Matthew Galsky, MD Icahn School of Medicine at Mount Sinai New York, NY

Metastatic Urothelial Cancer: Switch-Maintenance Pembrolizumab Improved Progression-Free Survival

MedicalResearch.com Interview with:

Matthew Galsky, MD Icahn School of Medicine at Mount Sinai New York, NY

Dr. Galsky

Matthew Galsky, MD
Icahn School of Medicine at Mount Sinai
New York, NY

MedicalResearch.com: What is the background for this study? Would you explain what is meant by switch maintenance immunotherapy?

Response: For decades, platinum-based chemotherapy has been standard first-line treatment for metastatic urothelial (bladder) cancer. The standard approach to first-line chemotherapy is to administered approximately 6 cycles of treatment (in the absence of disease progression or prohibitive side effects), and then to stop treatment and monitor. Unfortunately, virtually all patients with metastatic disease will experience disease progression after stopping chemotherapy. However, we know that if we just continue the same platinum-based chemotherapy until progression of cancer (rather than stopping after ~6 cycles), the side effects continue to accumulate but the benefits plateau.

Approximately 5 years ago, the first new systemic therapies were approved to treatment metastatic urothelial cancer in decades, immune checkpoint inhibitors (PD-1 or PD-L1 inhibitors). In fact, 5 PD-1/PD-L1 inhibitors have been approved by the FDA for the treatment of patients with metastatic urothelial cancer progressing despite prior platinum-based chemotherapy. Given that these drugs are non-cross resistant with chemotherapy in at least a subset of patients (i.e., they can provide benefit even when chemotherapy is no longer working), and because they are well tolerated by a large proportion of patients, a logical question is rather than waiting until cancer progresses after stopping first-line chemotherapy, what if we started immunotherapy immediately. Switch maintenance refers to switching from chemotherapy to a different class of drug (e.g., immunotherapy) and maintenance refers to trying to “maintain” the response achieved with initial chemotherapy.

MedicalResearch.com: How is pembrolizumab different from other forms of immunotherapy?

Response: Pembrolizumab is a PD-1 inhibitor approved by the US FDA for the treatment of patients with metastatic urothelial cancer progressing despite prior platinum-based chemotherapy based on a randomized phase 3 clinical trial that demonstrated an improvement in survival with this approach compared to “second line” chemotherapy. 

MedicalResearch.com: What are the main findings?

Response: The primary endpoint of the study was progression-free survival and this was a randomized double-blind phase 2 study. The study showed that switch maintenance pembrolizumab significantly improved progression-free survival compared with placebo.

MedicalResearch.com: What should readers take away from your report?

Response: This is a randomized phase 2 study with progression-free survival as a primary endpoint. Changing standard of care should be really based on larger trials that demonstrate patients live longer with this approach, our gold standard for informing oncology care (we initially reported our results at the ASCO annual meeting in June 2019). However, while our study was the first to test this approach and the first to report the results demonstrating a potential benefit, in January 2020, a press release indicated that a trial with a similar immunotherapy (PD-L1 inhibitor avelumab rather than the PD-1 inhibitor pembrolizumab we tested) demonstrated an improvement in SURVIVAL with the switch maintenance approach https://www.ascopost.com/issues/january-25-2020/javelin-bladder-100-study-of-avelumab-for-urothelial-cancer-meets-primary-endpoint/. The avelumab study has not yet been presented or published and we need to wait for those full results. However, it is the FIRST randomized phase 3 trials in several decades showing a survival benefit in the first-line treatment of patients with metastatic bladder cancer. So, we now have two randomized studies supporting this approach and once the results of the other study are presented/published, depending on the degree of benefit, it is highly likely that this will become a standard treatment approach. Physicians should await the results of the latter study, so that we can interpret the results of the two studies in total, before changing their current approach. 

MedicalResearch.com: What recommendations do you have for future research as a result of this work? 

Response: The switch maintenance setting may be a new “disease state” on which to build to further improve outcomes in this patient population. The key, and challenge, is to not increase the burden of treatment related side effects in this setting where patients historically had a “break” from chemotherapy and so this will require careful considerations of risks/benefits moving forward.

Any disclosures? This was an investigator initiated study that we initiated prior the the first approval of an immune checkpoint inhibitor in urothelial cancer – we designed the study in 2013-2014. The field has changed dramatically and there is palpable progress being made but more work to be done.

Merck provided funding for this study. I have also served on advisory boards for Merck.

Citation:

Matthew D. GalskyAmir MortazaviMatthew I. MilowskySaby GeorgeSumati GuptaMark T. FlemingLong H. DangDaniel M. GeynismanRadhika WallingRobert S. AlterMohamad KassarJue WangShilpa GuptaNancy DavisJoel PicusGeorge PhilipsDavid I. QuinnG. Kenneth Haines IIINoah M. HahnQianqian ZhaoMenggang Yu, and Sumanta K. Pal

Journal of Clinical Oncology 0 0:0

 

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Apr 10, 2020 @ 4:19 pm

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