Immunotherapy and TKI Combinations Are Emerging as Standard of Care in Advanced RCC

Targeted Therapies in OncologyApril 2 2019
Volume 8
Issue 6

The results of several studies presented at the 2019 Genitourinary Cancers Symposium confirmed that the combination of PD-1/PD-L1 checkpoint inhibitors with tyrosine kinase inhibitors of the VEGF pathway was superior to VEGF inhibitors alone in patients with clear cell renal cell carcinoma, which accounts for about 70% of patients with kidney cancer.

David F. McDermott, MD

The results of several studies presented at the 2019 Genitourinary (GU) Cancers Symposium confirmed that the combination of PD-1/PD-L1 checkpoint inhibitors with tyrosine kinase inhibitors (TKIs) of the VEGF pathway was superior to VEGF inhibitors alone in patients with clear cell renal cell carcinoma (RCC), which accounts for about 70% of patients with kidney cancer.1

Combination regimens of antiangiogenic therapies with checkpoint inhibitors in the first-line setting have shown superior antitumor activity in patients with metastatic or advanced RCC compared with standard-of-care, single-agent therapies, according to investigator presentations. But questions remain: Are the combined therapies superior to the previous standard of care with TKIs? And is first-line immunotherapy treatment effective in patients with advanced non—clear cell (ncc)RCC?

PD-1/VEGF Therapies in the Pipeline

Bradley A. McGregor, MD

“The big conference news was that the KEYNOTE-426 study showed that pembrolizumab [Keytruda] with axitinib [Inlyta] crushed sunitinib [Sutent] on nearly all major endpoints: the response rate, progression-free survival [PFS], and most significantly in the overall survival [OS] rates,” said David F. McDermott, MD, professor of medicine at Harvard Medical School and chief of medical oncology at the Leon V. & Marilyn L. Rosenberg Clinical Cancer Center at Beth Israel Deaconess Medical Center, both in Boston, Massachusetts.Patients with previously untreated advanced clear cell RCC (n = 861) were randomized 1:1 to receive intravenous (IV) pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus oral axitinib 5 mg twice daily (n = 432) or oral sunitinib 50 mg daily for the first 4 weeks of each 6-week cycle (n = 429).2

The 12-month OS rate was 89.9% in patients receiving the PD-1 inhibitor pembrolizumab plus axitinib, a second-generation small molecule inhibitor of VEGFR, compared with 78.3% in those receiving sunitinib (HR, 0.53; 95% CI, 0.38-0.74; P <.0001). This hazard ratio for OS in the open-label phase III trial was the lowest seen to date among frontline therapy trials, noted McDermott.

With a median follow-up of 12.8 months, the median PFS was 15.1 months in the pembrolizumab/axitinib group compared with 11.1 months in the sunitinib group (HR, 0.69; 95% CI, 0.57-0.84; P = .0001). The confirmed objective response rates (ORRs) were 59.3% (95% CI, 54.5%-63.9%) in the pembrolizumab/axitinib group versus 35.7% (95% CI, 31.1%-40.4%) in the sunitinib group (P <.0001) (FIGURE).

According to the presentation, grade &ge;3 adverse events (AEs) of any cause occurred in 75.8% of patients in the pembrolizumab/axitinib group and in 70.6% in the sunitinib group. Results of the phase Ib dose-finding study of the pembrolizumab/axitinib combination presented at the 2018 GU Cancers Symposium showed a similar safety profile as well as antitumor activity.3

In February, the FDA granted priority review for a new supplemental biologics license application (sBLA) for pembrolizumab in combination with axitinib as a frontline treatment for patients with advanced RCC based on data from KEYNOTE-426, with a target action date for the application of June 20194 and the results of the trial were subsequently published in the New England Journal of Medicine.5

&ldquo;We anticipate that this combination will become a standard of care for untreated patients with kidney disease,&rdquo; said McDermott.

