EIKCS 2021: Future Therapeutic Approaches in Renal Cell Carcinoma

Dr. Hammers highlighted that the first-line treatment landscape in RCC has evolved over the past 15 years. While we have long recognized that RCC is not responsive to cytotoxic chemotherapy. In the early 2000s, small molecular tyrosine kinase inhibitors targeting tumor angiogenesis we found to have benefit in first-line treatment in RCC. In the past few years, we have now seen the introduction of multiple immunotherapy-based combinations which have now become the standard of care.

Dr. Hammers reviewed the design and outcomes of the recently presented and published CLEAR study. This three-armed study randomized patients to lenvatinib + pembrolizumab, Lenvatinib + everolimus, or sunitinib. Dr. Hammers emphasized that lenvatinib + pembrolizumab was found to be a very active regime with an unusually long median progression-free survival of almost 2 full years.

Assessing treatment-related adverse events, the toxicity of this approach is driven by the Tyrosine Kinase Inhibitors (TKI). However, what is notably lacking is liver toxicity which is expected, but not observed in this study, to increase with the combination of Lenvatinib + pembrolizumab. As a result of this, the dose of Lenvatinib is able to be escalated, providing additional oncologic benefit.

Dr. Hammers then moved on to summarize studies that have shown an overall survival (OS) benefit. First, CheckMate214 found benefit of nivolumab and ipilimumab among patients with intermediate and poor risk disease. Notably, the more mature data has shown a difference in median overall survival of approximately 20 months. Moving rightwards in this table, we see increasing TKI activity from axitinib as a more selective TKI to cabozantinib and lenvatinib. However, the combination of axitinib and pembrolizumab had significant benefit. Dr. Hammers suggested that the durability of responses may be less profound in this combination as the benefit may be driven by TKI effect. However, further data from the KEYNOTE-426 study will be necessary to assess this. Dr. Hammers then highlighted that very few patients have progressive disease with either of the two most recently published regimes – cabozantinib and nivolumab or Lenvatinib and pembrolizumab.

Dr. Hammers emphasized that it is typically not clear how or when to choose between IO/IO and IO/TKI combinations. An alternative being actively studied is the combination of “the best of both worlds” with a triplet of cabozantinib, nivolumab and ipilimumab, as is being assessed in COSMIC-313. However, in his practice, Dr. Hammers felt that most patients do not require the early effects of TKI therapy.

In addition to these immunotherapy-based regimes, there are other treatment backbones under development, each of which he highlighted briefly. The first of these is bempegaldesleukin, a pegylated IL-2 molecule. This has not demonstrated activity as a single agent but is being assessed in combination with nivolumab in comparison to TKI monotherapy, acknowledging that this is not a current, modern standard of care comparator.

The second of these is the glutaminase inhibitor CB-839 which, like bempegaldesleukin, has almost no single agent activity. In the CANTATA study, CB-839 was studied in combination with cabozantinib. While not published, this study was reported (in press release) to be negative.

Third, he discussed what he termed a “transformative agent”, the HIF-2 inhibitor Belzutifan, This is a very targeted agent with few if any off-target effects. In early monotherapy trials, some benefit is observed in two-thirds of patients. In addition, there is reasonable durability of response.

This approach is also being tested in VHL-associated ccRCC.

Moving forward, one of the major transformative change will be the changing role of adjuvant therapy. While approved, the use of sunitinib has been low given its relatively poor efficacy. However, there is promise for the benefit of immune checkpoint inhibition in the adjuvant setting, based on a press release recently suggesting benefit for pembrolizumab in this indication. Whether an OS benefit is forthcoming remains to be assessed.

If the use of adjuvant PD-1 inhibitions becomes routine, we must consider how this affects the efficacy of our current standard of care first-line mRCC therapies. Dr. Hammers suggested that the benefit may be dramatically reduced. Thus, he postulated that we may need to expand the backbones of our therapies including considering dual and triple therapies.

In summary, Dr. Hammers highlighted that the treatment options in advanced RCC are rapidly expanding, with great promise for novel HIF-2 inhibitors and adjuvant immune checkpoint inhibitors.

Presented by: Hans Hammers, M.D., Ph.D. Associate Professor, Endowed Title: Eugene P. Frenkel, M.D. Scholar in Clinical Medicine, UT Southwestern Medical Center