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Optimizing Approaches to Improve Outcomes in Cancer

Publish Date

17 JUN 2021


Keyvan Tadjalli Mehr M.D.


There’s no magic bullet for cancer, but what inspires me most is that immuno-oncology—and especially checkpoint inhibitors—is redefining cancer treatment paradigms, but there’s more work to be done

The first checkpoint inhibitor was approved in 2011. By 2017, there were more than 240 immuno-oncology treatments in clinical trials, and the emergence of a variety of immunotherapy approaches including CAR T-cell therapy; inhibitors of checkpoint proteins including CTLA-4, PD-1 and PD-L1 and TIGIT; cancer vaccines; and BiTE antibodies.1 This explosion in research offers the potential to revolutionize the future treatment of cancer, but in the meantime, we can and must do more to optimize the treatments we already have available.

We need more answers
There’s no question that immunotherapy has the potential to truly change the outlook for many cancer patients. But while these new drugs and therapeutic mechanisms provide varying degrees of clinical benefit, unmet needs remain for many patients.2,3,4

This raises many questions. Can we make a tumor more immunogenic? Is immune suppression the reason why we’re not seeing the full potential of new drugs? Will combinations work, and which ones? How can we predict which patients will actually respond? At Merck KGaA, Darmstadt, Germany, we look to answer these questions not only by looking for new treatment options, but also examining the right approach to using them.

It’s about timing
We believe one way we can do more to improve outcomes in certain advanced cancers using immune checkpoint inhibitors is with a maintenance therapy approach.

While chemotherapy is currently a standard of care, due to its ability to shrink or stabilize tumors, it doesn’t always provide sustained benefit over the long-term. We wondered, would adding an immune checkpoint inhibitor after a patient has responded to chemotherapy make a difference? Could this maintenance approach keep the cancer under control longer, delaying the return or growth of tumors? Tumor cells use certain proteins to hide from the immune system, and a PD-L1 (human anti-programmed death ligand-1) antibody can prevent this from happening.

Traditionally first-line treatment for bladder cancer is chemotherapy. The 10th leading cause of cancer death globally, sadly people who are initially diagnosed with metastatic or advanced bladder cancer have a 5-year survival rate of only 5%.5,6 It is a challenging cancer. With our biology-driven strategy focusing on tackling challenging cancers, and as we learned more about PD-L1 inhibition, we wondered if an immunotherapy approach might be able to improve on the outcomes for people with bladder cancer that we saw with first-line chemotherapy. But how? As we looked at the best way to answer that question, it seemed rational from a biological standpoint to study a maintenance therapy approach.  

Our results
We conducted a Phase III clinical trial in patients with locally advanced or metastatic bladder cancer. This is the first Phase III study examining use of immunotherapy in the first-line setting in advanced bladder cancer that demonstrates a survival advantage, which is a goal of any cancer treatment.7

Making a real impact
There's no magic bullet for cancer, but what inspires me most is that immuno-oncology--and especially checkpoint inhibitors--is redefining cancer treatment paradigms, but there's more work to be done. We see an incredible transformation happening, and it’s extremely exciting to jump in with both feet for the benefit of patients and our communities.

Our next logical step to really make the most of immunotherapies to truly benefit patients is combinations. But we have work to do here, as we do not yet have very efficient pre-clinical markers to tell us whether a particular combination will provide benefit, and to whom. We need to carefully consider the next treatment candidates; we need to develop the right models and really understand the advantages of combinations.

Every effort and every step we make must be more thoughtful, and I believe the wisdom of our strategy is reflected in the clinically significant data that we have demonstrated in advanced bladder cancer. The fact that we have demonstrated overall survival in our clinical trial is compelling and continues to drive us. I’m humbled that we’re in a unique position to bring medicines to the market that can actually make a difference.  


1 PhRMA/ACS CAN, Medicines in Development 2017 Report: Immuno-Oncology. Available: phrma-docs.phrma.org/files/dmfil/MID-Report-ImmunoOncology-2017.PDF. Accessed: April 2021.

2 Kim JM, Chen DS. Immune-escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016;27(8):1492-1504.

3 Chen DS, et al. Molecular pathways: next generation immunotherapy-inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18(24)6580-6587.

4 Riella LV, et al. Role of the PD-1 pathway in the immune response. Am J Transplant 2012;12(10):2575-2587.

5 IARC. Bladder Fact Sheet. GLOBOCAN. Available at: https://gco.iarc.fr/today/data/facthseets/cancers/30-Bladder-fact-sheet.pdf. Accessed: April 2021

6 SEER. Cancer Stat Facts: Bladder Cancer. Available at: https://seer.cancer.gov/statfacts/html/urinb.html. Accessed: April 2021.

7 Powles T, et al. Avelumab maintenance therapy for advanced or metastatic urothelial cancer. N Engl J Med. 2020;383:1218-1230.