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evident
Original paper
2016NEJMHematology/Oncology

KEYNOTE-024

Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer

RCTNon-small-cell lung cancer

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Overview

In untreated advanced NSCLC with PD-L1 of at least 50% and no EGFR or ALK alteration, pembrolizumab prolonged PFS versus platinum chemotherapy.

Clinical takeaway

For previously untreated advanced NSCLC with PD-L1 on at least 50% of tumor cells and no sensitizing EGFR mutation or ALK translocation, start pembrolizumab rather than platinum chemotherapy. Overall survival was a secondary end point and also favored pembrolizumab.

Key result

Median PFS was 10.3 months with pembrolizumab versus 6.0 months with chemotherapy (HR for progression or death 0.50; 95% CI 0.37-0.68; P<0.001).

Practice impact

PD-L1 testing and first-line pembrolizumab became standard for PD-L1-high NSCLC without a driver alteration.

Evidence

Study design

Open-label phase 3 randomized trial with blinded, independent, central radiologic review of progression-free survival.

Enrollment

305

Follow-up

Median follow-up 11.2 months. Overall survival was estimated at 6 months.

Geography

Not listed

Clinical question

Does first-line pembrolizumab prolong progression-free survival compared with platinum-based chemotherapy in advanced NSCLC with PD-L1 expression on at least 50% of tumor cells?

Population

  • Previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing EGFR mutation or ALK translocation.

Intervention

Pembrolizumab 200 mg every 3 weeks.

Comparator

Investigator's choice of platinum-based chemotherapy. Crossover to pembrolizumab was permitted at disease progression.

Primary outcome

Progression-free survival, assessed by blinded, independent, central radiologic review.

Pembrolizumab prolonged progression-free survival compared with platinum-based chemotherapy.

Hazard ratio for disease progression or death / 0.5 / 95% CI 0.37-0.68 / p<0.001

Key results

  • Median PFS: 10.3 months (95% CI 6.7 to not reached) with pembrolizumab versus 6.0 months (95% CI 4.2-6.2) with chemotherapy; HR for disease progression or death 0.50 (95% CI 0.37-0.68; P<0.001).
  • Secondary end point, estimated 6-month overall survival: 80.2% versus 72.4%; HR for death 0.60 (95% CI 0.41-0.89; P=0.005).
  • Secondary end point, objective response: 44.8% versus 27.8%; median duration of response not reached (range 1.9+ to 14.5+ months) versus 6.3 months (range 2.1+ to 12.6+).

Harms

  • Treatment-related adverse events of any grade were less frequent with pembrolizumab than with chemotherapy (73.4% versus 90.0%).
  • Grade 3, 4, or 5 treatment-related adverse events were less frequent with pembrolizumab (26.6% versus 53.3%).

Clinical Use

Practice impact

  • Test PD-L1 and driver alterations before first-line therapy for advanced NSCLC.
  • For PD-L1 of at least 50% without EGFR or ALK alteration, pembrolizumab monotherapy is supported over platinum chemotherapy.

Applicability

  • Previously untreated advanced NSCLC with PD-L1 on at least 50% of tumor cells and no sensitizing EGFR mutation or ALK translocation.

Limitations

  • Open-label design; PFS used blinded central review.
  • Crossover from chemotherapy to pembrolizumab at progression can complicate interpretation of overall survival.
  • The chemotherapy comparator was investigator's choice among five platinum doublets; pemetrexed-containing regimens were limited to nonsquamous tumors.

Common misinterpretations

  • This is not a license for first-line pembrolizumab monotherapy in PD-L1-low or driver-positive NSCLC; those patients were excluded.
  • Overall survival is a secondary end point. The primary end point is progression-free survival.
  • Do not generalize to patients with a sensitizing EGFR mutation or ALK translocation.

Related evidence

NLST - Context

Citation

Reck M, Rodríguez-Abreu D, Robinson AG, et al. 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

In patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, pembrolizumab was associated with significantly longer progression-free and overall survival and with fewer adverse events than was platinum-based chemotherapy.