KEYNOTE-024

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Reck M, et al. "Pembrolizumab versus chemotherapy for PD-L1–positive non-small-cell lung cancer". The New England Journal of Medicine. 2016. 375(19):1824-1833.
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Clinical Question

Among patients with untreated advanced non-small-cell lung cancer (NSCLC) with PD-L1 expression and without EGFR mutations or ALK rearrangements, does pembrolizumab improve progression-free survival compared to platinum-based chemotherapy?

Bottom Line

Patients with untreated advanced NSCLC with PD-L1 expression ≥50% had longer progression-free and overall survival with pembrolizumab over platinum-based chemotherapy with fewer adverse events.

Major Points

Recent years have seen the approval of immune checkpoint inhibitors for the treatment of multiple malignancies. These agents improve the ability of the immune system to recognize and kill tumor cells. The first approved checkpoint inhibitor was ipilimumab, a monoclonal antibody targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), in the treatment of melanoma.[1] Further studies demonstrated that targeting the programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) axis using fully humanized IgG4 monoclonal antibodies against PD-1 (pembrolizumab, nivolumab) or PD-L1 (atezolizumab) was more effective than chemotherapy in first-line metastatic melanoma,[2] second-line advanced renal cell carcinoma,[3] second-line advanced nonsquamous NSCLC,[4] recurrent or metastatic squamous cell carcinoma of the head and neck,[5] and had significant responses in second-line advanced urothelial carcinoma[6] and refractory classical Hodgkin lymphoma.[7]

Nivolumab was shown to improve overall survival (OS) compared to second-line docetaxel in CheckMate 057, a randomized phase 3 study of 292 patients with advanced nonsquamous NSCLC who progressed during or after platinum-based doublet chemotherapy (median OS 12.2 vs. 9.4 months; HR 0.73; P=0.002).[8] KEYNOTE-010 showed that pembrolizumab in patients with previously treated advanced NSCLC with at least 1% PD-L1 expression was superior to docetaxel at both 2 mg/kg (median OS 10.4 vs. 8.5 months; HR 0.71; P=0.0008) and 10 mg/kg (median OS 12.7 vs. 8.5 months; HR 0.61; P<0.0001).[9] Patients with tumors with PD-L1 expression ≥50% did even better with pembrolizumab at 2 mg/kg (median OS 14.9 months vs 8.2 months; HR 0.54; P=0.0002) and 10 mg/kg (median OS 17.3 months vs 8.2 months; HR 0.50; P<0.0001).

The KEYNOTE-024 trial studied patients with advanced NSCLC and high PD-L1 expression defined as ≥50% of tumor cells (seen in about one quarter of advanced NSCLC patients) and no sensitizing EGFR mutations or ALK translocations. This enriched patient population was based upon data from KEYNOTE-001[10] and KEYNOTE-010[9] establishing PD-L1 as a positive predictive biomarker for responsiveness to PD-L1 inhibitors. In this trial, 305 patients were randomized 1:1 to receive pembrolizumab 200 mg IV every 3 weeks or standard platinum-doublet chemotherapy. The primary endpoint was progression-free survival (PFS), which was significantly longer in the pembrolizumab group (median PFS 10.3 months vs. 6.0 months; HR 0.50; P<0.001), and median OS was not reached but was also significantly improved with pembrolizumab (HR 0.69; P=0.005). Adverse events were more common in the chemotherapy group, and severe immmune-mediated toxicities were rare. Flat dosing of pembrolizumab at 200 mg every 3 weeks was shown to have similar benefit compared to patients in KEYNOTE-010 who received 10 mg/kg weight-based dosing. Responses to pembrolizumab were durable (median duration of response [DOS] was not reached) which is dramatically different from response to chemotherapy (median DOS of 6.3 months). The trial was stopped early due to clear benefit from pembrolizumab over chemotherapy.

This study is groundbreaking as it is the first to demonstrate the benefit of first-line immunotherapy over chemotherapy in NSCLC, and led to the drug's FDA approval for untreated NSCLC.

Guidelines

NCCN Guidelines (2016, adapted):[11]

  • For patients with untreated advanced NSCLC, PD-L1 expression ≥50%, and without EGFR mutations or ALK rearrangements, pembrolizumab is recommended as first-line therapy. (Category 1)

Design

  • Phase III, randomized, open-label, multicenter, international trial
  • N=305
    • Pembrolizumab (N=154)
    • Chemotherapy (N=151)
  • Setting: 102 centers in 16 countries
  • Enrollment: 2014-2015
  • Stratification: Eastern Cooperative Oncology Group performance status (ECOG PS, 0 vs. 1), tumor histology (squamous vs. nonsquamous), and region (East Asia vs. non-East Asia)
  • Mean follow-up: 11.2 months
  • Analysis: Intention-to-treat
  • Primary outcome: Progression-free survival

Population

Inclusion Criteria

  • Age ≥18 years
  • ECOG PS 0-1
  • Histologically or cytologically confirmed stage IV NSCLC
  • PD-L1 expression ≥50%
  • Measurable disease by RECIST v1.1 criteria
  • Life expectancy of greater than or equal to 3 months
  • Acceptable bone marrow, hepatic, and kidney function

Exclusion Criteria

  • Presence of a sensitizing EGFR mutation or ALK translocation
  • Prior systemic therapy for metastatic disease
  • Receiving systemic glucocorticoids (except for replacement for adrenal or pituitary insufficiency)
  • Receiving immunosuppressive treatment
  • Active autoimmune disease requiring systemic treatment in the last 2 years
  • Active interstitial lung disease
  • History of pneumonitis requiring glucocorticoids
  • Known brain metastases unless previously treated

Baseline Characteristics

From the pembrolizumab group.

