IO-TKI Combinations Have Potential as Preferred First-line mRCC Therapy

Metastatic renal cell carcinoma (mRCC) has seen increased treatment options in recent years, including immunotherapy (IO) combinations paired with tyrosine kinase inhibitors (TKI). A meta-analysis of phase 3 trials aimed to compare and rank available first-line treatments.

First-line therapy options for metastatic renal cell carcinoma (mRCC) have advanced in recent years with the rise of immunotherapy (IO) drug combinations, but research directly comparing the efficacy and outcomes of different therapy combinations is still lacking. A meta-analysis published in European Urology Open Science aimed to compare and rank first-line mRCC therapy options to provide insight into the most safe and effective treatment options for patients.

Researchers pulled the most up-to-date phase 3 randomized controlled trial data for first-line mRCC treatments with a focus on IO-based drug combinations. This included data from Ovid MEDLINE, EMBASE, Cochrane Library, Web of Science, and abstracts of major scientific meetings through June 2021.

Six phase 3 trials with a total of 5121 patients were included in the analysis. Four of the trials comprised IO plus tyrosine kinase inhibitor (TKI) combinations:

Javelin 101 (avelumab plus axitinib [AVEL-AXI])
CheckMate 9ER (nivolumab plus cabozantinib [NIVO-CABO])
Keynote 426 (pembrolizumab plus axitinib [PEMBRO-AXI])
CLEAR (pembrolizumab plus lenvatinib [PEMBRO-LENV])

Two studies included IO-IO combinations:

CheckMate 214 (nivolumab plus ipilimumab [NIVO-IPI])
IMmotion 151 (atezolizumab plus bevacizumab [ATEZO-BEV])

All 6 trials included in the analysis had similar two-arm study designs using sunitinib as the standard of care option for comparison against the IO-based therapies.

Primary end points were overall survival (OS) and progression-free survival (PFS), and secondary endpoints included objective response rate (ORR), complete response (CR), grade 3 or 4 treatment-related adverse events (TRAEs), treatment-related drug discontinuation (TRDD), and patients’ health-related quality of life (HRQoL).

Regarding OS, NIVO-CABO, NIVO-IPI, PEMBRO-AXI, and PEMBRO-LENV all showed better outcomes than sunitinib ([HR, 0.60; 95% CI, 0.40-0.90], [HR, 0.69; 95% CI, 0.59-0.81], [HR, 0.68; 95% CI, 0.55-0.84], and [HR, 0.66; 95% CI, 0.49-0.88], respectively). NIVO-CABO was most likely to be the preferred treatment compared to others and had the highest likelihood of an OS benefit in the intent-to-treat (ITT) populations with a surface under the cumulative ranking curve [SUCRA] of 82%.

In patients in a subgroup considered to have favorable risk, AVEL-AXI was most likely to have an OS benefit with a SUCRA of 65%. For those with an intermediate risk, PEMBRO-AXI was most likely to have an OS benefit with a 78% SUCRA. And patients with poor risk were most likely to see an OS benefit with PEMBRO-LENV (89% SUCRA).

For PFS, AVEL-AXI, NIVO-CABO, PEMBRO-AXI, and PEMBRO-LENV all performed better than sunitinib in the ITT population ([HR, 0.69; 95% CI, 0.57-0.83], [HR, 0.51; 95% CI, 0.41-0.64], [HR, 0.71; 95% CI, 0.60-0.84], and [HR, 0.39; 95% CI, 0.32-0.48], respectively). PEMBRO-LENV showed the most PFS benefit overall across risk groups.

All IO combinations except for ATEZO-BEV had higher odds for improved ORR compared with sunitinib. PEMBRO-LENV showed the highest ORR, followed by NIVO-CABO ([OR, 4.36; 95% CI, 3.19-6.00] and [OR, 3.39; 95% CI, 2.45-4.72], respectively). NIVO-IPI (SUCRA 85%) and PEMBRO-LENV (SUCRA 83%) were most likely to be the preferred treatment when it came to CR.

The highest likelihood of grade 3 or 4 TRAEs compared with sunitinib was with PEMBRO-LENV (OR, 1.77; 95% CI, 1.29-2.43) and NIVO-CABO (OR, 1.48; 95% CI, 1.08-2.04). On the other hand, NIVO-IPI and ATEZO-BEV were least likely to produce grade 3 or 4 TRAEs ([OR, 0.52; 95% CI, 0.41-0.67] and [OR, 0.56; 95% CI, 0.43-0.73], respectively).

Despite its higher TRAE rate, NIVO-CABO also had the lowest TRDD rate at 2%. And NIVO-IPI, which had a lower rate of TRAEs, saw the highest TRDD rate at 100%. NIVO-CABO, PEMBRO-LENV, and NIVO-IPI had the most favorable HRQoL compared with the other treatments based on patient-reported outcomes.

Overall, the meta-analysis found that IO-based drug combinations showed improvements in outcomes for patients with mRCC. In particular, the IO-TKI combinations NIVO-CABO and PEMBRO-LENV were the most preferred combinations based on the primary outcomes in this analysis. Despite higher TRAE rates, low TRDD rates indicate manageable side effects in these combinations.

The study authors noted, however, that when stratified by risk groups—which not all trials of IO combinations included—none of the IO drug combinations outperformed sunitinib’s OS benefit in the subgroup of patients considered to have favorable risk. This, the authors wrote, raises the question of whether sunitinib should still be a first-line treatment mainstay.

The analysis concludes further research on the benefits of IO-TKIs is necessary to find out whether the positive responses will be sustained and if IO-TKIs should be the favored first-line treatment strategy in mRCC.


Bosma NA, Warkentin MT, Gan CL, et al. Efficacy and safety of first-line systemic therapy for metastatic renal cell carcinoma: a systematic review and network meta-analysis. Eur Urol Open Sci. Published online January 22, 2022. doi:10.1016/j.euros.2021.12.007