Another combination that may move to the first line is the PD-L1 inhibitor avelumab (Bavencio) plus axitinib. The FDA granted another priority review to the sBLA for the avelumab/axitinib combination for patients with advanced RCC based on data from the JAVELIN Renal 101 trial. The application has been given a target action date of June 2019.6

Data from this clinical trial that were presented at the symposium and updated in the New England Journal of Med- icine showed that avelumab added to axitinib outperformed sunitinib, with a longer median PFS (13.8 vs 8.4 months; HR, 0.69; P <.001) and a higher ORR (51.4% vs 25.7%).7,8The benefits were observed in all patients regardless of PD-1/ PD-LI status and in all prognostic risk groups. However, 1 limitation of these data is that the combination has yet to demonstrate an OS benefit.

&ldquo;Now that it has been proved that an anti—PD-1 plus VEGF [inhibitor] is superior to VEGF alone, an important question to consider is which combination is best for which patients: Is it anti&ndash;PD-1 and VEGF or anti&ndash;PD-1 and anti&ndash;CTLA-4?&rdquo; asked McDermott.

Other combinations of anti—PD-1 and targeted VEGF therapies appear promising based on phase I trial data presented in posters at the symposium. In patients previously treated for metastatic RCC, pembrolizumab plus cabozantinib (Cabometyx) demonstrated antitumor activity and was tolerated; the maximum tolerated dose (MTD) was determined.9Based on the data, a 2-stage phase II study with the MTD of 60 mg cabozantinib daily plus 200 mg IV pembrolizumab every 3 weeks has begun in patients with RCC with either clear cell or ncc histology (NCT03149822).

Updated Data From CheckMate 214

Investigators also presented 30-month follow-up data from the phase III CheckMate 214 trial. The combination of the PD-1 inhibitor nivolumab (Opdivo) and the CTLA-4 inhibitor ipilimumab (Yervoy) sustained strong responses and an OS benefit as a frontline treatment in intermediate- and poor-risk patients with advanced RCC. At 30 months, the OS rate by International Metastatic Renal Cell Carcinoma Database Consortium risk was 60% with the immunotherapy combination versus 47% with sunitinib (HR, 0.66; 95% CI, 0.54-0.80; P <.0001) and 64% versus 56% in the intention-to-treat (ITT) population (HR, 0.71; 95% CI, 0.59-0.86; P = .0003), respectively. The ORR for the combination was 42.0%, with 11.3% achieving a complete response (CR), compared with 29.0% and 1.2% with sunitinib, respectively.10

Among the responders, 52% of patients receiving nivolumab/ipilimumab had a response lasting &ge;18 months compared with 28% of patients on sunitinib. No new safety signals were detected at the longer follow-up.

Of the 1096 patients in the ITT population, 23% were considered favorable risk; 61%, intermediate risk; and 17%, poor risk in each arm. Additionally, about one-fourth in the ITT population had PD-L1 expression &ge;1%.11The patients were randomized 1:1 to receive the combination of 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab every 3 weeks for 4 doses, followed by nivolumab every 2 weeks (n = 425) or sunitinib 50 mg once daily for a 4-weeks-on/2-weeks-off schedule (n = 422). Patients in the experimental arm receiving nivolumab monotherapy could switch to a 240-mg flat dose until disease progression or unacceptable toxicity, and those receiving sunitinib were permitted to cross over to receive the immunotherapy combination.

The FDA approved the combination of nivolumab and ipilimumab in April 2018 as a frontline treatment for intermediate- and poor-risk previously untreated advanced RCC based on the primary data analysis, which showed a 37% reduction in the risk of death versus sunitinib regardless of PD-L1 expression status (HR, 0.63; 99.8% CI, 0.44-0.89; P <.001).12,13

&ldquo;When the data were first presented at the European Society for Medical Oncology 2017 Congress, we were excited about the higher CR rate of 9.4%,13&rdquo; said Bradley A. McGregor, MD, clinical director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute in Boston. &ldquo;With the 30-month follow-up data from phase III, we see that the CR rate is slightly higher, and the majority of patients maintained their CRs even after treatment ended. This gives us hope that patients will have a durable remission.&rdquo;

McDermott, a coinvestigator on CheckMate 214, noted that the CR rate with nivolumab and ipilimumab was nearly double that observed in KEYNOTE-426 with pembrolizumab and axitinib (11.3% vs 5.8%, respectively).

