Pembrolizumab/Chemo Demonstrates Continued OS Improvement in Nonsquamous NSCLC

Jhanelle Gray, MD

Pembrolizumab (Keytruda) in combination with chemotherapy continued to show improved overall survival (OS) and progression-free survival (PFS) compared with chemotherapy alone in patients with previously untreated metastatic nonsquamous non–small cell lung cancer (NSCLC), according to updated data from the phase 3 KEYNOTE-189 trial that were presented virtually during the 2020 World Conference on Lung Cancer Singapore.¹

These data also included outcomes for patients completing all 35 cycles of pembrolizumab, demonstrating promising rates of survival for this group.

“Pembrolizumab plus pemetrexed-platinum continued to provide overall survival [OS] and progression-free survival benefit versus placebo plus chemotherapy,” Jhanelle Gray, MD, program coleader of Chemical Biology & Molecular Medicine and chair of the Department of Thoracic Oncology at Moffitt Cancer Center, said during a presentation of the data. “Patients who received 35 cycles, or 2 years, of pembrolizumab had durable responses and the safety profile was manageable.”

This study provided rationale for the use of frontline pembrolizumab plus platinum-based chemotherapy in the indicated patient population, leading to its FDA approval in 2018.² In the primary analysis, the median OS was not reached versus 11.3 months, respectively, indicating a 51% reduction in the risk of death with the use of this experimental therapy (HR, 0.49; 95% CI, 0.38-0.64; P <.001).³

With 4 years of follow-up, at a median of 46.3 months (range, 41.8-54.1), key efficacy and safety data for the trial were presented for both the intention-to-treat (ITT) population as well as for those completing 35 cycles, or 2 years, of therapy with pembrolizumab.

Patients included in the study were those with untreated stage IV disease without sensitizing EGFR or ALK alterations. Patients had to have an ECOG performance score of 0 or 1, availability of a tumor sample for PD-L1 testing, no brain metastases, and no pneumonitis requiring systemic steroids. Participants were randomized in a 2:1 fashion to either pembrolizumab 200 mg (n = 410) or placebo (n = 206) plus pemetrexed 500 mg/m² and either carboplatin AUC 5 or cisplatin 75 mg/m² every 3 weeks for up to 4 cycles. Maintenance therapy with pembrolizumab or placebo plus pemetrexed 500 mg/m² was continued for up to 31 cycles.

A second course of pembrolizumab therapy for up to 17 cycles was allowed in the triplet arm in patients who had experienced progressive disease after initially achieving stable disease (SD) or better after 35 cycles of therapy or in those who stopped therapy after a complete response (CR) to therapy. Patients in the placebo arm could crossover to receive pembrolizumab monotherapy after progressive disease per RECIST 1.1 by blinded independent central review.

“Of note, about 117 patients, or 57%, of those on the placebo-chemotherapy arm received a subsequent anti–PD-1 or anti–PD-L1 therapy, and this includes on-study crossover to pembrolizumab,” Gray said. “It will be important to keep this information in mind as we go through the data.”

Stratification factors included PD-L1 status, platinum therapy (cisplatin versus carboplatin), and smoking status. The study’s dual primary end points were OS and PFS, with secondary outcome measures including response rate, response duration, and safety.

Baseline characteristics were well balanced between the 2 arms. Of note, most patients (83.9%) receiving a full course of pembrolizumab, or 35 cycles, had a PD-L1 tumor proportion score (TPS) of 1% or greater, which is higher than about 60% of patients in the overall study population.

The median OS in the ITT population was more than double in the pembrolizumab arm versus the chemotherapy-alone arm, at 22.0 months versus 10.6 months, respectively (HR, 0.60; 95% CI, 0.50-0.72). Corresponding rates of OS at 3 years were 31.3% and 17.4%.

OS superiority was seen across PD-L1 expression groups, with the greatest numerical improvement observed in the patients with a PD-L1 TPS of 50% or greater. In this group, the median OS was 27.7 months with pembrolizumab versus 10.1 months without (HR, 0.71; 95% CI, 0.50-1.00). In patients with PD-L1 TPS between 1% and 49%, the median OS was 21.8 months versus 12.1 months, respectively (HR, 0.66; 95% CI, 0.47-0.93). Corresponding medians in the 1% or less PD-L1 TPS group were 17.2 months versus 10.2 months (HR, 0.52; 95% CI, 0.37-0.72).

PFS data support prior results initially published in the New England Journal of Medicine,3 with the pembrolizumab arm at a median of 9.0 months compared with 4.9 months with chemotherapy alone (HR, 0.50; 95% CI, 0.41-0.59). Rates at 3 years were 11.8% and 1.3%, respectively. PFS improvements were similarly observed across PD-L1 subgroups.

Time to progression on second-line therapy, or PFS-2, was also presented favoring initial therapy with pembrolizumab, at 17.0 months versus 9.0 months (HR, 0.52; 95% CI, 0.43-0.63). Corresponding rates at 3 years were 27.8% and 10.6%.

The objective response rate (ORR) and duration of response were improved in the pembrolizumab arm versus chemotherapy, supporting data from prior reports. This association was observed regardless of PD-L1 expression status.

The ORR and OS rate in patients completing at least 35 cycles of pembrolizumab therapy (n = 56) was also reported. Forty-nine (87.5%) had an objective response, including 6 CRs (10.7%) and 43 partial responses (PRs; 76.8%). The rate of OS at 2 years was 79.6%, and 80.4% of patients were alive at the time of data cutoff. In the 7 patients who went on to start a second course of pembrolizumab, 2 each had best responses of PR or SD.

The safety profile was consistent with those reported previously. In patients who completed 35 cycles of pembrolizumab, grade 3 or higher adverse effects occurred in 46.4%, which is in line with the rate observed in the overall study population. However, immune-mediated AEs occurred more frequently in this group at 39.3%, which is higher than 27.7% observed in the entire pembrolizumab group.

“In conclusion, pembrolizumab plus pemetrexed is a standard-of-care therapy for patients with newly diagnosed metastatic nonsquamous non–small cell lung cancer,” Gray said.

References

1. Gray JE, Rodríguez-Abreu D, Powell SF, et al. Pembrolizumab + pemetrexed-platinum for metastatic NSCLC: 4-year follow-up from KEYNOTE-189. Presented at: 2020 World Conference on Lung Cancer Singapore. January 27-31, 2021. Abstract FP13.02
2. FDA grants regular approval for pembrolizumab in combination with chemotherapy for first-line treatment of metastatic nonsquamous NSCLC. FDA. August 20, 2018. Accessed January 28, 2021. https://bit.ly/3ckDRJK
3. Gandhi L, Rodríguez-Abreu D, Gadgeel S; KEYNOTE-189 Investigators. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(22):2078-2092. doi:10.1056/NEJMoa1801005