(NEW Update) Pembrolizumab in NSCLC

(See Original Spotlight posted September 21, 2017 for commentary from lung cancer experts about the clinical use of pembrolizumab in NSCLC.)

Updates in First-Line Treatment

Pembrolizumab was first approved in 2015 for second-line treatment of patients with metastatic non–small cell lung cancer (NSCLC) whose tumors express PD-L1 and who have disease progression on or after platinum-containing chemotherapy or targeted therapy against ALK or EGFR, as appropriate. In 2018, the U.S. Food and Drug Administration (FDA) approved pembrolizumab in combination with pemetrexed and platinum as first-line treatment of patients with metastatic, nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations. Subsequently, in 2019, it was also approved as a single agent for the first-line treatment of patients with stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation or who have metastatic disease.¹

To be used as a single-agent in the stage III/metastatic disease setting, these patients’ tumors must express PD-L1 [tumor proportion score (TPS) ≥ 1%], as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. Approval was based on results from the KEYNOTE‑042 trial, in which treatment with pembrolizumab led to statistically significant improvements in overall survival compared with chemotherapy in three separate populations: the TPS ≥ 50% NSCLC subgroup, the TPS ≥ 20% NSCLC subgroup, and the overall population (TPS ≥ 1%).²

Since then, pembrolizumab has been studied in numerous clinical trials and approved for several more indications in the treatment of NSCLC.

Updates in Adjuvant Treatment

On January 26, 2023, on the basis of findings from the KEYNOTE-091 trial, the FDA approved single-agent pembrolizumab for adjuvant treatment after resection and platinum-based chemotherapy for stage IB (T2a ≥ 4 cm), II, or IIIA NSCLC.³ In the trial, treatment with pembrolizumab was associated with a clinically meaningful improvement in disease-free survival compared with placebo. For patients who received an adjuvant regimen, median disease-free survival was 58.7 months in the pembrolizumab arm and 34.9 months in the placebo arm.

The adverse reactions observed in KEYNOTE-091 were similar to those seen in other patients with NSCLC receiving single-agent pembrolizumab, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%).

Updates in Neoadjuvant/Perioperative Treatment

In the neoadjuvant setting, pembrolizumab was approved in October 2023 for use with platinum-containing chemotherapy for the preoperative treatment of patients with resectable (tumors ≥ 4 cm or node-positive) NSCLC. Pembrolizumab was then continued as single-agent adjuvant treatment after surgery.⁴ This marks the sixth approval for pembrolizumab-based regimens in NSCLC and was based on findings from the double-blind multicenter KEYNOTE-671 trial. Compared with neoadjuvant chemotherapy alone followed by surgery, neoadjuvant pembrolizumab plus chemotherapy followed by resection and adjuvant pembrolizumab significantly improved event-free survival, major pathologic response, and pathologic complete response.

A perioperative approach that includes both neoadjuvant and adjuvant immune checkpoint inhibition may provide benefit beyond either approach alone.

According to the investigators, among patients with resectable early-stage NSCLC, a perioperative approach that includes both neoadjuvant and adjuvant immune checkpoint inhibition may provide benefit beyond either approach alone.

Pembrolizumab Indications in NSCLC

In addition to these new approvals, pembrolizumab is indicated in combination with pemetrexed and platinum chemotherapy for the first-line treatment of patients with metastatic nonsquamous NSCLC, with no EGFR or ALK genomic tumor aberrations; in combination with carboplatin and either paclitaxel or paclitaxel protein-bound for the first-line treatment of patients with metastatic squamous NSCLC; and as a single agent for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥ 1%), as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have received FDA-approved therapy for these aberrations and have demonstrated disease progression prior to receiving pembrolizumab.⁵

Warnings and Precautions

Prescribing information for pembrolizumab includes warnings or precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryofetal toxicity. Pembrolizumab should be discontinued for patients with severe or life-threatening pneumonitis and should be withheld or discontinued for other severe or life-threatening immune-mediated adverse events when indicated.

REFERENCES

1. U.S. Food and Drug Administration. FDA expands pembrolizumab indication for first-line treatment of NSCLC (TPS ≥ 1%). Available at https://www.fda.gov/drugs/fda-expands-pembrolizumab-indication-first-line-treatment-nsclc-tps-1. Accessed February 18, 2024.
2. Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 2019;393:1819–1830.
3. O’Brien M, Paz-Ares L, Marreaud S, et al. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol 2022;23:1274–1286.
4. Wakelee H, Liberman M, Kato T, et al. Perioperative pembrolizumab for early-stage non-small-cell lung cancer. N Engl J Med 2023;389:491–503.
5. Merck & Co. Pembrolizumab (Keytruda) prescribing information. Updated January 2024. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125514s124lbl.pdf. Accessed February 20, 2024.