Pembrolizumab
Also known as Pembro, marketed as Keytruda
Pembrolizumab is an immunotherapy medication developed by Merck Sharp & Dohme. Pembrolizumab has been granted approval for the treatment of many advanced cancers.
Pembrolizumab is known as an "immune checkpoint inhibitor". Immune checkpoints are a normal part of the human immune system that prevent the immune system from attacking healthy cells. In some cancers, tumor cells start creating large amounts of immune checkpoint proteins, which stops the immune system from attacking the cancer cells. Pembrolizumab works by helping T cells from the human immune system to attack tumor cells that over-produce the PD-L1 and PD-L2 immune checkpoint proteins.
What prostate cancer patients are eligible for Pembrolizumab?
NOTE: this encyclopedia currently covers only prostate cancer.
This treatment may or may not be indicated for other conditions.
Pembrolizumab has been approved by the FDA for the treatment of numerous cancers. While Pembrolizumab does not have an approval that is specific to prostate cancer, it has two biomarker-based approvals for the treatment of all metastatic/unresectable solid tumors.
- Unresectable or metastatic solid tumors with high tumor mutational burden (TMB-H): This approval was based on the results of the KEYNOTE-158 clinical trial.
In this trial, patients with an unresectable/metastatic solid cancer and a high tumor mutational burden (TMB ≥10 mut/Mb) had an overall response rate of 29%. 57% of patients who responded to Pembrolizumab had responses lasting more than a year.
- Unresectable or metastatic solid tumors with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR): This approval was based on the results of the KEYNOTE-016 clinical trial.
In this collection of trials, patients with an unresectable/metastatic solid cancer and high microsatellite instability or mismatch repair deficiency had an overall response rate of 39.6%. 78% of patients who responded to Pembrolizumab had responses lasting more than half a year.
Does the evidence support using Pembrolizumab to treat prostate cancer?
The evidence for using Pembrolizumab in prostate cancer is currently inconclusive, and is being actively researched.
The trials that supported the approval of Pembrolizumab for TMB-H and MSI-H/dMMR metastatic solid cancers included few patients with prostate cancer. The KEYNOTE-158 study (TMB-H solid cancers) did not include any prostate cancer patients who had a high tumor mutational burden (Leigh Marcus et al, 2021, V Prasad and A Addeo, 2020), while the studies of MSI-H only included 2 prostate cancer patients. Additionally, only 5-10% of prostate cancer patients will have either of the TMB-H or MSI-H/dMMR biomarker statuses.
Because the pan-cancer trials used to approve Pembrolizumab only contained a limited number of prostate cancer patients, it is hard to know if the effectiveness seen in the trials will replicate for real world prostate cancer patients.
To better answer this question, researchers have looked retrospectively at real-world patient cases, to better understand how real world patients who have high TMB or high MSI respond to pembro.
| When was the study published? | How was the study run? | When was the study run? | What patients were included in the study? | What was learned? | References |
|---|---|---|---|---|---|
| 2019 | Chart review at Duke Cancer Center | 2013–2018 | 58 mCRPC patients | 17% (8 out of 48) of patients saw a ≥50% PSA decline, and 3 patients had radiographic response | Matthew D. Tucker et al, 2019 |
| 2020 | Real world data from Guardant360 | 2018–2020 | 14 mCRPC patients with high MSI | Of the 14 patients, 9 were treated with Pembrolizumab. They had a median time to next treatment of 9.9 months, and 4 of 9 patients had >50% PSA declines. | Pedro Barata et al, 2021 |
| 2022 | Real world data from Flatiron/Foundation Medicine | 2011–2021 | 741 mCRPC patients, who took a checkpoint inhibitor or taxane chemotherapy and had measured TMB | Patients with high TMB had improved (longer) time-to-next-treatment when taking checkpoint inhibitors than taxane chemotherapy. This effect was reversed for patients with low TMB. Caveat: Only 14 patients in this study were MSI-H and took a checkpoint inhibitor. | Ryon P. Graf et al, 2022 |
| 2024 | Chart review at the Mayo Institute | 2018–2023 | 22 mCRPC patients, who took a checkpoint inhibitor and had either TMB or MSI high | Of the 12 patients who were MSI-high, 9 (75%) responded to pembro, with higher TMB correlating with longer response. None of the 6 patients who were only TMB-high responded to pembro. | Osama Mosalem et al, 2024 |
In these studies, there are two concordant studies where prostate cancer patients who had high microsatelite instability were likely to respond well to Pembrolizumab. For patients with high tumor mutational burden, there are discordant results across studies. This may be explained by some of the results in Osama Mosalem et al, 2024: in this study, the authors observed that a significant portion of TMB-high prostate cancer patients were also MSI-high, which may explain some of the responses seen in other studies.
