0 months (range, 26.5-38.8), 17 patients in the pembrolizumab arm were still alive and receiving treatment compared with 1 patient in the placebo group. In addition, 84 patients crossed over from the placebo arm to the pembrolizumab arm.

The median overall survival (OS) was 22.0 months with pembrolizumab (95% CI, 19.5-24.5) versus 10.6 months (95% CI, 8.7-13.6) with placebo (HR, 0.56; 95% CI, 0.46-0.69). The median progression-free survival (PFS) was 9.0 months with pembrolizumab (95% CI, 8.1-10.4) versus 4.9 months (95% CI, 4.7-5.5) with placebo (HR, 0.49; 95% CI, 0.41-0.59).

The 2-year OS rate was 45.7% with pembrolizumab versus 27.3% with placebo, and the 2-year PFS rate was 22.0% versus 3.4%, respectively. The overall response rate (ORR) was 48.3% with pembrolizumab versus 19.9% with placebo. Among the 56 patients who completed 35 cycles of pembrolizumab treatment, the ORR was 85.7%, which included 4 complete responses, 44 partial responses, and 8 cases of stable disease.

Overall, 292 (72.1%) patients in the pembrolizumab arm and 135 (66.8%) patients in the placebo arm had grade 3 through 5 adverse events (AEs). Pembrolizumab in combination with pemetrexed and platinum chemotherapy had a manageable toxicity profile among these patients.

In an interview with Targeted Oncology, Delvys Rodriguez-Abreu, MD, medical oncologist at Hospital Universitario Insular de Gran Canaria in Gran Canaria, Spain, discussed the findings from the KEYNOTE-189, which established the combination of pembrolizumab plus pemetrexed and platinum chemotherapy as the new standard of care for patients with metastatic nonsquamous NSCLC.

TARGETED ONCOLOGY: Could you provide some background to the pivotal KEYNOTE-189 trial?

Rodiguez-Abreu: It was a phase 3 randomized trial that compared pembrolizumab plus pemetrexed and platinum chemotherapy versus placebo plus pemetrexed and platinum chemotherapy in nonsquamous NSCLC without EGFR or ALK sensitizing mutations, independent of the expression of PD-L1. Two years ago, we presented the data from the KEYNOTE-189, providing an improvement in OS, PFS, and ORR but with a short follow-up.

This is the final analysis, and the data cutoff was 31 months, which was longer. In this trial, we compared pemetrexed and platinum chemotherapy with or without pembrolizumab in a randomized 2:1. It was 410 patients in the pembrolizumab arm versus 206 patients in the placebo arm.

TARGETED ONCOLOGY: What were the findings from this final analysis?

Rodiguez-Abreu: At the time of the data cutoff, 17 patients were still receiving the study treatment in the pembrolizumab arm compared with 1 patient in the placebo arm. With the longer follow up, I'm happy to say that in the placebo arm, 84 patients crossed over to pembrolizumab. It is around 53% of the patients received immunotherapy as a crossover, and even with this high crossover rate, I’m glad to say that with a longer follow up in this final analysis, we can share with you that the median OS in the pembrolizumab arm was 22 months compared with 10.6 months in the placebo arm for a hazard ratio of 0.56. It is great. The 2-year OS rate in the pembrolizumab is 45% compared with 27% of the patients in the placebo arm. Median PFS was 9 months pembrolizumab plus chemotherapy compared with 4.9 months for the placebo plus chemotherapy arm, with a hazard ratio of 0.49, which is still positive. The 2-year PFS rate was 22% in the pembrolizumab arm versus 3.4% in the placebo arm.

The most important finding is that it [the benefit with pembrolizumab] was independent of expression of PD-L1. It was positive even in those patients with PD-L1 expression less than 1%. It was a very good result also in PD-L1-negative patients. Another good thing is that we analyzed PFS2, and we found that the PFS2 to was 17 months for the pembrolizumab arm versus 9 months for the placebo arm for a hazard ratio of 0.15. ORR is also important. When we combine pembrolizumab with chemotherapy in nonsquamous NSCLC, the probability of response was higher.

We were also worried about the toxicity and safety profile with a longer follow-up. I'm happy to share with you also that grade 3 to 5 AEs were 72% in the pembrolizumab arm compared with 67% in the placebo arm.

We can now say that in this final analysis of the KEYNOTE-189 study, pembrolizumab plus chemotherapy improved OS, PFS, PFS2, and ORR over placebo plus chemotherapy, regardless of the PD-L1 expression. I can say that this is a new standard of care for this group of patients.

TARGETED ONCOLOGY: Are there any remaining questions with this regimen?

Rodiguez-Abreu: We have another subgroup because we previously analyzed patients with brain metastases and liver metastasis and saw that this combination also works [in this subgroup]. It is important to know because we know that these groups of patients with brain and liver metastases usually have bad prognosis with the combination of pembrolizumab and chemotherapy.

TARGETED ONCOLOGY: Is there any other research being done in this space beyond this trial?

Rodiguez-Abreu: Yes, we are running right now a clinical trial based on the KEYNOTE-189 comparing pembrolizumab plus lenvatinib, an anti-angiogenic drug, and we hope to improve the good results of the KEYNOTE-189 in the future.

TARGETED ONCOLOGY: What is the take home message for other oncologists?

Rodiguez-Abreu: We can say that even with longer follow-up, we still have a good result with the combination of pembrolizumab and pemetrexed and platinum chemotherapy, improving OS, PFS, and also the quality of life. I can say that right now, for nonsquamous NSCLC, we don't have doubt that the KEYNOTE-189 is a new standard of care for these patients regardless of PD-L1.

Check out the data from the KEYNOTE-189 study