Despite many recent drug approvals for renal cell cancer (RCC), there remain several challenges in Renal cell carcinoma (RCC). Several pharma companies working to capture the market share presented results from their trials, however, DelveInsight has picked one that managed to catch the eyes of many. Have a look.
Abstract LBA5: Adjuvant RCC—under the radar among Immunotherapy Key players
The disease recurrence after nephrectomy is the major challenge posing threat to the lives of patients with renal cancer. A nephrectomy is the only acceptable standard of care worldwide for loco-regional renal cell carcinoma, no therapy has shown significant clinical benefit in the setting including cytokine therapy and VEGF-targeted therapy. Moreover, high mortality rates have been observed after disease progression to the advanced stage. The risk factors for recurrence post nephrectomy include the size of the tumor, nodal involvement and high nuclear grade.
Realizing the urgent need of the hour, a few pharmaceutical companies have jumped into the race to investigate their potential candidates for the setting. Some of the key players are Merck, Bristol Myer Squibb (BMS), Roche, AstraZeneca and others. Recently, Merck presented the first results from its adjuvant trial investigating pembrolizumab (Keytruda) in RCC after nephrectomy (Keynote-564) at the ASCO 2021 annual meeting, which was released during the plenary session of the medical conference.
Keynote-564 is a phase III, double-blind, a global trial investigating pembrolizumab (arm 1) versus placebo (arm 2) following nephrectomy in patients with clear cell RCC (ccRCC) with disease-free survival (DFS) as the primary endpoint and overall survival (OS) as the key secondary endpoint. The eligibility criterion of the study enrolled patients with ECOG status 0-1 and with no prior systemic therapy for the advanced disease. A total of 994 patients were randomized to either arm with more than 85% of patients with M0 intermediate-high risk score and 6% with M1 and no evidence of the disease (M1 NED).
As per the efficacy analysis in the intention-to-treat population (ITT), median DFS (mDFS) was not reached for either of the arms and had a ~10% of significant difference in the 12-month (85.7% Vs 76.2%) and 24-month (77.3% Vs 68.1%) DFS rates in the experimental vs placebo arm. The subgroup analysis also showed the HR values of less than 1 which showed the significant benefit in the pembrolizumab arm as compared to the placebo arm, especially in patients with M1 NED (HR 0.29). The interim analysis of OS was also presented and was not reached for either of the arms. The 12-month and 24-month OS rates were not statistically significant between either of the arms, therefore, an additional follow-up of the study is still required for the mature OS values. The safety results stated that arm 1 was more associated with grade 3-5 adverse events (AEs), serious all-cause AEs and treatment-related AEs (TRAEs).
The first-ever positive phase III study of the adjuvant immunotherapy met its primary endpoint and demonstrated a clinically meaningful improvement in DFS vs placebo. Moreover, the DFS benefit was also consistent in the subgroup analysis with no new safety signals. Therefore, it can be concluded from the above analysis that pembrolizumab could serve as a new standard of care for patients with RCC after nephrectomy.
Other key players in the market
After the recent clinical success of immunotherapies in the adjuvant setting of gastric cancers, it is likely that adjuvant RCC is the new target for these therapies with a handful of clinical trials in the setting. After receiving the green light from the US FDA for nivolumab (Opdivo) and ipilimumab (Yervoy) combination in the front-line treatment of RCC (Checkmate-214), BMS is now running a pivotal trial with the combination in the adjuvant setting of the disease. The company is relying its hopes on the trial, after watching the success in the advanced disease. Another contender, Roche, is running IMmotion010 phase III study to evaluate the efficacy and safety of atezolizumab (Tecentriq) versus placebo in participants with RCC who are at high risk of disease recurrence following nephrectomy. Another key candidature is held by AstraZeneca, whose RAMPART trial is in phase III evaluating durvalumab monotherapy or the combination of durvalumab and tremelimumab for the adjuvant therapy in patients with resected primary RCC at high or intermediate risk of relapse.
INSIGHTS: Upcoming years might provide patients with good immunotherapy options since there is a huge market size of the indication in this setting. The above analysis on Keytruda could prove itself as a new standard of care with the upcoming data readouts and could replace the dependency on the less beneficial VEGF-targeted therapy. Since there is a huge unmet need in the area, the different immunotherapy combinations might provide clinical benefits with manageable toxicity profiles.
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