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

Sep 27, 2022

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Pembrolizumab plus platinum/pemetrexed continued to demonstrate an overall survival and progression-free survival benefit vs platinum/pemetrexed alone in patients with previously untreated, metastatic squamous non–small cell lung cancer.

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
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