Immuno-Oncology/TKI Combinations Take the Lead in Frontline RCC Therapy

Targeted Therapies in OncologyApril 2, 2021
Volume 10
Issue 6
Pages: 18

Although curing advanced RCC is an admirable goal, there are many treatment options available on the horizon that result in substantial improvements in long-term outcomes.

Pooja Ghatalia, MD

Pooja Ghatalia, MD

Although there is resistance to use the word “cured” to describe patients with long-term progression-free survival (PFS) in renal cell carcinoma (RCC), “that word sometimes gets whispered around the meetings,” Christian Thomas, MD, director of clinical research at New England Cancer Specialists in Scarborough, Maine, said in an interview with Targeted Therapies in Oncology. “Sometimes patients are on the drugs for 5 years with no evidence of disease. But we don’t think we can routinely cure kidney cancer yet.”

Although curing advanced RCC is an admirable goal, there are many treatment options available on the horizon that result in substantial improvements in long-term outcomes. A handful of novel combination therapies have been approved for the frontline setting in the past few years, with others now in trials. These regimens mark a shift away from monotherapy, as seen in data shared at the 2021 Genitourinary (GU) Cancers Symposium, which highlighted a move toward combinations of immuno-oncology (IO) agents or an IO agent combined with a tyrosine kinase inhibitor (TKI), including VEGF inhibitors.

“I never use monotherapy anymore, like sunitinib [Sutent] or pazopanib [Votrient],” said Michael Humeniuk, MD, a hematologist/oncologist at the SMC Center for Hematology/Oncology in Spartanburg, South Carolina. “There are a lot of new first-line therapies.” If the patient has no contraindications, Humeniuk said he uses double IO or IO/VEGF-TKI combination therapies.

Advanced RCC, although a fairly loose descriptor, is unlikely to be surgically curable, so patients with metastatic RCC in the favorable-risk category based on the International Metastatic RCC Database Consortium (IMDC) scale may be just observed initially, Thomas said. For those in the intermediate- or poor-risk categories, Thomas would consider debulking nephrectomy. But he would also consider frontline double-IO combinations or an IO/TKI combination, a big change from treatment a decade ago, he said.

The current standard of care for someone with intermediate- or poor-risk disease is a combination of IO agents, such as ipilimumab (Yervoy)/nivolumab (Opdivo), or an IO/TKI combination, such as pembrolizumab (Keytruda)/axitinib (Inlyta), said Pooja Ghatalia, MD, assistant professor, Department of Hematology/Oncology at Fox Chase Cancer Center in Philadelphia, Pennsylvania.

“[Although] a combination of dual checkpoint inhibitors, [like] ipilimumab/nivolumab, isn’t the wrong answer based on data seen more recently, there is a greater number of treating physicians who prefer an IO/TKI combination for these patients,” Ghatalia said.

Based on data presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020 and 2021 GU Cancers Symposium, a patient with intermediate or poor risk can also receive frontline cabozantinib (Cabometyx)/nivolumab.

The newer, orally administered TKI agents have now been successfully combined with IO agents. “The first wave of IO drugs including nivolumab, pembrolizumab, and avelumab [Bavencio] are being combined with an oral agent,” Thomas said.

Current Frontline RCC Treatments


Tian Zhang, MD, MHS

Tian Zhang, MD, MHS

The FDA approved the ipilimumab/nivolumab combination for frontline treatment of advanced, intermediate or poor risk RCC in 2018.1 Approval was based on superior efficacy in this patient population compared with sunitinib monotherapy in the CheckMate 214 trial (NCT02231749).2

“Ipilimumab/nivolumab was the first [IO combination] to make a significant overall survival impact in this space, and it certainly changed our standards on treatment selection for patients with metastatic kidney cancer,” said Tian Zhang, MD, MHS, assistant professor of medicine at Duke Cancer Institute in Durham, North Carolina. “It is really improving outcomes in terms of targeting patients to get them to live longer and without progression for longer.”