References
- Leigh Marcus, Lola A. Fashoyin-Aje, Martha Donoghue, Mengdie Yuan, Lisa Rodriguez, Pamela S. Gallagher, Reena Philip, Soma Ghosh, Marc R. Theoret, Julia A. Beaver, Richard Pazdur, Steven J. Lemery. (2021) 'FDA Approval Summary: Pembrolizumab for the treatment of tumor mutational burden-high solid tumors', Clinical cancer research.
See article at PubMed Central See article at publisher's site - V Prasad, A Addeo. (2020) 'The FDA approval of pembrolizumab for patients with TMB >10 mut/Mb: was it a wise decision? No', Annals of Oncology.
See abstract at PubMed Central See article at publisher's site - Matthew D. Tucker, Jason Zhu, Daniele Marin, Rajan T. Gupta, Santosh Gupta, William R. Berry, Sundhar Ramalingam, Tian Zhang, Michael Harrison, Yuan Wu, Patrick Healy, Stacey Lisi, Daniel J. George, Andrew J. Armstrong. (2019) 'Pembrolizumab in men with heavily treated metastatic castrate‐resistant prostate cancer', Cancer Medicine.
See article at PubMed Central See article at publisher's site - Pedro Barata, Neeraj Agarwal, Roberto Nussenzveig, Benjamin Gerendash, Ellen Jaeger, Whitley Hatton, Elisa Ledet, Brian Lewis, Jodi Layton, Hani Babiker, Alan Bryce, Rohan Garje, Cy Stein, Lesli Kiedrowski, Philip Saylor, Oliver Sartor. (2021) 'Clinical activity of pembrolizumab in metastatic prostate cancer with microsatellite instability high (MSI-H) detected by circulating tumor DNA', Journal for ImmunoTherapy of Cancer.
See article at PubMed Central See article at publisher's site - Ryon P. Graf, Virginia Fisher, Janick Weberpals, Ole Gjoerup, Marni B. Tierno, Richard S. P. Huang, Nicolas Sayegh, Douglas I. Lin, Kira Raskina, Alexa B. Schrock, Eric Severson, James F. Haberberger, Jeffrey S. Ross, James Creeden, Mia A. Levy, Brian M. Alexander, Geoffrey R. Oxnard, Neeraj Agarwal. (2022) 'Comparative Effectiveness of Immune Checkpoint Inhibitors vs Chemotherapy by Tumor Mutational Burden in Metastatic Castration-Resistant Prostate Cancer', JAMA Network Open.
See article at PubMed Central See article at publisher's site - Osama Mosalem, Winston Tan, Alan H Bryce, Roxana S Dronca, Daniel S Childs, Lance C Pagliaro, Jacob J Orme, Adam M Kase. (2024) 'A real-world experience of pembrolizumab monotherapy in microsatellite instability-high and/or tumor mutation burden-high metastatic castration-resistant prostate cancer: outcome analysis', Prostate cancer and prostatic diseases.
See abstract at PubMed Central See article at publisher's site - Osama Mosalem, Winston Tan, Alan H Bryce, Roxana S Dronca, Daniel S Childs, Lance C Pagliaro, Jacob J Orme, Adam M Kase. (2024) 'A real-world experience of pembrolizumab monotherapy in microsatellite instability-high and/or tumor mutation burden-high metastatic castration-resistant prostate cancer: outcome analysis', Prostate cancer and prostatic diseases.
See abstract at PubMed Central See article at publisher's site