Ipilimumab–Nivolumab versus Sunitinib

A phase-III CheckMate 214 trial randomized 1,096 patients in 1:1 ratio into two arms, ipilimumab–nivolumab versus sunitinib.[5] A total of 423 patients were at intermediate risk and 416 had poor risk IMDC category. Ipilimumab–nivolumab was administered for four cycles every 3 weeks followed by nivolumab every 2 weeks. Sunitinib was given as 50-mg OD × 4 weeks followed by 2 weeks off (6-week cycle). The primary end points were OS, PFS, and ORR among patients with intermediate and poor risk. The 18-month OS rate was 75% (95%-CI: 70–78) with IO and 60%-with sunitinib (95%-CI: 55–65; HR for death = 0.63; 99.8%-CI: 0.44–0.89; p < 0.001). Median PFS, ORR, complete response (CR) rates, and median survival are mentioned in [Table 1]. Treatment-related adverse events occurred in 93%-in IO and 97%-in sunitinib arm. Grade 3 and 4 adverse events occurred in 46 and 63%-patients, respectively. Latest update of the trial continues to show benefit of IO combination in ORR (42 vs. 26%), CR (10 vs. 1%), PFS (12 vs. 8.3 months), OS (48.1 vs. 26.6 months), and median duration of response (DOR; not reached vs. 19.7 months).[11] A 4-year OS was 50%-with ipilimumab–nivolumab as compared with 35.8%-with sunitinib.

Despite the higher toxicity in sunitinib arm, treatment discontinuation was more common in IO arm, patient-reported outcomes suggested better tolerability of IO combination over sunitinib.[5]

Pembrolizumab–Axitinib versus Sunitinib

KEYNOTE 426 phase-III trial randomized 861 patients into two arms: pembrolizumab–axitinib versus sunitinib.[6] The study population included 30%-favorable-risk, 56%-intermediate-risk, and 13%-poor-risk category patients. Primary end points were OS and PFS in intent to treat (ITT) population. Secondary end point was ORR. The updated result of this study shows better efficacy of pembrolizumab–axitinib combination over sunitinib. ORR was 60%-versus 39.9%, CR was 8 versus 3%, and median survival was not reached in pembrolizumab-axitinib arm versus 36.7 months in sunitinib.[12] Median DOR was longer in pembrolizumab–axitinib versus sunitinib (23.5 vs. 15.9 months). No OS benefit was found in favorable risk patients. For IMDC intermediate- or poor-risk disease, PFS and OS were significantly better with pembrolizumab–axitinib with HR of 0.63 for OS and 0.69 for PFS. PFS was 8.3 months (95%-CI: 6.7–10.1) with sunitinib versus 12.7 months (95%-CI: 11.3–18.0) for pembrolizumab–axitinib combination. OS was 28.9 months (95%-CI: 23.7–34.3) with sunitinib versus not reached in pembrolizumab–axitinib combination. A post hoc analysis found that achieving CR improved the chances of OS in both arms. An exploratory analysis of patients with sarcomatoid features showed that the risk of death was reduced by 42%-with pembrolizumab–axitinib compared with sunitinib (HR = 0.58, 95%-CI: 0.21–1.59). Grade 3 or higher adverse events occurred in 75.8 versus 70.6%-of patients in pembrolizumab–axitinib and sunitinib, respectively.

Avelumab–Axitinib versus Sunitinib

Phase-III JAVELIN trial randomized 886 patients in 1:1 ratio into two arms: avelumab–axitinib versus sunitinib.[7] Dose of avelumab was 10 mg/kg in every 2 weeks along with axitinib 5 mg/day. Primary end points were PFS and OS in PDL1-positive patients. PFS was higher in overall, as well as PD L1-positive tumor, in avelumab–axitinib arm ([Table 1]). PFS in overall population was 13.4 versus 8.4 months (HR = 0.69, 95%-CI: 0.56–0.84; p < 0.001). Among PDL1-positive patients, PFS was 13.8 months with axitinib–avelumab versus 7.2 months with sunitinib (HR for disease progression or death = 0.61; 95%-CI: 0.56–0.84; p < 0.001). ORR was higher with avelumab–axitinib PDL1-positive patients (55.2 vs. 25.5%). Updated analysis confirms the efficacy of avelumab–axitinib in prolonging the PFS in overall, as well as PDL1 population. OS data are immature. Grade 3 or higher adverse events occurred in 71.2 and 71.5%-of patients, respectively.

