Oncology PI Shares Lessons Learned And Successes Working With Basic Scientists

A conversation with Ranee Mehra, MD, associate director for clinical research, director of head and neck medical oncology, solid tumor section head, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center

Whether a drug will receive FDA approval is anything but a given. A recent study confirms that the top pharma companies average a 14.3% likelihood of approval. Drugs for cancer can expect an even slimmer chance, with some sources reporting the success rate at just 3.4%.

Yet, Ranee Mehra, MD, perseveres. And with good reason: She’s found success as a PI with cancer drugs pembrolizumab (KEYTRUDA) and ceritinib.

In this Q&A, Dr. Mehra shares her experience with these two programs and discusses how those successes shape her approach to future research and the importance of working closely with basic scientists to better understand cancer biology.

Clinical Leader: You’ve conducted several clinical trials across all phases. From a PI perspective, what challenges or changes does each present?

Ranee Mehra, MD: Phase 1 trials require more oversight and a robust clinical trial infrastructure. Slots are usually limited and sometimes patients have to wait for a treatment slot. These are often conducted at academic cancer centers that have the teams and experience to conduct these studies safely. We also try to build relationships with community physicians who may send us a potential patient while they are still on standard therapy so we can build a relationship and have time to identify possible trials slots should they need it in the future. Phase 3 trials often take years to enroll and for data to mature and are often randomized studies, which patients have to accept, and our discussions with patients are often lengthy so that we can explain the rationale for the trial, the need for randomization, and reassure them that they are still getting appropriate care on either treatment arm.

Two trials you’ve worked on have earned regulatory approval — pembrolizumab (KEYTRUDA) and ceritinib. Thinking about those experiences and understanding that not all PIs will see success, how do you feel about the approvals and your role in obtaining them? At the time, were you confident that they would succeed?

I am very proud of the work done for those drug approvals. It was clearly a team effort, and it was an honor to be involved. Both of these programs started in the Phase 1 stage, and we did not know initially that they would succeed, but after treating a few patients and seeing success there was a building sense of excitement. The best part of those experiences was seeing patients who did not have a good standard treatment option benefit — with less pain, shrinkage of tumors, and an improvement in cough or shortness of breath — resulting in a better quality of life and longer life, and there is immense professional satisfaction in being part of a program that has increased access to care for patients all over the country.

How does being part of a successful trial prepare you for the next trial? Are there certain skills developed or lessons learned that translate across trials?

One does learn a lot from a successful program, including how to design the next trial, how to manage side effects, when a trial protocol should be modified, and how to communicate trial goals to a patient. For instance, in the LDK378 trial, we saw activity in untreated brain metastases, and this provided the experience and rationale to allow patients with brain metastases in future studies with agents that could have CNS activity. It is all a learning process.

In addition to these clinical experiences, you also work closely with basic scientists in understanding the biology of head and neck and thoracic malignancies. Why is this important to you?

We need to learn more about cancer biology in order to design future successful clinical trials. I think some of the most effective treatments are those that were developed for a particular patient population, and it is the basic scientists who help us to understand those pathways and biomarkers.

For instance, immune checkpoint inhibitors were initially studied among all head and neck cancers, but translational science helped to identify the PDL1 combined proportion score biomarker. Tumors that have positive and higher expression of PDL1 CPS have a better response to immunotherapy, and those patients often live longer on this treatment. After researchers identified the biomarker, it was studied in patient samples retrospectively, and then in prospective clinical trials, and it is now a standard clinical biomarker that helps identify which patients should get immunotherapy.

What are some of the discussions you’ve had? And how has each side learned from one another?

We discuss future efforts a lot. The scientists explain the interactions between cancer pathways, and I try to provide clinical context. Currently, we spend a lot of time discussing current and future grants and how we can use the data we gather to translate into better patient care.

One area that we have discussed at length is understanding the genomic profile of recurrent head and neck cancers. I often get next-generation sequencing data as part of the standard- of- care treatment for individual patients. With the collaboration of the basic scientists, we created a de-identified database so that they could analyze the entire set and try to find genomic alterations that help to determine which tumors are more aggressive or may respond to treatment.

About The Expert:

Ranee Mehra, MD, is a professor of medicine, director of head and neck medical oncology, solid tumor section head and associate director for clinical research at the University of Maryland Greenebaum Comprehensive Cancer Center. She treats patients with upper aerodigestive cancers, in particular head and neck cancers, salivary gland cancers, and thyroid cancers. Dr. Mehra was a lead investigator in the Keynote-012 trial, which led to the FDA approval of pembrolizumab, as well as the first-in-human trial of LDK-378, ceritinib, which led to the FDA approval for advanced ALK+ NSCLC. Her current research efforts include conducting novel trials studying immunotherapy and targeted therapies for advanced disease.