Pembrolizumab's Journey to the Frontline in NSCLC

The PD-1 inhibitor pembrolizumab (Keytruda) has shown an overall survival (OS) advantage across 3 phase III clinical trials studying its use in patients with metastatic non—small cell lung cancer (NSCLC). These positive results led to a frontline indication as a single agent and in combination with chemotherapy for both patients with squamous and nonsquamous NSCLC.

Tracey L. Evans, MD, director of thoracic oncology research at Main Line Hematology/Oncology and a thoracic oncologist at Penn Medicine, discussed these trials in detail during a presentation at the 36th Annual CFS^®.

Pembrolizumab was initially approved by the FDA in October 2015 for the treatment of patients with advanced, PD-L1—positive NSCLC whose disease has progressed after other treatments. In October 2016, the agency granted the PD-1 inhibitor frontline approval for patients with metastatic NSCLC who have PD-L1 expression ≥50% and do not harbor ALK or EGFR aberrations.

This regulatory decision was based on data from the KEYNOTE-024 study, in which pembrolizumab demonstrated a 40% improvement in OS versus standard platinum-based chemotherapy (HR, 0.60; 95% CI, 0.41-0.89; P <.005). Results also showed a statistically significant advantage in progression-free survival (PFS) at 10.3 months compared with 6.0 months, favoring pembrolizumab.¹

In August 2018, the FDA granted approval to frontline pembrolizumab in combination with carboplatin/pemetrexed for patients with nonsquamous metastatic NSCLC. This decision was based on data from the phase III KEYNOTE-189 study, said Evans, in which the combination had superior OS versus chemotherapy alone (HR, 0.49; 95% CI, 0.38-0.64; P = .00001).²

KEYNOTE-189 was a multicenter, double-blind phase III study with an active control arm. Importantly, patients with nonsquamous metastatic NSCLC were enrolled irrespective of PD-L1 expression. Patients had no prior systemic therapy and nor EGFR or ALK mutations. Their ECOG performance status was 0 or 1.

The 616 patients were randomized in a 2:1 fashion to receive pembrolizumab with chemotherapy or chemotherapy alone. Patients receiving the combination got 200 mg pembrolizumab plus 500 mg/m² and cisplatin at 75 mg/m² or carboplatin AUC 5 mg/mL. Patients received chemotherapy at 4 cycles every 3 weeks.

“If patients did not demonstrate disease progression, they moved on to pembrolizumab and pemetrexed at the same dose every 3 weeks until disease progression or unacceptable toxicity,” said Evans. “They could continue pembrolizumab treatment for up to 24 months.”

Of the 410 patients randomized to the chemoimmunotherapy combination, 206 were able to move on to the next cycle of treatment. Crossover to open-label pembrolizumab was permitted for patients in the control arm.

“Pemetrexed and platinum-based chemotherapy were chosen as the control arms because it is reasonable to say they were the standard of care for frontline treatment of these patients. I think thoracic oncologists were less than impressed with the survival advantage of bevacizumab (Avastin) given the toxicity we saw,” Evans said.

The primary endpoints of the study were OS and PFS assessed by blinded independent central review per RECIST v1.1 criteria; secondary endpoints were overall response rate (ORR) and duration of response. Patients were stratified by tumor PD-L1 status (TPS <1%; TPS ≥1%), cisplatin or carboplatin, and by smoking history.

Data showed a 51% reduction in the risk of death with the combination versus chemotherapy alone. Moreover, 1-year OS rates in the pembrolizumab arm was 69.2% compared with 49.4% in the control arm. Median OS was 11.3 months in the control arm and was not reached at time of data cutoff in the experimental arm, while the median PFS was 8.8 months versus 4.9 months, respectively, in favor of pembrolizumab.

ORR was 47.6% with pembrolizumab, with a median duration of response of 11.2 months. For patients treated with chemotherapy alone, ORR was 18.9% and a median duration of 7.8 months.

“Even the one-third of patients who had a PD-L1 expression of ≥1% derived an OS benefit with pembrolizumab,” said Evans.

