Kidney cancer is one of the top 10 most prevalent cancers, with over 150,000 new cases of kidney cancer diagnosed in the G7 countries in 2017, accounting for 3% of all new cancer cases. Renal cell carcinoma (RCC) comprises 90-95% of kidney cancer and almost one-fifth of patients are metastatic upon diagnosis.1
In the past decade, metastatic RCC treatment has rapidly evolved with 10 new FDA approved agents across three classes – VEGF ligand / receptor inhibitors, mTOR inhibitors and immunotherapy. The introduction of targeted anti-VEGF tyrosine kinase inhibitor (TKI) monotherapy in the mid-2000s shifted standard of care away from cytokine therapies such as IL-2 and Interferon-α given proven superior efficacy, improved tolerability, and ease of administration as oral regimens. TKI monotherapy has held its spot as the mainstay of RCC treatment for several years. Even to this day, patients currently receive a standard of care of Sutent® (suntinib, Pfizer) or Votrient® (pazopanib, Novartis), both of which are VEGF-targeted TKIs, as fir-line treatment for advanced / metastatic disease. However, physicians report over 60% of patients will progress on first-line therapy and receive additional treatment.2 So despite these developments, there is a need for more effective and durable first-line options for advanced / metastatic RCC.
In 2015, the gears for checkpoint inhibitor immunotherapy for RCC were set in motion, with the approval of Opdivo® (nivolumab, Bristol-Myers Squibb / Ono Pharmaceuticals) for patients who previously received anti-angiogenic therapy. Approval was based on the CheckMate-025 study, which demonstrated an overall survival (OS) benefit with Opdivo, with fewer adverse events, compared to the mTOR inhibitor Afinitor® (everolimus, Novartis).3 This was the first checkpoint inhibitor approved for the treatment of advanced RCC and physicians responded with rapid uptake in the second-line setting.2 This approval primed the field for investigation of checkpoint inhibitors in the first-line setting. Given checkpoint inhibitor monotherapy exhibits response rates in only about 25% of patients,3 the field has turned to combination strategies in the first-line – in combination with other checkpoint inhibitors and/or in combination with angiogenesis-targeted inhibitors – to boost response rates and durability of response. The two combinations that are likely to keep the gears turning in favor of checkpoint inhibitors for first-line RCC in the near future are Opdivo plus Yervoy® (ipilimumab, Bristol-Myers Squibb / Ono Pharmaceuticals) and Tecentriq® (atezolizumab, Roche / Genentech / Chugai) plus Avastin® (bevacizumab, Roche / Genentech / Chugai).
At the European Society of Medical Oncology (ESMO) annual meeting in September 2017, data was presented from the Phase III CheckMate-214 trial that compared Opdivo plus Yervoy to Sutent in previously untreated patients. The median OS for MSKCC intermediate- and poor-risk patients has not yet been reached for the Opdivo plus Yervoy arm, and was 26 months in the Sutent arm.4 When considering PD-L1 expression, benefit was statistically significant independent of PD-L1 level, but there was an enrichment in OS benefit shown for patients with PD-L1 levels ≥1% (HR 0.45 for PD-L1 ≥1% patients compared to HR 0.73 for PD-L1 <1% patients).5 The overall response rate (ORR) for intermediate- and poor-risk patients was 42% in the combination arm versus 27% in the Sutent arm, and this response rate was enriched in PD-L1 ≥ 1% versus PD-L1 < 1% (58% versus 37% respectively). In regard to progression-free survival (PFS), no statistically significant difference was observed between the two arms, though a numerical trend in favor of Opdivo plus Yervoy was seen, particularly in PD-L1 positive patients. Interestingly, for patients with favorable-risk RCC Sutent was actually shown to be superior to Opdivo plus Yervoy in terms of ORR and PFS, suggesting dual checkpoint inhibition may not be appropriate in these patients. In addition, the combination of Opdivo plus Yervoy came with considerable toxicity, with 46% of patients in CheckMate-214 experiencing Grade 3-4 adverse events4 (compare this to 19% in patients treated with Opdivo monotherapy in Checkmate-0253). Also, adverse events leading to discontinuation were reported in 22% of patients in the Opdivo plus Yervoy combination group, compared with 12% of patients in the Sutent group in CheckMate-214.4 Since the Checkmate-214 trial reached its primary endpoints of OS and ORR, the companies have filed with global regulatory authorities and will likely receive approval as first-line therapy for use in intermediate- and poor-risk RCC.
Keeping the checkpoint inhibitor momentum going, results for the IMmotion 151 trial – which studied Tecentriq plus Avastin compared to Sutent in first line RCC – were presented on February 10, 2018 at the 2018 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium.6 The study included treatment-naïve advanced or metastatic RCC patients across all risk scores, with a risk-distribution (20% favorable risk, 70% intermediate risk, 10% poor risk) that was fairly consistent with the Checkmate-214 trial intent-to-treat (ITT) population. The combination achieved a statistically significant difference in the co-primary endpoint of investigator-assessed PFS compared to Sutent in the PD-L1 positive population (11.2 versus 7.7 months, HR=0.74, p=0.02). This PFS benefit for Tecentriq plus Avastin also trended across patient subgroups including MSKCC risk (in PD-L1+ patients: HR 0.62 for favorable risk, 0.79 for intermediate risk, and 0.52 for poor risk) and in the ITT population (11.2 versus 8.4 months, HR 0.83), which was a secondary endpoint. The combination elicited an ORR rate of 43% (including 9% complete responders) versus 35% (including 4% complete responders) of patients in the Sutent arm. The response was also shown to be durable, where the median duration of response has not yet been reached in the combination arm, but was 12.9 months in the Sutent arm. The other co-primary endpoint, OS in the ITT population, has not matured (29% of events have occurred), though current data trends suggest a possible survival benefit (HR 0.81, p=0.09). The secondary endpoint of OS in PD-L1+ patients suggests another possible trend to benefit in favor of Tecentriq plus Avastin (HR 0.68).