Atezolizumab–Bevacizumab versus Sunitinib

IMmotion151 phase-III study randomized 915 patients into 1:1 ratio into two arms: atezolizumab (1,200 mg) + bevacizumab 15 mg/kg in every 3 weeks versus sunitinib 50-mg OD × 4 weeks (6-week cycle). A total of 40%-patients were PDL1-positive. Primary end points were investigator-assessed PFS in PDL1-positive patients and OS in ITT population. This study showed that the median PFS was higher in atezolizumab + bevacizumab arm (11.2 months in the atezolizumab plus bevacizumab arm vs. 7.7 months in the sunitinib arm, HR of 0.74 [95%-CI: 0.57–0.96]; p = 0.0217). In the ITT population, median OS had an HR of 0.93 (0.76–1.14). Also, 40 and 54%-patients had grade 3 and 4 adverse events, respectively, and 5 and 8%-patients had to discontinue treatment due to toxicity in atezolizumab–bevacizumab and sunitinib arm, respectively. Longer follow-up of the study is required.

Cabozantinib–Nivolumab versus Sunitinib

Phase-III CheckMate 9ER study results have been recently presented in ESMO 2020 meeting.[9] The study included 651 patients in all IMDC risk categories (favorable, 22.7%; intermediate, 57.6%; and poor, 19.7%) and randomized patients into two groups: cabozantinib 40 mg/day + nivolumab 240 mg every 2 weeks versus sunitinib 50 mg/day × 4 weeks, every 6-week cycle. Primary end point was PFS, secondary end points were OS, ORR, BICR, and safety. Median PFS was 16.6 versus 8.3 months (HR = 0.51; 95%-CI: 0.41–0.64, p < 0.0001). The OS, ORR, and median DOR were significantly improved with nivolumab + cabozantinib versus sunitinib. Median OS was not reached (HR = 0.60; 98.89%-CI: 0.40–0.89; p = 0.0010), ORR was 55.7% (95%-CI: 50.1–61.2) with the combination versus 27.1% (95%-CI: 22.4–32.3) with sunitinib (p < 0.0001), the median DOR (DOR) was 20.2 versus 11.5 months, respectively. CR rate was 8%- versus 4.6%. Treatment-related adverse events lead to discontinuation of nivolumab in 5.6%-of patients, and of cabozantinib in 6.6%-patients, whereas 3.1%-of patients discontinued the combination (total 15.3%) and 8.8%-of patients discontinued sunitinib.

Lenvatinib–Pembrolizumab versus Sunitinib

Recently published phase-III trial randomized 1,069 patients into three arms: lenvatinib + pembrolizumab, lenvatinib + everolimus, and sunitinib.[10] Primary end point was PFS assessed by independent review committee. Secondary end points were ORR, OS, safety, and PFS assessed by investigators. Also, 90%-patients were either favorable- or intermediate-risk IMDC category. PFS was significantly longer in lenvatinib–pembrolizumab versus sunitinib (median = 23.9 vs. 9.2 months, 95%-CI: 20.8–27.7), versus 9.2 months (95%-CI: 6–11.0, HR for disease progression or death was 0.39; 95%-CI: 0.32–0.49; p < 0.001, also significantly longer in lenvatinib–everolimus versus sunitinib (median = 14.7 months, 95% CI: 11.1–16.7) versus 9.2 months (95% CI: 6–11.0, HR = 0.65; 95%- CI: 0.53–0.80, p < 0.001). Median OS was not reached in any arm. Pembrolizumab–lenvatinib arm had longer OS as compared with sunitinib (HR for death = 0.66; 95%-CI: 0.49–0.88; p = 0.005). OS benefit was seen across all subgroups except favorable risk IMDC. OS was 71.0, 53.5, and 36.1% with lenvatinib–pembrolizumab, lenvatinib–everolimus, and sunitinib arm, respectively. CR rate was 16.1, 9.8, and 4.2%-in three arms, respectively. Grade 3 or higher adverse events occurred in 82.4, 83.1, and 71.8% of patients, respectively.

Single-Agent Immunotherapy as First Line Therapy

All patients may not be fit to receive combination therapy upfront. Recently, results of open-label, single–arm phase-II study of pembrolizumab monotherapy as first-line therapy in advanced clear cell RCC have been published.[13] A total of 110 patients were enrolled. Primary end point was ORR. ORR was 36.4%, CR was 3.6%, PR was 32.7%, and disease control rate was 58.2%. Median DOR was 18.9 months (range: 2.3–37.6 months). Median PFS was 7.1 months (95% CI: 5.6–11.0). Median OS was not reached. Durable responses were seen in all three IMDC subgroups. There is no phase-III study comparing single-agent IO versus IO–TKI combination. Single-agent IO may be a potential therapy option for patients who are not fit to receive IO combination upfront