For patients in the favorable-risk category, however, the advantages of ipilimumab/nivolumab over sunitinib are more questionable. In fact, exploratory analyses in CheckMate 214 revealed that sunitinib produced a significantly better objective response rate (ORR) and PFS for patients with favorable-risk disease, although the complete response (CR) rate was higher with ipilimumab/nivolumab.2


The FDA approved the pembrolizumab/axitinib combination for frontline treatment of advanced RCC in 20193 based on data from the KEYNOTE-426 trial (NCT02853331). Updated data were presented at GU Cancers Symposium 2021.4 A poster showed that per the KEYNOTE-426 protocol, patients could discontinue pembrolizumab or axitinib and continue the other agent because of toxicity. However, pembrolizumab was stopped for all patients at 2 years, whereas axitinib could be continued until the patient progressed or experienced toxicity.

Results in patients treated with pembrolizumab showed that extended follow-up of the combination of pembrolizumab/axitinib continued to demonstrate clinically significant improved efficacy when compared with sunitinib for previously untreated patients with advanced RCC.


The pembrolizumab/axitinib combination and the axitinib/avelumab regimen from the JAVELIN Renal 101 trial (NCT02684006) were the first IO/VEGF-TKI combinations for frontline treatment of advanced RCC, Zhang said. The axitinib/avelumab combination was approved in 2019.5 A poster presentation at the 2021 GU Cancers Symposium shared JAVELIN Renal 101 efficacy data from the second interim overall survival (OS) analysis of axitinib/ avelumab compared with sunitinib, based on various IMDC risk factors and target tumor sites at baseline.6

Although OS data were still immature, the results showed that with extended follow-up, the combination generally showed efficacy benefits compared with sunitinib. Specifically, median follow-up for OS for the axitinib/ avelumab arm was 19.2 months versus 19.3 months for the sunitinib arm. Median PFS was 16.8 months for the axitinib/avelumab arm versus 15.2 months for the sunitinib arm.


Data from the CheckMate 9ER trial (NCT03141177) investigating the nivolumab/ cabozantinib combination in patients with previously untreated clear cell RCC were also presented at GU Cancers Symposium 2021 and ESMO 2020.7,8 Results published in the New England Journal of Medicine9 showed that the combination had a significant OS and PFS improvement compared with sunitinib. “I’ve switched everyone over to cabozantinib/ nivolumab [based on the study] if I have to use an IO/VEGF[-TKI] combination. Cabozantinib is just a better overall inhibitor of kidney cancer because there are more off-target hits. I think it’s a better drug,” Humeniuk said. The combination gained an FDA approval on January 22, 2021.

CheckMate 9ER also analyzed qualityof-life data, with patients reporting better health-related quality of life in the combination arm compared with sunitinib. “I haven’t seen quality-of-life data in the other studies yet,” Ghatalia said, adding that this study included a greater number of patients in the poor-risk category versus the KEYNOTE-426 or CLEAR study (NCT02811861), which evaluated lenvatinib (Lenvima)/pembrolizumab versus lenvatinib/everolimus (Afinitor) versus sunitinib.


The pembrolizumab/lenvatinib combination has not yet been approved by the FDA; however, “the data presented at [GU 2021 were] encouraging,” Ghatalia said, noting “It had a very good response rate and improvement in all efficacy end points.” Ghatalia said she would consider using this combination and anticipates it will receive FDA approval based on the CLEAR study results: 71% ORR compared with 53.5% for lenvatinib/everolimus and 36% for sunitinib; and 16.1% CR rate compared with 9.8% for lenvatinib/everolimus and 4.2% for sunitinib.10 Pembrolizumab/ lenvatinib “demonstrated significant progression-free survival benefit and overall survival benefit compared with sunitinib,” Zhang said.

However, the 18-mg lenvatinib dose can cause significant adverse effects for patients, Ghatalia said. She expressed surprise that patients in the CLEAR study were given lenvatinib in a 20-mg dose along with pembrolizumab. “Investigators reassured us that in the frontline setting, patients can tolerate higher treatment doses because they’re not receiving prior treatment or prior toxicity,” said Ghatalia.

Choosing a Frontline RCC Treatment It is challenging to decide what to use for a first-line treatment in RCC, Zhang said. “We now have multiple trials that are showing the benefits of immunotherapy-based treatments in all comers, in particular in patients with IMDC intermediate- and poor-risk disease.”

