Pembrolizumab Plus Chemo Maintains Survival Benefit in Treatment-Naïve Nonsquamous NSCLC

Pembrolizumab (Keytruda) plus platinum/pemetrexed continued to demonstrate an overall survival (OS) and progression-free survival (PFS) benefit vs platinum/pemetrexed alone in patients with previously untreated, metastatic squamous non–small cell lung cancer (NSCLC), according to 5-year data from the phase 3 KEYNOTE-189 trial (NCT02578680).¹

At a median follow-up of 64.6 months (range, 60.1-72.4), the median OS with pembrolizumab was 22.0 months (95% CI, 19.5-24.5) in the intention-to-treat (ITT) population vs 10.6 months (95% CI, 8.7-13.6) with placebo, translating to a 40% reduction in the risk of death (HR, 0.60; 95% CI, 0.50-0.72). The 5-year OS rates in the investigative and control arms were 19.4% and 11.3%, respectively.

The median PFS was 9.0 months (95% CI, 8.1-10.4) with pembrolizumab plus chemotherapy vs 4.9 months (95% CI, 4.7-5.5) with placebo plus chemotherapy, translating to a 50% reduction in the risk of disease progression or death (HR, 0.50; 95% CI, 0.42-0.60). The 5-year PFS rate in the investigative arm was 7.5% vs 0.6% in the control arm.

The survival benefits achieved with pembrolizumab plus chemotherapy were observed irrespective of PD-L1 expression.

“These results continue to support the combination of first-line pembrolizumab plus pemetrexed/platinum as a standard of care in patients with metastatic nonsquamous NSCLC without EGFR or ALK alterations,” lead study author Marina C. Garassino, professor of medicine at the University of Chicago Medicine & Biological Sciences, Knapp Center for Biomedical Discovery, said in a presentation on the data.

The trial enrolled patients with pathologically confirmed metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations.² Patients needed to be at least 18 years of age, have an ECOG performance status of 0 or 1, and at least 1 measurable lesion per RECIST v1.1 criteria. They could not have previously received systemic therapy for metastatic disease.

Study participants were randomly assigned 2:1 to receive pembrolizumab at 200 mg or placebo, both given intravenously every 3 weeks for up to 35 treatment cycles. Patients were stratified based on PD-L1 expression (TPS ≥1% vs <1%), choice of platinum therapy (cisplatin vs carboplatin), and smoking history (never vs former or current).

All patients were given 4 cycles of investigator’s choice of cisplatin at 75 mg/m² or carboplatin at area under the curve 5 plus pemetrexed at 500 mg/m2 given every 3 weeks followed by pemetrexed at 500 mg/m2 every 3 weeks.

The primary end points of the trial were OS and PFS. Secondary end points were response rate, DOR, and safety.

In August 2018, the FDA granted a full approval to frontline pembrolizumab for use in combination with standard chemotherapy in patients with metastatic nonsquamous NSCLC based on data from KEYNOTE-189.³

Earlier data from the trial showed that the addition of pembrolizumab to chemotherapy significantly improved OS and PFS over chemotherapy alone in this population. At a median follow-up of 10.5 months (range, 0.2-20.4), the hazard ratio (HR) for OS was 0.49 (95% CI, 0.38-0.64; P < .001), and the HR for PFS was 0.52 (95% CI, 0.43-0.64; P < .001). At a median follow-up of 31.0 months (range, 26.5-38.8), the HR for OS and PFS was 0.56 (95% CI, 0.46-0.69) and 0.49 (95% CI, 0.41-0.59), respectively.

Moreover, 57.3% of 206 patients crossed over from the placebo arm to the pembrolizumab arm either on (n = 84) or off (n = 34) the study.

Additional data showed that among those with a PD-L1 tumor proportion score (TPS) for 50% or higher who received pembrolizumab/chemotherapy (n = 132) vs chemotherapy alone (n = 70), the HR for OS was 0.68 (95% CI, 0.49-0.96). The 5-year OS rates were 29.6% and 21.4%, respectively. In those with a PD-L1 TPS between 1% and 49% who received pembrolizumab (n = 128) or placebo (n = 58), the HR for OS was 0.65 (95% CI, 0.46-0.90). The 5-year OS rates in these groups were 19.8% and 7.7%, respectively. In those with a PD-L1 TPS of less than % who were given pembrolizumab (n = 127) or placebo (n = 63), the HR for OS was 0.55 (95% CI, 0.39-0.76). The OS rates at 5 years in the investigative and control arms were 9.6% and 5.3%, respectively.

