For Vassiliki Karantza, MD, PhD, the past seven years have been a whirlwind. Since starting her first job in the pharmaceutical industry in 2014, the former Damon Runyon Clinical Investigator has overseen the development of a new drug for breast cancer from early clinical trials to approval by the Food and Drug Administration. As of March 2021, the drug, pembrolizumab (Keytruda), is FDA-approved for the treatment of metastatic triple-negative breast cancer (TNBC), which accounts for 10-15% of breast cancer diagnoses. It is a remarkable achievement, especially considering that the company’s breast cancer program did not yet exist when Dr. Karantza arrived.

Meeting Urgent Need

Pembrolizumab is a form of immunotherapy. It works by blocking a protein called PD-L1, found on the surface of cancer cells, from binding to immune T cells and deactivating them. By inhibiting PD-L1, pembro (as Dr. Karantza and her team familiarly call it) allows T cells to launch their immune response without interference. Patients are considered good candidates for pembro if they test positive for PD-L1 expression.

Pembro qualified for accelerated FDA approval due to the urgent need among TNBC patients for new therapies. In triple-negative breast cancer, the tumor cells lack all three receptors usually targeted by hormone therapies or other drugs. For many TNBC patients, highly toxic chemotherapy is the only treatment option, and even then, the prognosis for patients with metastatic disease is poor.

Drugs like pembro are used in combination with chemotherapy to increase antitumor activity, and in some cases to shrink tumors prior to surgery. The team’s goal, according to Dr. Karantza, is to eventually use pembro to treat early-stage TNBC, when the patient’s immune system is more robust and curative treatment is possible. “If we can not only treat the cancer, but also prevent it from returning and becoming metastatic – that is where immunotherapy can make a big difference,” she says. The drug is not yet approved for patients with early-stage disease, but recent clinical trials show promising data.

Seeking FDA Approval

For metastatic cancer treatments, success is measured by progression-free survival (PFS) – the length of time before a patient’s tumor shows progression – and overall survival (OS).

The key to obtaining FDA approval is being able to show a significant effect on either (or both) of these measures. “You have to make a prediction,” Dr. Karantza explains. “If this is what chemotherapy alone will do, I predict that by adding immunotherapy, I will improve the PFS by X. To do that, I need Y number of patients. You design your study to have enough power to show a statistically significant result.”

If researchers show that a drug prolongs PFS, the FDA will likely issue accelerated approval. Longer follow-up or additional studies may be required to verify the drug’s clinical benefit.

Dr. Karantza arrived at Merck alongside favorable results from a Phase 1 clinical study on pembro. Based on this data, the breast cancer team assembled under Dr. Karantza’s leadership and launched a Phase 2 study, involving a larger population of patients with metastatic TNBC. Typically, this would precede a Phase 3 study, in which the new drug is compared to the standard of care – in this case, chemotherapy – to determine whether there is significant additional benefit. Given the degree of enthusiasm and promise, however, the timeline was shortened; Phase 2 and Phase 3 studies ran concurrently. “Anything involving immunotherapy moves very fast and a little out of order compared to classical drug development,” Dr. Karantza explains. “Essentially, while still getting a signal, we think our signal will be good enough that we invest in comparing it with the standard of care.” Thankfully, their prediction was correct.

From Academia to Industry

Dr. Karantza’s background as a physician-scientist prepared her well for an industry role. Her clinical experience guides her decision-making, and she continues to be driven by the investigatory mindset of basic science research.

Still, the past seven years have taught her a lot. “Coming from academia, you only see one side of clinical trials,” she notes. “You enroll the patients, you put your data in the database, and that’s it. But what it takes to set up a study is incredible – all of the different functions that have to come together. We call it a clinical trial, but behind it is statistics, commercial assessment, marketing, regulatory agencies. You realize how big a village is needed to make the drug and get it to patients.” Since joining the company, Dr. Karantza has advanced from Director of Clinical Research to Associate Vice President of Global Clinical Development, where she now oversees the breast cancer program.

Does she ever miss clinical practice? Yes. “But the way I see it now, rather than helping one patient at a time, I’m hopefully helping many patients. So, I lose a little bit of the personal connection, but ultimately, I’m doing what I set out to do by going into oncology. Patients are still at the center.”

From this vantage, she reflects on the broader challenges facing physician-scientists. “It’s hard starting out, when you are called to do clinical activities while maintaining a lab and funding on par with senior researchers,” she says. “That's where an organization like Damon Runyon plays a huge role.”

Dr. Karantza celebrates this milestone approval of pembro for patients with metastatic TNBC as one of the most meaningful accomplishments of her career. “I want to thank Damon Runyon for providing critical support early on and for giving me the confidence to aim high and do my best to help patients with breast cancer live longer and hopefully happier lives,” she says. “I feel like I’m fulfilling the trust that Damon Runyon showed to me. It’s a very happy story.”