&ldquo;Those CR differences are not likely statistically significant, but they may be relevant in clinical decision making for some patients and physicians. With single-agent immunotherapies (eg high-dose IL-2 and anti—PD-1), we have seen how deep responses (eg CRs) can translate into long-term survival and, in a small subset, remis- sions of advanced disease,&rdquo; McDermott said. However, &ldquo;some physicians will choose the anti&ndash; VEGF/PD-1 strategy because the current efficacy signal is impressive and the toxicity profile may be more familiar and easier to manage,&rdquo; he added.

Of note, improved OS, PFS, and ORR endpoints for the CheckMate 214 trial were maintained only for patients with intermediate- and poor- risk disease compared with all subgroups in the KEYNOTE-426 trial.

Papillary Renal Cell Carcinoma

The ongoing single-arm phase I/II CALYPSO trial, which had interim data presented at the symposium, is looking at the combination of the PD-LI inhibitor durvalumab (Imfinzi) and the novel MET inhibitor savolitinib with a 4-week savolitinib run-in, in patients with treatment-naïve or previously treated metastatic papillary renal cancer. Response rate by RECIST 1.1 is the primary endpoint, with PFS, tolerability, and OS as secondary endpoints. Efficacy data is immature but showed an ORR of 27%. The rates of median OS and PFS at the analysis were not reached and 5.3 months, respectively, with the combination.14

Non—Clear Cell Renal Carcinoma

McDermott, the principal investigator of the KEYNOTE-427 study, presented data on the first-line treatment of patients with nccRCC with single-agent pembrolizumab, which showed encouraging antitumor activity, especially with papillary or unclassified histology.15

KEYNOTE-427 was a 2-cohort study of patients with recurrent or advanced metastatic RCC, measurable disease, and a Karnofsky performance status &ge;70%. No prior systemic therapy was allowed. Histology was confirmed by a central pathologist. In cohort B, which comprised 165 patients with nccRCC, 72% of patients had papillary, 13% had chromophobe, and 16% had unclassified histology. Sixty-eight percent of patients were considered intermediate/poor risk, and 62% were PD-L1 positive, according to the data presented.

The ORR was 24.8% in the patients with nccRCC (95% CI, 18.5%-32.2%). By histology subgroups, the ORRs were 25.4% (95% CI, 17.9%-34.3%) in the patients with papillary histology, 34.6% (95% CI, 17.2%-55.7%) in those with unclassified histology, and 9.5% (95% CI, 1.2-30.4) in those with chromophobe histology.

At a median follow-up of 11.1 months, the median PFS was 4.1 months (95% CI, 2.8-5.6) and the estimate for 12-month OS rate was 72%. Grade &ge;3 treatment-related AEs (TRAEs) occurred in 11% of patients, and 6% discontinued because of TRAEs. Six patients died as a result of AEs, 1 each from grade 5 pneumonia and cardiac arrest.

The ORRs were 28.3% (95% CI, 16.8%-42.3%) in favorable-risk and 23.2% (95% CI, 15.8%-32.1%) in intermediate/poor-risk patients. By PD-L1 expression, ORRs were 33.3% (95% CI, 24.3%- 43.4%) and 10.3% (95% CI, 3.9%-21.2%) in patients with a combined positive score (CPS) &ge;1 and CPS <1, respectively.

McDermott noted that patients with nccRCC have historically been excluded from clinical trials largely based on their lack of response to cytokine-based immune therapy. The National Comprehensive Cancer Network guidelines for advanced nccRCC recommend that these patients enroll in an appropriate clinical trial or be treated with sunitinib based on its efficacy in clear cell RCC.16In addition, there are no FDA-approved therapies for this type of cancer.

&ldquo;There is a significant and unmet need for safe and effective treatment options for patients with nccRCC,&rdquo; McDermott said during his presenta- tion at the symposium.

Patients received IV pembrolizumab 200 mg every 3 weeks for up to 35 cycles or until disease progression, unacceptable toxicity, or withdrawal. Response was assessed at week 12 and then every 6 weeks until week 54 and every 12 weeks thereafter. At analysis, 49 patients had died and 3 had withdrawn. At a median follow-up duration of 11.1 months (range, 0.9-21.3), 56% of patients discontinued pembrolizumab because of disease progression or clinical progression, according to the presentation.