Tecentriq plus Avastin was shown to be well-tolerated. Grade 3/4 adverse events were experienced in 40% of patients treated with the combination versus 54% of patients treated with Sutent. Very few immune-related toxicities were observed and only 16% of patients in the Tecentriq /Avastin arm required systemic corticosteroids to manage immune-adverse events. In addition, only 12% of patients in the Tecentriq plus Avastin arm discontinued treatment with either component due to toxicity, compared to 8% of patients in the Sutent arm. Concerning, however, is the higher rate of deaths in the Tecentriq plus Avastin arm compared to the Sutent arm (1.1% versus 0.2%) The combination also showed an improvement in quality of life compared to Sutent, specifically 11.3 versus 4.3 months as a median time to symptoms interfering with daily activity. Data from IMmotion151 will likely support filing with globally regulatory authorities and subsequent approval.
Given two checkpoint inhibitor trials had readout positive results in the first-line setting in the last six months, RCC is poised for a paradigm shift in favor of upfront immunotherapy. But which of these two will more dramatically shift the standard of care?
Both Checkmate-214 and IMmotion151 successfully met at least one of their primary efficacy endpoints. However, considering the target patient populations evaluated for efficacy differ between the two studies, cross-trial comparisons must be made cautiously. Although Opdivo plus Yervoy reported mature OS data showing a survival benefit, this advantage may be short-lived given OS data for Tecentriq plus Avastin are not yet mature and trending toward a benefit. Tecentriq plus Avastin has the added benefit of showing a statistically significant PFS advantage over Sutent, something that was elusive for the Opdivo plus Yervoy combination. Another advantage for Tecentriq plus Avastin is demonstrating activity in the favorable risk population where Opdivo plus Yervoy actually performed worse than Sutent.
Tolerability is more of a differentiating factor for Tecentriq plus Avastin compared to Opdivo plus Yervoy. The PD-L1 inhibitor and VEGF inhibitor combination was considered well-tolerated with no apparent overlapping toxicities. Conversely, combinations of PD-L1 and CTLA-4 inhibitors are commonly associated with increased toxicities, as evidenced by the Checkmate-214 data. For Opdivo plus Yervoy, 22% of patients discontinued treatment due to toxicity versus 12% of patients treated with Tecentriq plus Avastin. Additionally, more patients experienced immune-related adverse events commonly associated with checkpoint inhibitor therapy when treated with the dual checkpoint blockade. Supporting this assertion is the significantly higher proportion of patients requiring corticosteroid treatment to manage immune-toxicities while on Opdivo plus Yervoy (60% of patients) versus 16% of patients on Tecentriq plus Avastin.
Considering both efficacy and safety data, it appears Tecentriq plus Avastin may have the upper hand. However, with current TKI monotherapy, these two new combination options, and the recently expanded label of TKI Cabometyx® ([marketed as Cometriq® for medullary thyroid cancer] cabozantinib, Exelixis / Ipsen) into first-line based on PFS superiority over Sutent in the randomized Phase II CABOSUN trial,7 the decision for which frontline treatment option to choose will not be clear cut and may increasingly become stratified based on patient factors including risk and PD-L1 status.
For patients with intermediate- and poor-risk disease with PD-L1 positive disease, checkpoint inhibitor combinations are a more likely option given demonstrated OS benefit with Opdivo plus Yervoy and PFS (and potential OS) benefit with Tecentriq plus Avastin. Those with a poorer performance status or more comorbidities may lean more toward Tecentriq plus Avastin given better tolerability. Those with PD-L1 negative disease may still benefit from checkpoint inhibitor therapy, but response may not be as robust. While Opdivo plus Yervoy is not effective in favorable risk patients, Tecentriq plus Avastin may have a role in treatment as might TKI monotherapy in this group – it will compete with newly-approved Cabometyx in this setting, as well as the historical standards of care, Sutent and Votrient.
With several other checkpoint inhibitor combination trials to read out in the near future, the immunotherapy gears are expected to keep spinning, adding to the complexity of the RCC treatment paradigm. With the growing number of regimens entering the space, standard of care will continue to evolve. Further data is needed to personalize treatment based on risk, PD-L1 or other yet to be determined genetic signatures to determine when checkpoint inhibitors, angiogenesis inhibitors or both in combination may be needed to generate the optimal response or maybe even a cure.
- Kantar Health, CancerMPact® Patient Metrics, accessed February 10, 2018. Citing incidence and 5-year prevalence for RCC in the U.S. and total kidney cancer in EU5 and Japan.
- Kantar Health, CancerMPact® Treatment Architecture U.S. RCC, accessed February 10, 2018.
- Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. New England Journal of Medicine. 373:1803-1813. 2015
- Escudier B, et al. CheckMate 214: Efficacy and safety of nivolumab + ipilimumab (N+I) v sunitinib (S) for treatment-naïve advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups. Annals of Oncology. ESMO Abstract LBA5. 2017
- Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab + Ipilimumab (N+I) vs Sunitinib (S) for treatment‐naïve advanced or metastatic renal cell carcinoma (aRCC): results from CheckMate 214, including overall survival by subgroups. Journal for Immunotherapy of Cancer. SITC Abstract O38. 2017
- Motzer RJ, Powles T, Atkins MB, et al. IMmotion151: A Randomized Phase III Study of Atezolizumab Plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma (mRCC). Journal of Clinical Oncology. ASCO GU Abstract 578. 2018
- Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. Journal of Clinical Oncology. 6:591-597. 2017