Keytruda Treatment-New Standard of Care for Squamous Non-Small Cell Lung Cancer

Keytruda alone or combined with chemotherapy Improves treatment for NSCLC independent of PD-1 expression

Keytruda Changes Management of Squamous Non-Small Cell Lung Cancer

by C.H. Weaver M.D. 8/28/2018

An analysis of the phase III KEYNOTE-407 trial evaluating combined chemotherapy and immunotherapy showed a more than four-month longer median overall survival for metastatic squamous non–small-cell lung cancer (NSCLC) patients who treated with keytruda (pembrolizumab) plus traditional chemotherapy compared with those who received placebo plus chemotherapy regardless of tumor PD-L1 expression.

Keytruda combined with chemotherapy (carboplatin and either paclitaxel or nab-paclitaxel) significantly improved overall survival and reduced the risk of death by 36% compared to chemotherapy alone. This marks the first time an anti-PD-1 regimen has been approved for the first-line treatment of squamous NSCLC regardless of tumor PD-L1 expression status.

About Lung Cancer

Lung cancer remains the leading cause of cancer-related deaths worldwide. In the United States, NSCLC accounts for 75–80% of all lung cancers. Although progress has been made in recent years, the majority of patients with advanced stage lung cancer still die from their disease. New treatments are needed, and precision cancer medicines are leading the way. Research into genomics and genetics has leading to unprecedented progress in improving lung cancer outcomes. Tailored treatments have emerged to match a person’s genetic make­up or a tumor’s genetic profile. As a result, patients with lung cancer now typically re­ceive molecular testing that guides their physicians in determining which therapies are more likely to boost the chances of survival while limiting the potential for adverse effects. Results from studies evaluating immune-modulatory approaches using anti-PD-1 and anti-PD-L1 antibodies (checkpoint inhibitors) have demonstrated promising results and are advancing the standard of care for lung cancer.

About Keytruda Checkpoint Inhibitors

Keytruda belongs to a class of medicines called “checkpoint inhibitors.” Checkpoint inhibitors are a novel precision cancer immunotherapy that helps to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD-L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade detection and attack by certain immune cells in the body. A checkpoint inhibitor can block the PD-1 and PD-L1 pathway and enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 ligand these drugs restore an immune cells’ ability to recognize and fight the colon cancer cells. A diagnostic test to measure the level of PD-L1 is available.

For the KEYNOTE-407 clinical trial a total of 559 patients with previously untreated metastatic squamous NSCLC were treated with either keytruda plus chemotherapy or chemotherapy alone and directly compared. At the time of interim analysis the average duration of survival was improved to 15.9 months for the Keytruda treated patients compared to only 11.3 months for chemotherapy alone.

Keytruda plus chemotherapy should become the new standard of care for the first-line treatment of metastatic squamous NSCLC across all different levels of PDL1 expression according to the study investigator, Luis Paz-Ares, MD, PhD, professor of medicine at the Hospital Universitario 12 de Octubre.

Keytruda® Demonstrates Superior Survival Compared to Chemotherapy Treatment for Advanced Non-Small Cell Lung Cancer

Treatment with Keytruda® for previously untreated advanced NSCLC whose tumors expressed high levels of PD-1 is well known to be superior to standard chemotherapy.

The KEYNOTE-024 clinical trial that directly compared Keytruda to standard platinum-based chemotherapies in patients with advanced NSCLC whose tumors expressed high levels of PD-L1. The study enrolled 305 patients to receive Keytruda or platinum-based chemotherapies: paclitaxel+carboplatin, pemetrexed+carboplatin, pemetrexed+cisplatin, gemcitabine+carboplatin, or gemcitabine+cisplatin. Patients treated with platinum based chemotherapy had the option of crossing over to Keytruda upon disease progression.

Keytruda was found to be superior compared to chemotherapy for delaying the time to cancer progression-and improving overall survival. Based on these results, an independent Data Monitoring Committee (DMC) has recommended that the trial be stopped, and that patients receiving chemotherapy in KEYNOTE-024 be offered the opportunity to receive Keytruda.

Based on these findings, Merck initiated two phase 3 trials in patients with previously untreated NSCLC. KEYNOTE-189 is evaluating the combination of Keytruda plus a platinum/pemetrexed-based chemotherapy regimen and the KEYNOTE-407 trial mentioned previously compared Keytruda combined with carboplatin and paclitaxel or nab-paclitaxel in patients with squamous NSCLC.

PD-1 Inhibitor Keytruda® Combined with Chemotherapy Showed Early Promise in NSCLC Leading to Evaluation in Larger Clinical Trials

According to experts at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting in Chicago, new data evaluating Keytruda® (pembrolizumab) in combination with chemotherapy appears promising for the treatment of non-small cell lung cancer (NSCLC). Based on these initial results, two comparative clinical trials have been initiated.

The FDA’s initial approval of Keytruda was based in part on data from the KEYNOTE-001 trial, which showed that Keytruda alone had an overall response rate of nearly 20% among 495 previously treated and treatment-naive patients with advanced NSCLC and 45.2%, among individuals whose cancers expressed high levels of PD-L1.

Results from a smaller pilot clinical trial evaluating Keytruda combined with standard treatments in previously untreated patients with NSCLC showed overall response rates ranging from 48 to 71 percent in 74 patients who were treated with Keytruda and one of three different chemotherapy regimens.

The highest response rates were observed in a group of 24 patients who received Keytruda in combination with the chemotherapy drugs carboplatin plus pemetrexed. Another group of patients that received Keytruda plus carboplatin and paclitaxel had a 52% response rate.

References:

  1. https://www.marketwatch.com/press-release/fda-approves-mercks-keytruda-pembrolizumab-in-combination-with-carboplatin-and-either-paclitaxel-or-nab-paclitaxel-for-the-first-line-treatment-of-patients-with-metastatic-squamous-non-small-cell-lung-cancer-nsclc-2018-10-30
  2. http://investors.merck.com/news/press-release-details/2018/Merck-Provides-Update-on-KEYNOTE-407-Trial/default.aspx
  3. Gadgeel SM, Stevenson J, Langer C, et al. Pembrolizumab (pembro) plus chemotherapy as front-line therapy for advanced NSCLC: KEYNOTE-021 cohorts A-C. J Clin Oncol 34, 2016 (suppl; abstr 9016).
  4. Merck’s KEYTRUDA (pembrolizumab) demonstrates superior progression-free and overall survival compared to chemotherapy as first line treatment in patients with advanced non-small cell lung cancer.
  5. http://www.mercknewsroom.com/news-release/oncology-newsroom/mercks-keytruda%C2%A0pembrolizumab-demonstrates-superior-progression-free- Accessed June 21, 2016.
  6. Gadgeel SM, Stevenson J, Langer C, et al. Pembrolizumab (pembro) plus chemotherapy as front-line therapy for advanced NSCLC: KEYNOTE-021 cohorts A-C. J Clin Oncol 34, 2016 (suppl; abstr 9016).

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