The HR for PFS in the population of patients with a PD-L1 TPS of at least 50% was 0.35 (95% CI, 0.25-0.49). The 5-year PFS rate in the pembrolizumab/chemotherapy arm was 12.8% vs 0% with chemotherapy alone. In the population of patients with a PD-L1 TPS ranging from 1% to 49%, the HR for PFS was 0.57 (95% CI, 0.41-0.80). The 5-year PFS rates in the investigative and control arms were 6.5% and 1.9%, respectively. Lastly, the HR for PFS in the population of patients with a PD-L1 TPS of less than 1% was 0.67 (95% CI, 0.49-0.92). The 5-year PFS rate with pembrolizumab plus chemotherapy was 2.4% vs 0% with chemotherapy alone.

In the ITT population, pembrolizumab plus chemotherapy (n = 410) elicited an objective response rate (ORR) of 48.3% vs 19.9% with chemotherapy alone (n = 206). The median duration of response (DOR) in these arms was 12.7 months (range, 1.1+ to 68.3+) and 7.1 months (range, 2.4-31.5).

In the population of patients with a PD-L1 TPS of at least 50%, pembrolizumab plus chemotherapy induced an ORR of 62.1% vs 25.7% with chemotherapy alone. The median DOR in the investigative arm was 15.3 months (range, 1.2+ to 68.3+) vs 7.1 months (range, 3.4-31.5) in the control arm.

In those with a PD-L1 TPS ranging from 1% to 49%, pembrolizumab plus chemotherapy produced an ORR of 50.0% vs 20.7% with chemotherapy alone. The median DOR in the pembrolizumab arm was 13.6 months (range, 2.1+ to 67.6+) vs 7.6 months (range, 2.4 to 31.0+) in the placebo arm.

In the population of patients with a PD-L1 TPS of less than 1%, pembrolizumab plus chemotherapy elicited an ORR of 33.1% vs 14.3% with chemotherapy alone. The median DOR in the investigative and control arms were 10.8 months (range, 1.1+ to 59.4+) and 7.8 months (range, 4.1 to 28.3+), respectively.

In patients who completed 35 cycles of pembrolizumab (n = 57), the ORR was 86.0% (95% CI, 74.2%-93.7%), which included a complete response rate of 14.0% and a partial response rate of 71.9%. The median DOR in this group was 57.7 months (range, 4.2 to 68.3+). The 3-year OS rate following the completion of 35 cycles was 71.9%. Moreover, 40.4% of patients were alive without disease progression or in need of subsequent treatment.

The toxicity of the regimen was consistent with what had previously been reported.

Any-grade adverse effects (AEs) were experienced by 99.8% of those who received pembrolizumab plus chemotherapy (n = 405) vs 99.0% of those given chemotherapy alone (n = 202); these effects were grade 3 to 5 in 72.8% and 67.3% of patients, respectively. Moreover, 35.8% and 17.3% of patients in the investigative and control arms, respectively, experienced AEs that resulted in treatment discontinuation; 7.2% and 6.9% of patients, respectively, experienced AEs that resulted in death.

Treatment-related toxicities were experienced by 93.1% of those in the pembrolizumab arm and 90.6% of those in the placebo arm; these cases were grade 3 to 5 in severity for 52.3% and 42.1% of patients, respectively.

Immune-mediated AEs and infusion reactions were experienced by 27.9% of those in the investigative arm and 13.4% of those in the control arm; these effects were grade 3 to 5 in 12.8% and 4.5% of patients, respectively.

References

1. Garassino MC, Gadgeel SM, Speranza G, et al. KEYNOTE-189 5-year update: first-line pembrolizumab (pembro) + pemetrexed (pem) and platinum vs placebo (pbo) + pem and platinum for metastatic nonsquamous NSCLC. Ann Oncol. 2022;33(suppl 7):S992-S993. doi:10.1016/j.annonc.2022.07.1101
2. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. doi:10.1056/NEJMoa1801005
3. FDA grants regular approval for pembrolizumab in combination with chemotherapy for first-line treatment of metastatic nonsquamous NSCLC. News release. FDA. August 20, 2018. Accessed September 26, 2022. https://bit.ly/3fqhy8I