Pembrolizumab in the treatment of metastatic non-small-cell lung cancer: patient selection and perspectives

Our plain-English summary of Pembrolizumab in the treatment of metastatic non-small-cell lung cancer: patient selection and perspectives, by A. Somasundaram, T.F. Burns (Lung Cancer, 2017).

The study

• Authors: A. Somasundaram, T.F. Burns
• Journal: Lung Cancer
• Published: 2017;8:1-11
• Type of article: Review
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Lung cancer is the leading killer of both men and women in the US, and the 5-year survival remains poor. However, the approval of checkpoint blockade immunotherapy has shifted the treatment paradigm and provides hope for improved survival. The ability of non-small-cell lung cancer (NSCLC) to evade the host immune system can be overcome by agents such as pembrolizumab (MK-3475/lambrolizumab), which is a monoclonal antibody targeting the programmed death 1 (PD-1) receptor. In early studies, treatment with pembrolizumab led to dramatic and durable responses in select patients (PD-L1+ tumors). This remarkable efficacy lead to approval of pembrolizumab in the second-line setting as response rates were almost doubled compared to standard of care (SOC) chemotherapy. Most recently, data in the first-line setting from the KEYNOTE-024 study have redefined the SOC therapy for a selected subset of patients. In patients with ≥50% PD-L1+ tumors, pembrolizumab had a clear progression-free survival and overall survival benefit. Toxicity was mostly immune related and similar to checkpoint blockade toxicities observed in previous studies. The initial approval and subsequent studies of pembrolizumab required and utilized a companion diagnostic test, Dako's IHC 22C3, to assess PD-L1 status of patients. The evaluation and scoring system of this assay has been used by other companies as a reference to develop their own assays, which may complicate selection of patients. Finally, the impact of pembrolizumab in NSCLC is growing as evidenced by the numerous, ongoing trials open for combinations with chemotherapy, chemoradiation, other immunotherapeutics, immunomodulators, tyrosine kinase inhibitors, PI3K inhibitors, MEK inhibitors, hypomethylating agents, and histone deacetylase inhibitors. Further studies are also evaluating pembrolizumab in small-cell lung cancer and malignant pleural mesothelioma. This explosion of studies truly conveys the lack of therapeutic answers for lung cancer patients and the promise of pembrolizumab.

In plain English

This article was a review, not an original study, and it did not examine asbestos exposure. The authors reviewed published results and ongoing clinical trials of pembrolizumab, an antibody drug that blocks the PD-1 receptor, in patients with advanced non-small-cell lung cancer. It included brief sections on small-cell lung cancer and malignant pleural mesothelioma. Among the trials described, KEYNOTE-024 reported a median progression-free survival of 10.3 months with pembrolizumab versus 6.0 months with chemotherapy. That trial enrolled untreated patients whose tumors showed PD-L1 staining of 50% or more. For malignant pleural mesothelioma, the review reported interim results from the KEYNOTE-028 study in PD-L1-positive patients. Of 25 patients accrued, seven had a partial response and 12 had stable disease, and the rest were still being evaluated. The review also described a published case of a 62-year-old patient with malignant pleural mesothelioma who developed a kidney disorder (minimal change disease) 10 days into pembrolizumab therapy and improved on steroids. The authors concluded that early analyses in mesothelioma were showing promise. They also wrote that many questions remained unanswered, including the lack of standardized PD-L1 tests.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published and ongoing clinical trials (not an original study)
• Who was studied: Clinical trials and reports of pembrolizumab, mainly in patients with advanced non-small-cell lung cancer (NSCLC), with brief coverage of small-cell lung cancer and malignant pleural mesothelioma; published 2017 by authors at the University of Pittsburgh Cancer Institute
• Exposure: No asbestos or fiber exposure is studied. The 'exposure' reviewed is treatment with the drug pembrolizumab, for example 200 mg every 3 weeks in KEYNOTE-024, compared with chemotherapy
• Main results:
  • KEYNOTE-024 (as reported by the review), untreated advanced NSCLC with PD-L1 of 50% or more: median progression-free survival 10.3 months with pembrolizumab versus 6.0 months with chemotherapy, HR 0.50 (95% CI 0.37 to 0.68; p less than 0.001)
  • KEYNOTE-024: 6-month overall survival 80.2% with pembrolizumab versus 72.4% with chemotherapy, HR 0.60 (95% CI 0.41 to 0.89; p=0.005)
  • KEYNOTE-024: grade 3 and higher treatment-related adverse events in 26.6% of the pembrolizumab arm versus 53.5% of the chemotherapy arm
  • KEYNOTE-010 (as reported by the review), previously treated PD-L1-positive NSCLC: median overall survival 8.5 months with docetaxel, 10.4 months with pembrolizumab 2 mg/kg and 12.7 months with pembrolizumab 10 mg/kg
  • KEYNOTE-028 interim results in PD-L1-positive malignant pleural mesothelioma (Phase Ib): of 25 patients accrued, 7 had a partial response and 12 had stable disease; the remaining patients were still being evaluated
  • A published case report described one 62-year-old patient with malignant pleural mesothelioma who developed minimal change disease (seen on kidney biopsy) after edema and renal failure 10 days into pembrolizumab therapy, and who improved on steroids
• The authors' conclusion: The authors concluded that pembrolizumab had drastically altered lung cancer therapy, and that early analyses in PD-L1-positive small-cell lung cancer and malignant pleural mesothelioma were showing promise
• Limitations the authors state:
  • The authors stated that many questions about pembrolizumab in lung cancer remained unanswered
  • The authors noted that PD-L1 tests had not been standardized
  • The authors noted that no head-to-head comparison of pembrolizumab and nivolumab had been conducted

Topics

Medical terms in this study, explained in our Lexicon: Pembrolizumab (Keytruda), Lung Cancer, Immunotherapy, Monoclonal Antibody, PD-L1, Second-Line Therapy, Chemotherapy, Progression-Free Survival.

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