Zhang said she thinks about the full continuum of treatment when considering frontline options. “We think about potential resistance patterns,” she noted. In addition to considering which frontline treatments are available, she takes the patient’s treatment goals into account. “Some of the treatment combinations have yielded higher response rates,” she said. For example, the ipilimumab/nivolumab combination or the pembrolizumab/lenvatinib combination have CR rates of more than 10%. That is meaningful if patients can get to CR and potentially consider discontinuing treatment a year or 2 after sustained CR. “Those are the type of things I think about when starting on first-line treatment and selecting from these options,” Zhang said

Zhang is pleased about the handful of immunotherapy-based combinations with positive OS impacts, which are all considered superior to more traditional treatments for patients with intermediate-risk disease. “We are looking at this era of checkpoint inhibitor–based combination strategies as the main go-to for most patients,” she said, adding that these combinations were all benchmarked against sunitinib as a control. Patients whose disease is more driven by angiogenesis may benefit more from IO/ VEGF-TKI combinations.

Both IO and VEGF-TKI are important classes of RCC therapies, said Humeniuk, but patients with autoimmune disease should not use a double-IO combination. He recommends going with a single IO or a VEGF-TKI agent for patients with severe autoimmune disease.

Despite the many options, clinicians still need longer-term OS data, Ghatalia said. “These are all studies with a median follow-up of about 18 to 30 months. More mature data will inform our decisions going forward.”

Data are more limited for patients with metastatic non–clear cell RCC (nccRCC), who represent a fraction of patients with RCC. A poster presented at GU Cancers Symposium 2021 shared results of a retrospective analysis of IMDC data from 1181 patients with nccRCC. Patient outcomes were compared based on type of frontline therapy: IO-based monotherapy or combination therapy, VEGF-TKI monotherapy, or mTOR inhibitor monotherapy. Data showed that for advanced nccRCC, frontline IO-based treatment produced the best OS result.11

Other Frontline RCC Treatments

Currently in Trials Other trials are underway and producing data. What follows are a few to watch.

Ipilimumab/Nivolumab and Cabozantinib

The PDIGREE trial (NCT03793166) is evaluating ipilimumab/nivolumab and cabozantinib in patients with intermediate- or poor-risk clear cell RCC.12

“This adaptive phase 3 trial is based on induction with ipilimumab/nivolumab, and at the 3-month cutoff, response is assessed,” Zhang said. Patients with a CR then receive nivolumab alone, and those with disease progression receive cabozantinib alone. All other patients are randomized to receive nivolumab alone or combined with cabozantinib, she said. Investigators will examine optimal sequencing of drugs in this trial. “We’ll have some understanding of [which patients will be] complete responders and [whose disease] might recur. It’s an important study in terms of trying to benchmark treatments against the standard of ipilimumab/nivolumab,” Zhang said.


In the COSMIC-313 study (NCT03937219), patients are randomized to receive 4 doses of triplet therapy comprising ipilimumab/ nivolumab/cabozantinib or ipilimumab/ nivolumab/placebo (the CheckMate 214 regimen; FIGURE13), followed by nivolumab/ cabozantinib or nivolumab/placebo.13 Zhang said this trial is almost finished with enrollment.

“Ipilimumab/nivolumab is a strong competitor in the IO/TKI space. So it will be interesting to see what the addition of the TKI to the combination will do,” Ghatalia said.

Immunotherapy With Surgery

The PROBE trial (NCT04510597) is exploring the effects of adding cytoreductive nephrectomy to standard-of-care immunotherapy. Patients with metastatic RCC are randomized to receive 4 cycles of an immunotherapy combination, either alone or followed by cytoreductive nephrectomy, Zhang said.

Challenges With Current Trials

One criticism of current trials is that the studies have not been “totally clean in terms of using just patients with intermediate- or [poor-risk] disease,” Thomas said, noting that the trials often include patients with favorable-risk disease as well.

Another issue is that in studies such as CheckMate 9ER and CLEAR, the comparator arm used “a fairly ineffective old-style drug, [sunitinib],” Thomas said. He looks forward to seeing trials combining IO and new oral TKIs compared with new oral TKI agents as monotherapy.