The cohort A data were reported at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting and showed promising antitu- mor activity in 110 patients with advanced clear cell RCC who received pembrolizumab. The ORR was 38.2%, with a CR rate of 2.7% and a partial response rate of 35.5%. The safety profile was similar to that previously reported for pembrolizumab in other tumor types.17

&ldquo;The results were surprisingly good in both cohorts, with higher response rates and less toxicity than expected. This supports further evaluation of pembrolizumab particularly in patients with advanced nccRCC,&rdquo; said McDermott.

&ldquo;These advances in clear cell RCC with immunotherapy and targeted therapy are now making their way to nccRCC,&rdquo; said McGregor. &ldquo;The data seen in smaller, phase II trials support the role of continuing this approach in nccRCC.&rdquo;

McGregor was also an investigator on a phase II single-arm, open-label trial evaluating the efficacy of the anti—PD-L1 agent atezolizumab (Tecentriq) plus bevacizumab (Avastin) in patients with nccRCC or clear cell RCC with >20% sarcomatoid differentiation. The results showed that atezolizumab plus bevacizumab therapy was safe and demonstrated antitumor activity in both types of RCC.18

A total of 65 patients were enrolled in the multicenter trial, and 52 had &ge;1 response assessment and were included in this analysis. Thirty-six patients had nccRCC, and 16 patients had clear cell RCC with sarcomatoid differentiation. Of the 17 patients who received prior systemic therapy, 16 had nccRCC. Prior PD-1/PD-L1 therapy was not allowed.

The ORR was 31% in the overall cohort, with rates of 44% and 25% in patients with clear cell and nccRCC, respectively. Ten patients (19%) developed grade 3 TRAEs, half of which were immune related. There were no grade &ge;4 AEs. This regimen was well tolerated, with responses exceeding those seen with TKI monotherapy.

Further analyses will report on the ORR by histo- logic subtype and PD-L1 expression status. There is an ongoing analysis of tissue and blood-based biomarkers involved in responses, said McGregor.

Next Steps in Therapy

Longer follow-up and potentially different trial designs are necessary to address remaining questions related to immunotherapy and TKI combinations in RCC. Investigators will need to determine whether benefits of these agents are synergistic or additive and whether similar results will be achievable through sequential use of these agents.

&ldquo;These comparative questions are currently based on opinion rather than facts. We need head-to-head randomized trials to answer those questions, which is unlikely to happen anytime soon,&rdquo; said McDermott.

In addition, investigators will need to determine whether the combination approach is always superior or whether there are situations in which single-agent therapy is preferred.

Regarding the question of who receives the single agent versus the combination, McDermott referred to the IMmotion150 trial, whose data were presented at the 2017 ASCO Annual Meeting. &ldquo;Our IMmotion150 study was the first randomized phase II trial of a PD-L1/PD-1 pathway inhibitor, atezolizumab, alone or combined with an anti-VEGF agent, bevacizumab, versus sunitinib in patients with metastatic RCC. This 3-arm design gave us a sense of how different groups of patients benefited from one drug more than another versus the combination.&rdquo;19

In addition, McDermott said investigators need to push the drug-trial sponsors for longer follow-up. &ldquo;The data look good now, but I would argue that we need to know more about long-term outcomes, toxicities, and impact on quality of life so patients can make more informed decisions,&rdquo; he said. &ldquo;Therapy for RCC is evolving, and it is great to have many options. With more follow-up, we should have greater clarity on the relative risks and benefits of each therapy,&rdquo; McDermott concluded.