How to Choose among Various Immunooncology Drugs

There is no head-to-head comparison among the six phase-III trials which have tested various IO or IO–TKI combinations. Cross-trial comparisons may not be appropriate. Choosing one treatment among the six combinations is difficult. There is no predictive marker to select treatment. There is no correlation of PDL1 status and survival. From whatever information we have, we have to choose the treatment based on response rate, survival, and toxicity profile. IMDC criteria should be factored in decision-making. Disease biology, patient characteristics, toxicity pattern, and cost are factors to be considered. If rapidity of response is desired (in high disease burden and symptomatic patient), IO with VEGF TKI combination is preferred over IO–IO combination. IO–TKI combinations have shown higher response rate and more tumor shrinkage. Among the six FDA approved combinations, lenvatinib–pembrolizumab combination has resulted in the highest PFS, and this combination has shown OS benefit in intermediate- and poor-risk IMDC group. Ipilimumab–Nivolumab and pembrolizumab–axitinib combinations have also shown OS benefit only in intermediate- and poor-risk IMDC group, and not in favorable risk. All three of these combinations should be used in intermediate- and poor-risk IMDC category. Cabozantinib–nivolumab has shown OS advantage in all three IMDC groups. The median follow-up of ipilimumab–nivolumab, pembrolizumab–axitinib, avelumab–axitinib, atezolizumab–bevacizumab, cabozantinib–nivolumab, and lenvatinib–pembrolizumab studies was 4 years, 30.6 months, 10.8 months, 24 months, 18.1 months, and 26.6 months, respectively. Longer follow-up of these studies will clarify which combination provides the best OS and which IMDC group benefits most. Immune-mediated side effects are more in IO–IO combinations. For atezolizumab–bevacizumab and avelumab–axitinib, mature results on OS are awaited.

Recent systemic review and network meta-analysis including six trials and 5,121 patients has been published.[14] It concludes that the nivolumab–cabozantinib has the highest likelihood of providing maximum OS, lenvatinib–pembrolizumab has the highest likelihood of PFS and ORR. CR were more likely with ipilimumab–nivolumab. The highest likelihood of adverse event-related treatment discontinuation was associated with ipilimumab–nivolumab and lenvatinib–pembrolizumab.

A study from the United States on clinical and economic outcome of treatment sequences in intermediate- and poor-risk mRCC patients favors cost effectiveness of IO combination followed by TKI versus the reverse sequence [15]. Another study from the United States evaluating the cost effectiveness of pembrolizumab–axitinib and ipilimumab–nivolumab in first-line mRCC suggests that pembrolizumab–axitinib treatment is associated with greater quality-adjusted life years (QALYs) compared with ipilimumab–nivolumab treatment in patients with advanced RCC but may not be cost effective.[16]

Sequencing of Therapy

As more patients will be receiving first-line IO combinations in mRCC, it is critical to choose the second-line therapy, but presently we do not have published prospective studies to guide the second-line therapy. Retrospective studies are presently the guide to base our treatment decision. Dudani and colleagues[17] analyzed 188 patients of which 113 were treated with first-line IO–TKI and the rest were treated with ipilimumab–nivolumab combination. Response to subsequent therapy was higher in patients who received first-line ipilimumab–nivolumab than those who received first-line IO–TKI (45 vs. 15%, p = 0.040). Efficacy of cabozantinib post-IO therapy has been retrospectively analyzed and shows a disease control rate of 82%-in patients treated with prior IO and 75%-in patients treated with IO–TKI.[18] PDIGREE is an ongoing phase-III clinical trial (NCT03793166) where patients will be treated with first-line ipilimumab–nivolumab combination. Patients who achieve CR will receive single-agent nivolumab, patients who have progressive disease will receive cabozantinib, and patients who do not achieve CR and do not have PD are randomized to nivolumab maintenance or cabozantinib–nivolumab. Results of the trial are awaited. Axitinib has been studied in a phase-II study by Ornstein and colleagues[19] in patients treated with IO in first line. This study showed a PFS of 8.8 months, ORR of 20%, and stable disease of 50%.

Nonclear Cell Histology

Patients with nonclear histology were poorly represented in VEGF TKI studies. Pembrolizumab–axitinib study included patients with sarcomatoid histology (17.9% in pembrolizumab–axitinib arm and 18.4%-in sunitinib arm), lenvatinib–pembrolizumab study had 7.9 and 6.6%-patients with sarcomatoid features in IO versus sunitinib arm, and cabozantinib–nivolumab study had 10.9 and 12.9%-patients with sarcomatoid features in the two arms, respectively. A meta-analysis of four randomized controlled trials provided data on 467 patients with sarcomatoid RCC. This study showed IO drugs to be associated with higher ORR (>50 vs. 20%- with sunitinib), higher PFS, higher chance of achieving CR, and higher OS.[20]

The number of patients with sarcomatoid histologies in IO studies is small, and firm conclusion cannot be drawn regarding efficacy of IO in this variety of RCC. However, IO appears to be the better treatment option for sarcomatoid RCC as compared with VEGF TKI.

Toxicity of Immunooncology Combinations

[Table 2] shows the adverse events, dose reduction, and discontinuation of therapy due to toxicity.

Deepak Dabkara, MBBS, MD, DM (Medical Oncology)

Department of Medical Oncology, Tata Medical Center

Kolkata, West Bengal 700136

India   

Email: deepakdabkara@yahoo.com