June 22, 2017 will be the first World Kidney Cancer Q&A Day, where international kidney cancer communities in collaboration with the international kidney cancer coalition, a community of patients, caregivers, healthcare professionals and patient organizations will raise awareness and funds for kidney cancer. Renal cell carcinoma is among the 10 most common cancers worldwide. The majority (approximately 85% in G7) of newly diagnosed renal cancer are renal cell carcinomas, and the vast majority belongs to clear cell histology. According to Decision Resources Group’s proprietary epidemiology, 112,000 cases were diagnosed with renal cell carcinoma in 2015 in the G7 countries, out of which 50,353 were from the United States and approximately 44,785 from the Europe (for more details see our Renal Cell Carcinoma Epidemiology Forecast).
Until recently, the treatment of renal cell carcinoma was largely dominated by small molecule multitargeted kinase inhibitors and anti-VEGF therapy. With the numerous treatment options already approved for renal cell carcinoma, the major challenge was in treating renal cell carcinoma resistance to such targeted therapies. However, in 2015, approval of the immune checkpoint inhibitor, Opdivo, for second-line treatment of advanced or metastatic renal cell carcinoma transformed the treatment armamentarium, increasing MOS to 25.5 months as compared with Afinitor (MOS 19.7 months), in a space where until now only improvement in PFS was evaluated in pivotal registration studies. Another significant change is the choice in primary end points, previously approved small molecule TKIs (Sutent, Inlyta, Avastin), and mTOR inhibitor (Afinitor) have evaluated improvement in PFS as the primary endpoint, whereas Opdivo and Torisel pivotal study assessed MOS as the primary endpoint. Regulatory approval of Cabometyx and Lenvima/Kisplyx + Afinitor in 2016 has further crowded the second-line setting, increasing the median PFS to 14.6 months as compared to Afinitor (mPFS 7.4 months).
The approach to treating renal cell carcinoma is rapidly evolving and becoming more complex, for example, Sutent remains the preferred first-line advanced or metastatic treatment, along with Votrient, but this is expected to change soon, as Cabometyx was shown to be superior over Sutent in PFS for treatment-naïve patients with poor and intermediate prognosis. Meanwhile, current treatment decisions and sequence of therapy is dependent on the response to prior drug received, for example, patients treated with a small molecule TKIs (such as, Sutent, Votrient, or Inlyta) in first-line are most likely to be prescribed with PD-1 inhibitor, Opdivo as the next treatment choice, or patients who do not respond to Opdivo or cannot tolerate Cabometyx in the second-line setting, could receive Inlyta as it is very well-tolerated at its standard dose. The treatment guidelines (NCCN, ESMO) have also listed Opdivo, Cabometyx as ‘category 1’ for the second-line treatment similar to Inlyta; indicating that the new entrants have similar recommendations due to their significant efficacy profile, a fact which has also been supported by interviewed physicians. The increasing number of treatment options and a limited number of comparative studies have created an opportunity for identifying factors that impact the appropriateness of various therapies for different patient subgroups. Additionally, growing preference for novel agents, such as Opdivo, has pushed the use of drugs like Torisel, Inlyta, and Afinitor to later lines of treatment or specific subpopulations. This has fueled debate around the current reimbursement scenario, wherein drugs that are less-preferred by physicians or have been relegated to smaller patient subpopulations have better market access but less efficacious and/or less favorable side effect profile than newly approved drugs.
The approval of Opdivo has paved the way for clinical studies that are assessing novel combination regimens composed of small molecule kinase inhibitors and PD-1 inhibitors [such as Opdivo (anti-PD-1) + Yervoy (anti-CTLA-4) + Cabometyx (multi TKI) in Phase III; Keytruda (anti-PD-1) + epacadostat (IDO-1 inhibitor) in Phase I/II; Keytruda (anti-PD-1) + Votrient (multi TKI) in Phase III)] in an effort to target major unmet needs, including overcoming tumor resistance, improving PFS, and maintaining quality of life.
The future of immunotherapy and the era of combinatorial approaches in renal cell carcinoma is certainly expanding rapidly and is expected to improve efficacy with more durable response as indicated by the enthusiasm of thought leaders interviewed by DRG. However, they also indicate potential concern over additive toxicity of combination regimens. What remains to be seen is achievement of optimal balance between efficacy and safety among the newly-approved and upcoming regimens.
For information on the current treatment landscape and our ten-year forecast for renal cell carcinoma across the seven major pharmaceutical markets, see our Renal Cell Carcinoma Disease Landscape & Forecast.