Concurrent Pembrolizumab Plus Chemoradiation Therapy Elicits Antitumor Activity in NSCLC

Article

Pembrolizumab plus concurrent chemoradiation therapy induced antitumor effects in patients with unresectable, locally advanced, stage III non–small cell lung cancer irrespective of PD-L1 expression or tumor histology.

Salma K. Jabbour, MD

Salma K. Jabbour, MD

Pembrolizumab (Keytruda) plus concurrent chemoradiation therapy (cCRT) induced antitumor effects in patients with unresectable, locally advanced, stage III non–small cell lung cancer (NSCLC) irrespective of PD-L1 expression or tumor histology, according to updated findings from the phase 2 KEYNOTE-799 (NCT0363178) that were presented virtually during the 2021 ASCO Annual Meeting.1

“[Historically] the standard of care for patients with resectable, locally advanced stage III NCSLC includes concurrent chemoradiation therapy followed by consolidation therapy with durvalumab [Imfinzi],” said Salma K. Jabbour, MD, professor and vice chair of clinical research and faculty development at The Rutgers Cancer Institute of New Jersey, during a presentation of the data. “However, approximately 20% to 30% of patients who begin chemoradiation therapy experience disease progression or toxicity and are ineligible to receive durvalumab as consolidated therapy, representing an unmet clinical need. Pembrolizumab plus concurrent chemoradiation therapy represents a promising therapy [for these patients].”

Jabbour presented findings from the nonrandomized, open-label phase 2 KEYNOTE-799 study, with 3 additional months of follow-up. A total of 216 patients, 18 years or older, were enrolled in the study. All patients had previously untreated, unresectable, pathologically confirmed stage IIIA-C NSCLC, with measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, adequate pulmonary function, and no prior systemic immunosuppressive therapy within 7 days.

Patients were divided into 2 cohorts: A consisted of patients with both squamous and nonsquamous NSCLC (n = 112); cohort B included patients with nonsquamous NSCLC only (n = 102). Jabbour’s presentation focused on median follow-up of 18.5 months (range, 13.6-23.8) in cohort A and 13.7 months (range, 2.9-23.5) in cohort B, with a cutoff date of October 28, 2020.

All patients in the study received up to 17 cycles of pembrolizumab, administered in a dose of 200 mg every 3 weeks. Patients in cohort A also received one cycle of carboplatin and paclitaxel followed by added standard thoracic radiology for cycles 2 and 3, and subsequent pembrolizumab monotherapy. Patients in cohort B received the same dosing for pembrolizumab, with the addition of cisplatin and pemetrexed, plus thoracic radiotherapy in cycles 2 and 3, followed by single-agent pembrolizumab for cycles 4 through 17.

Primary end points were overall response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR) and incidence of grade 3 or higher pneumonitis. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety.

Both cohorts reported an ORR of 70%: cohort A, 70.5% (95% CI, 61.2%-78.8%); cohort B, 70.6% (95% CI, 60.7%-79.2%). Complete responses were reported in 3.6% of patients in cohort A and in 4.9% of cohort B. Neither cohort reached a median duration of response (DOR), PFS, or OS. More than three-quarters of patients in each arm had a DOR of at least 1 year (cohort A, 79.7%; cohort B, 75.6%). The 12-month PFS rate for cohort A was 67.1% and 71.6% for cohort B. The 12-month OS rate for cohort A was 81.3% and 87% for cohort B.

Responses were observed regardless of PD-L1 expression level and tumor histology. In cohort A, for those with negative PD-L1 expression (tumor proportion score [TPS] <1%) the ORR was 66.7% and 75.8% for those with positive expression (TPS ≥1%). In cohort B, ORRs were 71.4% and 72.5% for negative and positive PD-L1 expression, respectively. Patients with nonsquamous disease had an ORR of 69.2% in cohort A and squamous patients in cohort A had an ORR of 71.2%. All patients in cohort B had nonsquamous disease.

“Toxicity was manageable,” said Jabbour, noting that incidence of grade 3 or higher pneumonitis occurred in 9 patients (8.0%) in cohort A and in 7 patients (6.9%) in cohort B, which she considered to be “consistent with studies of anti–PD-1 or PD-L1 therapy with concurrent chemoradiation in stage III NSCLC.” Grade 3-5 treatment-related adverse events occurred in 72 patients (64.3%) in cohort A and in 51 patients (50.0%) in cohort B. Grade 3-5 immune-mediated adverse events and infusion reactions were observed in 16.1% of patients in cohort A and in 9.8% of cohort B patients.

Results of phase 2 KEYNOTE-799 study will now help guide phase 3 testing, which is currently ongoing in KEYLYNK-012 (NCT04380636).2 The KEYLYNK study will look at the earlier incorporation of pembrolizumab with concurrent chemoradiotherapy with or without olaparib (Lynparza) and will compare it to the standard of care, which is to receive immunotherapy after the completion of chemoradiotherapy for patients with stage III NSCLC.

References

  1. Jabbour SK, Lee KH, Frost N, et al. KEYNOTE-799: phase 2 trial of pembrolizumab plus platinum chemotherapy and radiotherapy for unresectable, locally advanced, stage 3 NSCLC. J Clin Oncol. 2021;39(suppl 15):8512. doi:10.1200/JCO.2021.39.15_suppl.8512
  2. Jabbour SK, Cho BC, Bria E, et al. Phase 3 study of pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab with or without olaparib versus concurrent chemoradiation therapy followed by durvalumab in unresectable, locally advanced, stage III non-small cell lung cancer: KEYLYNK-012. J Clin Oncol. 2021;39(suppl 15):TPS8580. doi:10.1200/JCO.2021.39.15_suppl.TPS8580
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