Fortunately, that process has already begun. “We’re phasing out sunitinib based on these phase 3 trials for metastatic kidney cancer,” Zhang said.

Treatment sequencing will be an even more important issue moving forward because of the lack of data on how to best sequence administration of these advanced agents. “That’s where the field is going now,” Thomas said. “What we clearly have now is a plethora of options relating to first-line treatment, especially for intermediate- and [poor]-risk disease.”

Future studies will include comparator arms using combination therapies, rather than single agents. “Randomizing patients to single-agent TKI as a comparator arm will probably be unethical” considering the robust data for combining 2 agents, Ghatalia said.

Research will also continue to search for treatments for RCC associated with specific genetic abnormalities, Thomas said. “We haven’t found a molecular Achilles’ heel for RCC yet.” Although the VHL tumor suppressor gene is lost or inactivated in most cases of clear cell RCC, it is not yet understood how to correct the resulting functional effects on the cell.14

Although there is a lot of work to be done, Zhang said the kidney cancer field has blossomed recently with the addition of immunotherapy and novel targeted treatments. “It’s a really exciting time for GU oncology,” she said.


1. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. FDA. Updated April 16, 2018. Accessed March 18, 2021.

2. Sheng IY, Ornstein MC. Ipilimumab and nivolumab as first-line treatment of patients with renal cell carcinoma: the evidence to date. Cancer Manag Res. 2020;12:4871-4881. doi:10.2147/CMAR.S202017

3. FDA approves pembrolizumab plus axitinib for advanced renal cell carcinoma. FDA. Updated April 22, 2019. Accessed March 18, 2021.

4. Plimack ER, Rini BI, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC): updated analysis of KEYNOTE-426. J Clin Oncol. 2020;38(suppl 15):5001. doi:10.1200/JCO.2020.38.15_suppl.5001

5. FDA approves avelumab plus axitinib for renal cell carcinoma. FDA. Updated May 15, 2019. Accessed March 18, 2021.

6. Tomita Y, Motzer RJ, Choueiri TK, et al. Efficacy of avelumab plus axitinib (A + Ax) versus sunitinib (S) by number of IMDC risk factors and tumor sites at baseline in advanced renal cell carcinoma (aRCC): extended follow-up results from JAVELIN Renal 101. J Clin Oncol. 2021;39(suppl 6):302. doi:10.1200/JCO.2021.39.6_suppl.302

7. Motzer RJ, Choueiri TK, Powles T, et al. Nivolumab + cabozantinib (NIVO+CABO) versus sunitinib (SUN) for advanced renal cell carcinoma (aRCC): outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER. J Clin Oncol. 2021;39(suppl 6):308. doi:10.1200/JCO.2021.39.6_suppl.308

8. Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: First results from the randomized phase III CheckMate 9ER trial. Ann Oncol. 2020;31(suppl 4):S1142-S1215. doi: 10.1016/j.annonc.2020.08.2257

9. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982

10. Motzer R, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. Published online February 13, 2021. doi:10.1056/NEJMoa2035716

11. Graham J, Wells C, Dudani S, et al. Effectiveness of first-line immune checkpoint inhibitors (ICI) in advanced non-clear cell renal cell carcinoma (ccRCC). J Clin Oncol. 2021;39(suppl 6):316. doi:10.1200/JCO.2021.39.6_suppl.316

12. Zhang T, Ballman KV, Choudhury AD, et al. PDIGREE: an adaptive phase 3 trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704). J Clin Oncol. 2019;37(suppl 15):TPS4596. doi:10.1200/JCO.2019.37.15_suppl.TPS4596

13. Choueiri TK, Albiges L, Powles T, et al. A phase III study (COSMIC-313) of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in patients (pts) with previously untreated advanced renal cell carcinoma (aRCC) of intermediate or poor risk. J Clin Oncol. 2020;38(suppl 6):TPS767. doi:10.1200/JCO.2020.38.6_suppl.TPS767

14. Dizman N, Philip EJ, Pal SK. Genomic profiling in renal cell carcinoma. Nat Rev Nephrol. 2020;16(8):435-451. doi:10.1038/s41581-020-0301-x

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