ASCO 2019: Evolving Front-Line Therapy in Metastatic Renal Cell Carcinoma

Chicago, IL (UroToday.com) Rana McKay, MD, provided a discussion following the presentation of three renal cell carcinoma abstracts. These abstracts included Abstract 4500 “Pembrolizumab plus axitinib versus sunitinib as first-line therapy for mRCC: Outcomes in the combined IMDC intermediate/poor risk and sarcomatoid subgroups of the phase 3 KEYNOTE-426 study”, Abstract 4501 “A pilot randomized study evaluating nivolumab or nivolumab + bevacizumab or nivolumab + ipilimumab in patients with mRCC eligible for cytoreductive nephrectomy, metastasectomy or post-treatment biopsy”, and Abstract 4502 “Randomized, double-blind phase III study of pazopanib versus placebo in patients with metastatic renal cell carcinoma who have no evidence of disease following metastasectomy: A trial of the ECOG-ACRIN cancer research group (E2810)”.

In the last 15 years, the landscape of treatment for mRCC has changed immensely, as Dr. McKay notes in this timeline figure of approved treatment modalities:
Currently, we have three combination therapy regimens approved in the first-line setting:
  • Nivolumab + ipilimumab (CheckMate 214)1; OS HR 0.68 (99.8% CI 0.49-0.95)
  • Pembrolizumab + axitinib (KEYNOTE-426) 2; OS HR 0.53 (95% CI 0.38-0.74)
  • Avelumab + axitinib (JAVELIN Renal 101) 3; OS HR 0.78 (95% CI 0.55-1.08)
KEYNOTE-426 evaluated 861 eligible patients with clear-cell mRCC, no prior systemic therapy for mRCC, and KPS ≥70 that were randomized 1:1 to pembrolizumab 200 mg IV every 3 weeks for a maximum of 35 cycles plus axitinib 5 mg orally BID (n = 432) or sunitinib 50 mg orally daily (4-weeks on/2-weeks off) (n = 429). The primary endpoints were OS and PFS (RECIST v1.1 by blinded, independent central review). ORR (RECIST v1.1 by blinded, independent central review) was the key secondary endpoint. Dr. McKay notes that Dr. Rini’s assessment of percent change in baseline target lesion size highlights the shortcomings of using RECISTv1.1 for measurement of tumor response to immunotherapy: complete response is defined as disappearance of all target lesions, the disappearance of all non-target lesions, and lymph nodes <1.0 cm. But, is there a threshold of response that correlates with durability and survival? Dr. McKay subsequently mentioned that a post-hoc exploratory analysis of CheckMate 214 highlighted the durability of immunotherapy: Treatment-free survival, defined as time from cessation of therapy to initiation of subsequent therapy or death, was 19% at 24 months in CheckMate 214. 

In KEYNOTE-426, benefit was observed independent of risk groups across all efficacy parameters. Dissecting out the favorable risk patients in KEYNOTE-426 and CheckMate 214, Dr. McKay notes that (i) 2/3 of patients in KEYNOTE-426 had an ORR, (ii) 11% of patients in the nivolumab + ipilimumab arm of CheckMate 214 had a complete response, (iii) there was over performance of sunitinib in the control arm of CheckMate 214, and (iv) OS data in KEYNOTE-426 is immature, with only 5% of patients experiencing an event. She concludes the discussion of this abstract by highlighting that immunotherapy combinations are now the new standard frontline treatment for all patients with mRCC without contraindications. Furthermore, deep responses can be achieved in a subset of patients, and the presence of sarcomatoid differentiation is associated with improved outcomes with immunotherapy combination therapy. 

The randomized study evaluating nivolumab or nivolumab + bevacizumab or nivolumab + ipilimumab in patients with mRCC was initially designed as a pilot peri-operative study, but given slower accrual it was expanded to include non-operable patients willing to undergo an on-treatment biopsy. As Dr. Gao mentioned in his talk, this was not intended to compare outcomes between arms or between surgical and non-surgical patients. However, of note, the combination of multi-modality treatment with nivolumab-based systemic therapy and surgery was safe and results in dramatic responses. Even in these at high-risk patients, there was a 3.8% complete response rate. Unfortunately, there was limited data presented regarding surgical decision making. To compliment this study, Dr. McKay made note of the JAVELIN Renal 101 biomarker assessment study presented at ASCO. Dr. McKay concluded that this study showed that cytoreductive nephrectomy and metastasectomy are safe in the context of nivolumab-based systemic therapy and this combination have a role in select patients with mRCC. Indeed, there is a need to identify and validate predictive biomarkers to guide therapy selection. 

The phase III E2810 study was a phase III trial testing pazopanib versus placebo in patients with metastatic renal cell carcinoma who have no evidence of disease following metastasectomy. Unfortunately, this study did not meet the primary endpoint as the hazard ratio for DFS was 0.85 (95% CI 0.55-1.31; p=0.47) in favor of pazopanib. Furthermore, at the time of unblinding, 17% of subjects had died and the HR for OS was 2.65 (95% CI 1.02-6.9; p=0.05) in favor of placebo. This is another in the line of negative studies testing TKIs in the adjuvant setting:
Dr. McKay notes that 36% of patients in the treatment arm did not complete protocol therapy for reason other than progression or death, and 52% of patients received <50% of the pazopanib intended dose. Although there was an OS trend potentially favoring placebo, Dr. McKay states that given unblinding post-progression, subsequent therapies may have impact OS. She concluded stating that VEGF targeted therapies have limited impact on micrometastatic disease, even in the highest risk individuals and this remains an unmet need for patients. 

Speaker: Rana R. McKay, MD, UC San Diego Health, San Diego, CA

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

References:
  1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carinoma. N Engl J Med 2018;378(14):1277-1290.
  2. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019;380(12):1116-112N Engl J Med 2019;380(12):1116-1127N Engl J Med 2019;380(12):1116-1127.
  3. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019;380(12):1103-1115.N Engl J Med 2019;380(12):1103-1115.
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