  • Demographics: Age 64.5 years, 40.3% female
    • Geographic region: 13.6% East Asia, 86.4% Non-East Asia
  • ECOG 0: 35.1%, ECOG 1: 64.3%
  • Smoking status: 22.1% current, 74.7% former, 3.2% never
  • Histology: 18.8% squamous, 81.2% nonsquamous
  • Brain metastases: 11.7%
  • Prior systemic neoadjuvant therapy: 1.9%
  • Prior systemic adjuvant therapy: 3.9%

Interventions

  • Randomization 1:1 to one of two groups:
    • Pembrolizumab: pembrolizumab 200 mg IV every 3 weeks for 35 cycles
    • Chemotherapy: investigator's choice of platinum-based chemotherapy for 4-6 cycles:
      • carboplatin AUC 5 or 6 IV and pemetrexed 500 mg/m2 IV every 3 weeks (nonsquamous tumors only)
      • cisplatin 75 mg/m2 IV and pemetrexed 500 mg/m2 IV every 3 weeks (nonsquamous tumors only)
      • carboplatin AUC 5 or 6 IV every 3 weeks and gemcitabine 1250 mg/m2 IV days 1 and 8 every 3 weeks
      • cisplatin 75 mg/m2 IV every 3 weeks and gemcitabine 1250 mg/m2 IV days 1 and 8 every 3 weeks
      • carboplatin AUC 5 or 6 IV every 3 weeks and paclitaxel 200 mg/m2 IV every 3 weeks
      • Maintenance pemetrexed was allowed after completed of combination carboplatin/pemetrexed or cisplatin/pemetrexed as long as this was decided prior to randomization
  • Patients were assessed every 9 weeks by imaging
  • Treatment continued until the planned number of cycles, disease progression, or unacceptable level of adverse events; crossover to pembrolizumab was allowed for patients in the chemotherapy group who progressed
  • Continuation of treatment was allowed after disease progression if patients were deemed by the investigator to be deriving clinical benefit

Outcomes

Comparisons are pembrolizumab vs. chemotherapy.

Primary Outcomes

Median PFS
10.3 months vs. 6.0 months (HR 0.50; 95% CI 0.37-0.68; P<0.001)

Secondary Outcomes

Median OS
Not reached in either group (HR 0.60; 95% CI 0.41-0.89; P=0.005)
Overall response rate
44.8% (95% CI 36.8%-53.0%) vs. 27.8% (95% CI 20.8%-35.7%)

Subgroup Analysis

The hazard ratio for disease progression of death favoring pembrolizumab was not statistically significant in the following subgroups (see details in figure 1 on page 1828.):

  • Women (HR 0.75; 95% CI 0.46-1.21)
  • Current smokers (HR 0.68; 95% CI 0.36-1.31)
  • Never smokers (HR 0.90; 95% CI 0.11-7.59)
  • Patients with baseline brain metastases (HR 0.55, 95% CI 0.20-1.56)

Adverse Events

Any event
73.4% vs. 90.0%
Any event leading to death
0.6% vs. 2.0%
Grade 3 or greater
Neutropenia: 0% vs. 13.3%
Decreased WBCs: 0% vs. 2.0%
Thrombocytopenia: 0% vs. 5.3%
Anemia: 1.9% vs. 19.3%
Nausea: 0% vs. 2.0%
Vomiting: 0.6% vs. 0.7%
Fatigue: 1.3% vs. 3.3%
Diarrhea: 3.9% vs. 1.3%
Grade 3 or greater immune-related events
Any: 9.7% vs. 0.7%
Pneumonitis: 2.6% vs. 0.7%
Severe skin reaction: 3.9% vs. 0%
Colitis: 1.3% vs. 0.7%
Hypophysitis: 0.6% vs. 0%
Nephritis: 0.6% vs. 0%
Pancreatitis: 0.6% vs. 0%
Type 1 diabetes mellitus: 0.6% vs. 0%

Criticisms

  • The study was done in an enriched patient population using a proprietary PD-L1 assay (only 30.2% of tumor specimens screened were eligible for enrollment). The ongoing KEYNOTE-042 trial (NCT02220894) will study patients with PD-L1 expression with the lower cutoff of ≥1%.
  • Patients with targetable molecular lesions (EGFR mutations or ALK rearrangements) were excluded; therefore, the role of checkpoint inhibitors prior to targeted therapy remains unknown.[12]
  • The study excluded patients with poor performance status.
  • Median overall survival in both arms has not yet been reached.
  • Merck personnel were involved in trial design, data analysis and interpretation, and the first draft was written with input from Merck employees, creating potential bias.

Funding

Merck, the manufacturer of pembrolizumab under the trade name Keytruda.

Further Reading

  1. Hodi FS et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 2010. 363:711-23.
  2. Robert C et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 2015. 372:320-30.
  3. Motzer RJ et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 2015. 373:1803-13.
  4. Borghaei H et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2015. 373:1627-39.
  5. Ferris RL et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N. Engl. J. Med. 2016. :.
  6. Rosenberg JE et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016. 387:1909-20.
  7. Ansell SM et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N. Engl. J. Med. 2015. 372:311-9.
  8. Borghaei H et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2015. 373:1627-39.
  9. 9.0 9.1 Herbst RS et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016. 387:1540-50.
  10. Garon EB et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 2015. 372:2018-28.
  11. NCCN Guidelines for Non-Small Cell Lung Cancer, Version 2.2017.
  12. Johnson BE & Divide and Conquer to Treat Lung Cancer. N. Engl. J. Med. 2016. :.