  1. What is kidney cancer? American Cancer Society website. Updated August 1, 2017. Accessed March 26, 2019.
  2. Powles T, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for locally advanced or metastatic renal cell carcinoma (mRCC): phase III KEYNOTE-426 study. J Clin Oncol. 2019;37(suppl 7; abstr 543). doi: 10.1200/JCO.2019.37.7_suppl.543.
  3. Atkins MB, Plimack ER, Puzanov I, et al. Safety and efficacy of axitinib (axi) in combination with pembrolizumab (pembro) in patients (pts) with advanced renal cell cancer (aRCC). J Clin Oncol. 2018;36(suppl 6; abstr 579). doi: 10.1200/JCO.2018.36.6_suppl.579.
  4. FDA grants priority review to Merck&rsquo;s supplemental biologics license application for Keytruda (pembrolizumab) in combination with Inlyta (axitinib) as first-line treatment for advanced renal cell carcinoma [news release]. Kenilworth, NJ: Merck; February 15, 2019. Accessed March 26, 2019.
  5. Rini BI, Plimack ER, Stus V, et al. KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1116-1127. doi: 10.1056/NEJMoa1816714.
  6. FDA accepts sBLA and grants priority review for Bavencio (avelumab) plus Inlyta (axitinib) for the treatment of advanced renal cell carcinoma [news release]. Rockland, MA, and New York, NY: Merck KGaA and Pfizer Inc; February 11, 2019. Accessed March 26, 2019.
  7. Choueiri TK, Motzer RJ, Campbell MT, et al. Subgroup analysis from JAVELIN Renal 101: outcomes for avelumab plus axitinib (A + Ax) versus sunitinib (S) in advanced renal cell carcinoma (aRCC). J Clin Oncol. 2019;37(suppl 7; abstr 544). doi: 10.1200/JCO.2019.37.7_suppl.544.
  8. 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. doi: 10.1056/NEJMoa1816047.
  9. Keeler ME, Kessler ER, Bernard B, et al. Pembrolizumab (pembro) and cabozantinib (cabo) in patients (pts) with metastatic renal cell carcinoma (mRCC): phase I results. J Clin Oncol. 2019;37(suppl 7; abstr 600). doi: 10.1200/JCO.2019.37.7_suppl.600.
  10. Tannir NM, Ar&eacute;n Frontera O, Hammers HJ, et al. Thirty-month follow-up of the phase III CheckMate 214 trial of first-line nivolumab + ipilimumab (N+I) or sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol. 2019;37(suppl 7; abstr 547). doi: 10.1200/JCO.2019.37.7_suppl.547.
  11. Motzer RJ, Tannir NM, McDermott DF, et al; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Eng J Med. 2018;378(14):1277-1290. doi: 10.1056/NEJMoa1712126.
  12. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. FDA website. Published April 16, 2018. Accessed March 26, 2019.
  13. Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: efficacy and safety of nivolumab + ipilimumab (N+I) v sunitinib (S) for treatment-na&iuml;ve advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups. Ann Oncol. 2017;28(suppl 5; abstr LBA5). doi: 10.1093/annonc/mdx440.
  14. Powles T, Larkin JM, Poulam P, et al. A phase II study investigating the safety and efficacy of savolitinib and durvalumab in metastatic papillary renal cancer (CALYPSO). J Clin Oncol. 2019;37(suppl 7; abstr 545). doi: 10.1200/JCO.2019.37.7_suppl.545.
  15. McDermott DF, Lee J-L, Ziobro M, et al. First-line pembrolizumab (pembro) monotherapy for advanced non-clear cell renal cell carcinoma (nccRCC): results from KEYNOTE-427 cohort B. J Clin Oncol. 2019;37(suppl 7; abstr 546). doi: 10.1200/JCO.2019.37.7_suppl.546.
  16. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Kidney Cancer, version 3.2019. Published February 6, 2019. Accessed March 26, 2019.
  17. McDermott DF, Lee J-L, Szczylik C, et al. Pembrolizumab monotherapy as first-line therapy in advanced clear cell renal cell carcinoma (accRCC): results from cohort A of KEYNOTE-427. J Clin Oncol. 2018;36(suppl 15; abstr 4500). doi: 10.1200/JCO.2018.36.15_suppl.4500.
  18. McKay RR, McGregor BA, Gray K et al. Results of a phase II study of atezolizumab and bevacizumab in non-clear cell renal cell carcinoma (nccRCC) and clear cell renal cell carcinoma with sarcomatoid differentiation (sccRCC). J Clin Oncol. 2019;37(suppl 7; abstr 548) doi: 10.1200/JCO.2019.37.7_suppl.548.
  19. Atkins MB, McDermott DF, Powles T, et al. IMmotion150: a phase II trial in untreated metastatic renal cell carcinoma (mRCC) patients (pts) of atezolizumab (atezo) and bevacizumab (bev) vs and following atezo or sunitinib (sun). J Clin Oncol. 2017;35(suppl 15; abstr 4505). doi: 10.1200/JCO.2017.35.15_suppl.4505.
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