by Dr. C.H. Weaver M.D. updated 12/2019
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 Non Small Cell 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. Precision cancer medicines 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 immune-modulatory approaches using anti-PD-1 and anti-PD-L1 antibodies have demonstrated promising results and are advancing the standard of care for lung cancer.
About Keytruda Checkpoint Inhibitors
Keytruda is a precision cancer medicine that 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.
Keytruda Superior to Chemotherapy as Initial Treatment
The KEYNOTE-024 a clinical trial directly compared Keytruda to standard platinum-based chemotherapy 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 chemotherapy: 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 the trial was stopped, and patients receiving chemotherapy in KEYNOTE-024 were offered the opportunity to receive Keytruda.
Follow up at three years from initiation of treatment was released in September 2019 at The International Association for the Study of Lung Cancer (IASLC) annual meeting. The average overall survival duration among Keytruda treated patients is now 26.3 months compared to 14.2 months for those treated with chemotherapy. The 36-month overall survival is 43.7% for Keytruda compared to 24.9% for chemotherapy.
With prolonged follow-up, first-line Keytruda monotherapy continues to demonstrate an survival 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 addition of Keytruda to Alimta - platinum chemotherapy improve survival in NSCLC. The KEYNOTE-189 clinical trial evaluated Keytruda in combination with Alimta (pemetrexed) and cisplatin or carboplatin chemotherapy for the first-line treatment of patients with NSCLC regardless of programmed death-ligand 1 (PD-L1) expression.
The U.S. Food and Drug Administration (FDA) granted approval for Alimta in combination with Keytruda and platinum chemotherapy for the first-line treatment of patients with metastatic NSCLC with no EGFR or ALK genomic tumor aberrations.
KEYNOTE-189 Results was a phase III clinical trial performed in 616 patients with previously untreated metastatic non-squamous NSCLC without EGFR or ALK genomic tumor aberrations who were treated with either Alimta and cisplatin or carboplatin chemotherapy with or without Keytruda. (2)
The overall the response to treatment was improved to 48% from 19% with the addition of Keytruda. The addition of Keytruda also delayed cancer progression from 4.9 to 8.8 months prolonged overall survival.
This was the second clinical study demonstrating that the combination of a checkpoint inhibitor combined with chemotherapy improves treatment outcomes for NSCLC compared to treatment with chemotherapy alone. (3)
Keytruda and KRAS
KRAS mutations are detected in approximately 15% to 30% of lung adenocarcinomas and analyses of two clinical trials shows that Keytruda immunotherapy is more effective than chemotherapy for treating NSCLC with KRAS including G12C mutations. Precision cancer medicines targeting KRAS and G12C specifically are currently in clinical trials.
Two analyses presented at the ESMO Immuno-Oncology Congress 2019 in Geneva, Switzerland (11-14 December) support use of Keytruda in patients with non-squamous non-small cell lung cancer (NSCLC), regardless of the KRAS mutational status.
KEYNOTE-042 compared Keytruda monotherapy to platinum-based chemotherapy in patients with advanced NSCLC that were also PD-L1-positive, as defined by having a proportion score (TPS) ≥1%. KRAS mutations were identified in 23% of patients, including 10% with the G12C mutation. Patients with KRAS mutation tended to have a higher PD-L1 score.
Patients with any KRAS mutation receiving Keytruda had an objective response rate of 56.7% compared to 18.0% for patients treated with chemotherapy. Patients with KRAS G12C mutations responded similarly. Patients with KRAS mutations survived more than twice as long without cancer progression following Keytruda treatment compared to chemotherapy. Overall survival duration with Keytruda was 28 months versus 11 months for chemotherapy in patients with any KRAS mutation.
KEYNOTE-189 compared pemetrexed and platinum chemotherapy with or without Keytruda patients with metastatic non-squamous NSCLC; 31% of patients had KRAS mutation, including 13% patients who were G12C carriers. Patients with KRAS mutations also had higher PD-L1 median TPS of 30% versus median 5% and higher median TMB.
Keytruda plus chemotherapy produced superior response rates, delayed cancer progression and prolonged survival compared to chemotherapy in patients with KRAS.
Keytruda with or without chemotherapy comprising pemetrexed and a platinum should be standard first-line treatment for patients with metastatic non-squamous NSCLC regardless of KRAS mutation status. (12,13)
Keynote-021 also evaluated 123 previously untreated patients with metastatic nonsquamous NSCLC with no EGFR or ALK genomic markers irrespective of PD-L1 expression. In this trial, Keytruda + Alimta and carboplatin demonstrated an objective response rate of 55% which is nearly nearly double the 29% achieved with chemotherapy alone. The Keytruda regimen also delayed the time to cancer progression from 8.9 months to 13 months extending the overall cancer free survival.
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.
- Abstract LBA1_PR ‘Primary PFS and safety analyses of a randomized phase III study of carboplatin + paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC (IMpower150)‘ will be presented by Martin Reck during the Proffered Paper session ‘Combining immune checkpoint inhibitors and VEGF targeted therapies in cancer treatment’ on Thursday, 7 December, 18:15 to 19:15 (CET) in Room A. Annals of Oncology, Volume 28, 2017 Supplement 11.
- Herbst RS, Lopes G, Kowalski DM, et al. Association of KRAS mutational status with response to pembrolizumab monotherapy given as first-line therapy for PD-L1-positive advanced non-squamous NSCLC in KEYNOTE-042.
- Gadgeel S, Rodriguez-Abreu D, Felip E, et al. KRAS mutational status and efficacy in KEYNOTE-189: Pembrolizumab (pembro) plus chemotherapy (chemo) vs placebo plus chemo as first-line therapy for metastatic non-squamous NSCLC.