Novel Therapies in Advanced RCC

Robert Alter, MD: The amazing evolution of therapies over the course of 15 years utilizing initial TKI [tyrosine kinase inhibitor] therapies, going back to December of 2005 with the FDA approval of Nexavar [sorafenib], coupled with a total of 13 new drugs over the course of the last 14.5 years, has really been truly, and I have to quote Nicholas Vogelzang, MD, FASCO, FACP, an “embarrassment of riches.” I think the fact that we are making significant progress is good, yet we are still able to take care of patients with progression. I think we are still trying to achieve the ultimate curability of the disease. That’s something that we got a taste of when we used high-dose IL-2 [interleukin-2] in the late 1990s and early 2000s.

That being said, there are many studies that are being completed or have recently completed that I think we should be interested in. Presented at ASCO [the American Society of Clinical Oncology annual meeting] 2020 was a study of patients who had progression of disease after immunotherapy. This was an open-label, phase 2 clinical trial looking at axitinib and pembrolizumab. There was an overall response rate of 55%. The median duration of response was approximately 12 months. Median progression-free survival of patients who achieved a response was close to 12 months.

And not only do we have the ability to utilize this combination of axitinib and pembrolizumab as a first-line therapy, based upon the KEYNOTE-426 clinical trial, but now I see a benefit of utilizing this as a second-line therapy after first-line immunotherapy.

We also have the CheckMate-9ER clinical trial coming out looking at the combination of Cabometyx, or cabozantinib, and nivolumab. Toni Choueiri, MD, presented the data on an oral HIF [hypoxia-inducible factor]-2 alpha inhibitor, MK-6482, demonstrating an overall response of 24% when used as a second-line agent. And whether you progressed after immunotherapy or TKI therapy, a disease control rate of 80% was quite impressive.

And then, we also have the update to the KEYNOTE-426 clinical trial utilizing axitinib and pembrolizumab. Again, we are thinking about how to consider these agents for intermediate and poor risk, but also for good risk, with a CR [complete response] rate of approximately 11%.

My message to community oncologists is that our approach should be the same to how we approach all of our patients. I think we have to, again, as we discussed earlier, consider risk stratification by identifying the patients in the risk categories to help us determine which therapy they may derive benefit from, And utilize the NCCN [National Comprehensive Cancer Network] guidelines, which again, are very helpful. The guidelines are not the law, but they are definitely insightful, in terms of how we should think our patients could be treated best. Also, think about sequences of therapy and believe that our patients will receive more than 1 round of therapy. As I speak to other community oncologists, I think our patients are receiving 4 to 5 lines of systemic therapy, not just with benefit but with great tolerability and now minimal toxicity.

As always, you should think about clinical trials. If you have the opportunity, enroll patients at your site or refer patients to a tertiary care unit. Either for first-line therapy or subsequent lines of therapy, this can be quite helpful as well.

We have to think about patients, as always. I always tell my patients it’s not about the cancer, it’s about the patient who has the cancer. We need to think about their small factors that we don’t always think about—their accessibility to the office, their financial toxicities. I think data may drive us to believe what may be the best therapy for a patient, but if it’s unaffordable, it may be very important for the patient to consider other therapies as well.

I think that as a whole team, incorporating your patients in parts of the discussions of options of therapy allows them to not only feel as if they’re part of it, but it improves their communication to the physician and the physician's staff, nurse navigators, nurse clinicians as well. I think the important care that the patient has during first-line therapy or during any line of therapy dictates their quality of life. And our goal should be their goal—not only improvement of survival but quality of life as well.

Transcript edited for clarity.

Case: A 58-Year-Old Man With Advanced Renal Cell Carcinoma

• August 2018: A 58-year-old man complained of fatigue and anorexia; after appropriate workup the patient was diagnosed with clear cell renal cell carcinoma
  • He underwent left total nephrectomy
• March 2019: He developed metastatic disease to the lungs bilaterally (30 x 35 mm), mediastinum and soft tissue metastatic deposits
  • MSKCC risk status: intermediate
  • ECOG 1
  • He was started on pembrolizumab 200 mg IV every 21 days + axitinib 5 mg PO q2Days
• September 2019: He developed progressive disease (45 x 50 mm); pulmonary lymph nodes increased in size and new mediastinal and hilar lymphadenopathy was noted
  • He was started on lenvatinib 18 mg PO qDay + everolimus 5 mg PO qDay
• October 2019: Due to grade 1 diarrhea, reduced dose of lenvatinib to 14 mg PO qDay + everolimus 5 mg PO qDay
• December 2019: Lesions reduced to 20 x 20 mm from September 2019; achieved partial response
• January 2020: He remained on therapy with lenvatinib + everolimus