In October 2018, pembrolizumab received another first-line indication, this time in combination with carboplatin and paclitaxel or nab-paclitaxel (Abraxane) for patients with squamous metastatic NSCLC. In KEYNOTE-407, the addition of immunotherapy to the chemotherapy regimen showed superior OS versus chemotherapy alone (HR, 0.64; 95% CI, 0.49-0.85; P= .001).³

KEYNOTE-407 was a double-blind, placebo-controlled, phase III study in which patients were again enrolled regardless of their tumor’s PD-L1 status. Patients with squamous metastatic NSCLC had to be previously untreated with an ECOG performance status of 0 or 1.

The 559 patients were randomized 1:1 to pembrolizumab at 200 mg every 3 weeks plus carboplatin AUC 6 mg/mL every 3 weeks plus paclitaxel 200 mg/m² every 3 weeks or nab-paclitaxel 100 mg/m² once weekly for 4 3-week cycles. Once patients completed 4 cycles of chemoimmunotherapy, they would move on to up to 31 cycles of 200 mg pembrolizumab every 3 weeks. In the control arm, patients would complete the same dose of chemotherapy before moving on to placebo every 3 weeks for up to 31 cycles.

OS, PFS, and ORR were the primary endpoints of the study. Median age of the patients was 65, with 55% of the cohort older than 65. About 60% of patients received paclitaxel and 40% received nab-paclitaxel. Fewer patients had brain metastases than in KEYNOTE-189, Evans said.

Results showed a 36% reduction in the risk of death with the addition of pembrolizumab to carboplatin plus paclitaxel/nab-paclitaxel. The 1-year OS rates were 65% and 48% with chemoimmunotherapy and chemotherapy, respectively. Median OS was 15.9 months with the addition of pembrolizumab compared with 11.3 months for chemotherapy alone. Median PFS in the experimental arm was 6.4 months versus 4.8 months in the control arm. The survival benefit was observed irrespective of PD-L1 status.

Adverse Events

Common adverse events (AEs) associated with pembrolizumab are pneumonitis, colitis, hepatitis, nephritis, and severe skin reaction. Based on the severity of the AEs, Evans noted, pembrolizumab should be withheld or discontinued with the administration of corticosteroids if appropriate.

“It’s important to understand some of the downsides to this class of agents,” Evans said. “There are immune-mediated AEs associated with pembrolizumab, and some of these have been severe or fatal.”

In KEYNOTE-189, pembrolizumab was discontinued because of AEs in 20% of the patients. The most common AEs in that study were pneumonitis (3%) and acute kidney injury (2%). AEs leading to interruption of treatment with pembrolizumab occurred in 53% of the patients, the most common of which being neutropenia and diarrhea.

Moreover, in KEYNOTE-407, treatment with pembrolizumab was permanently discontinued in 15% of the patients due to AEs. Thrombocytopenia and anemia were among the most common unacceptable toxicities. Pneumonia and urinary tract infection were also seen in 6% of patients.

“The factor to focus on in this study is that if you do a comparison with the addition of pembrolizumab versus chemotherapy alone, pembrolizumab really didn’t add much toxicity that we aren’t accustomed to seeing with chemotherapy alone or in patients with metastatic NSCLC,” Evans said. “The combination was very well tolerated.”

References

• Reck M, Rodriguez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1—positive non–small-cell lung cancer. N Engl J Med. 2016;375(19):1823-1833. doi: 10.1056/NEJMoa1606774.
• Gandhi L, Rodgríguez-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.
• Paz-Ares LG, Luft A, Tafreshi A, et al. Phase 3 study of carboplatin-paclitaxel/nab-paclitaxel (Chemo) with or without pembrolizumab (Pembro) for patients (Pts) with metastatic squamous (Sq) non-small cell lung cancer (NSCLC). J Clin Oncol. 2018;36 (suppl; abstr 105). doi: 10.1200/JCO.2018.36.15_suppl.105.

Originally published by OncLive^® as “Thoracic Oncologist Highlights Recent Pembrolizumab Data in NSCLC”