by Dr. C.H. Weaver M.D. updated 2/2019
Lung cancer remains the leading cause of cancer-related deaths worldwide. In the United States, NSCLC accounts for 75–80% of all lung cancers. Progress has been made in recent years using immunotherapy and novel precision cancer medicines.
The FDA’s initial approval of Keytruda (pembrolizumab) immunotherapy was based in part on data from the KEYNOTE-001 clinical trial, which initially showed that Keytruda alone had an overall response rate of nearly 20% among previously treated and treatment-naive patients with advanced NSCLC whose cancers expressed high levels of PD-L1.
At ASCO 2019 researchers reported updated 5-year safety and effectiveness outcomes from the KEYNOTE-001 clinical trial. This update provides the longest follow-up information for NSCLC patients treated with Keytruda.
Overall 101 treatment-naïve and 449 previously treated NSCLC patients were enrolled prior to November 5, 2018 and have now been followed for an average or 60.6 months. Currently the estimated 5-year overall survival rate is 23.2% for treatment-naive patients and 15.5% for previously treated patients which is significantly better than the historical rate of 5% achieved with chemotherapy. The average duration of response was 16.8 and 38.9 months with the longest response ongoing at 72 months. Immune-mediated side effects have occurred in 17% of patients
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.
Precision medicine continues to impact the lives of lung cancer patients with research into genomics and genetics leading to unprecedented progress in improving 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 immunomodulatory approaches using anti-PD-1 and anti-PD-L1 antibodies have demonstrated promising results and are advancing the standard of care for lung cancer.
PD-1 is a protein that inhibits certain types of immune responses. Drugs that block PD-1, such as Keytruda may enhance the ability of the immune system to fight cancer. In earlier studies Keytruda has demonstrated anticancer activity in lung cancer and has been previously approved for the treatment of advanced melanoma.
Keytruda Superior to Chemotherapy as Initial Treatment
KEYNOTE-024 is a clinical trial that directly compared Keytruda to standard platinum-based chemotherapies in the treatment of 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.
It was initially reported that Keytruda was 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) recommended that the trial be stopped, and that patients receiving chemotherapy in KEYNOTE-024 be offered the opportunity to receive Keytruda.
Additional follow up now demonstrates that the average overall survival for Keytruda patients is 30 months compared to only 14 months for chemotherapy treated patients. The 24-month overall survival rate was 51.5 percent in the KEYTRUDA group compared to 34.5 percent in the chemotherapy group.
With prolonged follow-up, first-line Keytruda monotherapy continues to demonstrate an OS benefit over chemotherapy in patients with previously untreated, advanced NSCLC without EGFR/ALK aberrations, despite crossover from the control arm to Keytruda as subsequent therapy.
Keytruda + Chemotherapy Superior to Chemotherapy Alone
The phase III KEYNOTE-407 trial evaluating combined chemotherapy and immunotherapy showed a more than four-month longer median overall survival when used to treat metastatic squamous non–small-cell lung cancer patients with Keytruda 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. regardless of tumor PD-L1 expression status.
In 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.
- <a href="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">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</a>
- 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).
- http://www.mercknewsroom.com/news-release/oncology-newsroom/mercks-keytruda%C2%A0pembrolizumab-demonstrates-superior-progression-free- Accessed June 21, 2016.
- 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)
- 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. [Press release.] http://www.mercknewsroom.com/news-release/oncology-newsroom/mercks-keytruda%C2%A0pembrolizumab-demonstrates-superior-progression-free- Accessed June 21, 2016.
- Reck M, et al "Updated analysis of KEYNOTE-024: Pembrolizumab versus platinum-based chemotherapy for advanced non -- small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater" J Clin Oncol 2019; DOI: 10.1200/JCO.18.00149.