Improved Outcomes With Novel and Combination Therapies

Robert Alter, MD: Let’s go back to when and how these drugs came about. I don’t want to say that I predate the Cytokine Working Group, but that was the foundation for how immunotherapies got to be. Prior to 1992, we were using agents for which we were just guessing. I know people were giving circadian rhythm 5-FU [5-fluorouracil] and materials like that, but in 1992 when the FDA approved high-dose IL-2, it was sometimes still being associated with interferon, though interferon did not get its FDA approval until it was combined with Avastin [bevacizumab]. We were working with immunotherapy for a good 13 years until December 20, 2005, when sorafenib got FDA approval. Five weeks later, sunitinib got approval. We suddenly had an embarrassment of riches. We suddenly had 3 drugs FDA approved for a disease for which we had none, and that’s where the wheels started coming off. It started becoming a population of patients to whom we were given access, and pharmaceutical companies were getting drugs by expanded access. Then mTORs came into the world. Soon enough, it was between temsirolimus and everolimus. Shortly after that, we started getting pazopanib, axitinib, and a slew of other therapies.

Historically, we’ve been watching the initial immunotherapies, followed by TKIs [tyrosine kinase inhibitors] and followed by mTORs. In 2015, we suddenly started getting second-line data on using nivolumab as a therapeutic option for patients. It comes full-circle: We now have patients getting immunotherapy all over again only to find out that immunotherapies are becoming the backbone for first-line therapy, sometimes in combination with immunotherapy or combinations with tyrosine kinase inhibitors. Through these novel therapies and combination regimens, we’ve made tremendous strides over the last 28 years, and we’re suddenly offering patients clinical trials with competitive therapies in combination compared with single-agent guessing. It’s back to the embarrassment of riches.

Michael Atkins, MD: Yes. I’ve frequently been asked to comment on whether there’s a need for tolerable, effective therapies or how important it is to focus on quality of life. From the beginning of my career working with high-dose IL-2, I’ve always used therapies for kidney cancer with the goal of trying to cure patients. Patients’ preferred outcome is to have their disease go away, have their treatment stopped, and have them get back to their normal life. Immunotherapy offers that possibility, whether it was a 5% to 10% chance with high-dose IL-2 or potentially as high as a 30% to 40% chance with nivolumab-ipilimumab. That is the preferred strategy. Patients returning to their normal lives ultimately results in the best quality of life, even though that may result in more toxicity for a short period of time. Curative therapies have always been my preferred strategy, and I find that patients are willing to put up with a lot of toxicity if the ultimate goal is a chance for cure.

In the absence of curative therapies, that’s when you start talking about therapeutic index being important, and one has to balance the toxicity and efficacy of treatment choices to maximize the quality of a patient’s life. That’s where one might still focus on single agents and only selectively target the tumor with minimal off-target toxicities. Fortunately, that is not a first-line consideration for most patients with kidney cancer, but it’s still something one has to take into consideration if the patients don’t respond to up-front immunotherapy regimens.

Transcript Edited for Clarity