Use of Nivolumab and Ipilimumab in Special Populations

Brain Metastases

Although 10% of patients with mRCC develop brain metastases, the overwhelming majority of clinical trials exclude these patients from participating.25 Given the antitumor activity of ipilimumab and nivolumab on brain metastases in both melanoma and NSCLC, two trials have addressed this patient population in mRCC.

Continue Reading

In the GETUG-AFU 26 NIVOREN trial, 73 patients with mRCC and asymptomatic brain metastasis, who progressed on VEGFR therapy, were treated with nivolumab monotherapy.26 This study included patients with untreated brain metastasis (cohort A) as well as patients who underwent prior brain radiation (cohort B). At a median follow up of 23.6 months, 28 patients in cohort A had an intracranial ORR of 12% and a median intracranial PFS of 2.7 months (95% CI 2.3–4.6 months). All patients with an intracranial response also had concurrent extracranial response. Of note, 51% of patients required corticosteroid use because of symptoms related to brain metastases. Patients in cohort B had a longer median intracranial PFS (4.8 months, 95% CI 3.0–8.0) compared to cohort A (2.7 months, 95% CI 2.3–4.6 months). However, they had a shorter 12-month OS (58.8%, 95% CI 40.6–73.2%) compared to cohort A (67%, 95% CI 49.6–79.1%). Because the intracranial response rates were significantly lower than rates seen in extracranial metastases, the authors concluded that single agent nivolumab has limited activity in patients with untreated brain metastasis.

In CheckMate 920, 28 patients with untreated mRCC and asymptomatic brain metastases were treated with the ipilimumab 3 mg/kg and nivolumab 1 mg/kg for 4 cycles followed by nivolumab 480 mg every 4 weeks maintenance for up to 2 years.27 At a minimum follow up of 6.47 months, the objective response rate was 29% (all PR) and the median PFS was 9.0 months (2.9-NE). Intracranial response was not reported. OS analysis remains immature. Seven of the 14 patients who experienced grade 3 or higher TRAE had to discontinue therapy. Like in previous studies, the most common grade 3–4 immune mediated adverse events were diarrhea, colitis, diabetic ketoacidosis, hepatitis, hypophysitis, and rash (n=1 each).

In general, ipilimumab and nivolumab has shown favorable antitumor activity in this population and similar rates of adverse events as previous studies with this combination. Thus, the combination of ipilimumab and nivolumab can be considered in this specific population and warrants further investigation. Timing of brain-directed therapy (surgery, radiation, etc.) is not yet defined and should be addressed individually with each patient.

Favorable Risk mRCC

While the primary endpoint in CheckMate 214 focused on IMDC intermediate and poor risk patients, the authors performed exploratory analyses looking at IMDC favorable risk patients who were included in the trial as well. Although the ORR (29% vs 52%) and PFS (15.3 months vs 25.1 months; HR 2.18, p<0.001) favored sunitinib therapy, the CR rate (11% vs 6%) favored the nivolumab plus ipilimumab arm.22 More recently, the 42 month follow up of Checkmate 214 continued to show not only a higher CR rate in the ipilimumab nivolumab arm (13% vs 6%) but also more ongoing responses (69% vs 54%).24 It remains unclear if there is a survival benefit (HR 1.19; 95% CI 0.77–1.85, p=0.44), although the authors note the PFS curve for the combination arm is stabilizing while the PFS curve for sunitinib continues to decline. Given these findings, ipilimumab and nivolumab can be considered for patients with favorable-risk mRCC.

Non-Clear Cell Histology

Non-clear cell (ncc) histology makes up approximately 25% of diagnosed mRCC.28 There is limited prospective data to guide treatment of nccRCC, thus treatments for these subtypes are extrapolated from the ccRCC data. In a meta-analysis of nccRCC treated with PD-1/PD-L1 inhibitors, papillary RCC was the only subtype with significant benefit (ORR 29%, 1 CR).29 Two other retrospective series with nivolumab monotherapy showed similar efficacy, in regard to ORR (20%, all PR) and median PFS (ranging between 3.5–5.4 months).30,31 Given the benefit of combination ipilimumab and nivolumab therapy in mccRCC, Gong et al published a retrospective analysis of mnccRCC receiving ipilimumab and nivolumab and noted a best ORR of 33.3% (no CR) and a median PFS of 7.1 months.28 Another series of 18 patients who were treated with ipilimumab and nivolumab for nccRCC at various lines of therapy showed that this combination was feasible with strong anti-tumor activity (33% PR, 17% SD).32

Currently, there are two phase II trials investigating the role of ipilimumab and/or nivolumab in nccRCC. One trial compares nivolumab plus ipilimumab versus sunitinib in nccRCC (NCT 03075423)33 and the other investigates sequential treatment with single agent nivolumab followed by combination therapy in metastatic or unresectable nccRCC.34 Results from these trials should help direct CPI therapy in this population.

RCC with Sarcomatoid and Rhabdoid Features

Sarcomatoid and rhabdoid differentiation can occur in both ccRCC and nccRCC and is associated with a poor prognosis. Tumors with this particular histology are thought to be more immunotherapy responsive because of increased expression of PD-L1 and PD-L1, as well mutations in p53 and BAP1.35–37 In a post hoc exploratory analysis of CheckMate 214, 214 patients were identified to have sarcomatoid RCC (sRCC), of which 112 patients had intermediate to poor risk features.38 At a minimum follow up of 30 months, there was an improvement in ORR (56.7% vs 19.2%, p<0.001), median PFS (8.4 mo vs 4.9 mo, HR 0.61, 95% CI 0.38–0.97, p<0.03) and median OS (31.2 mo vs 13.6 mo, HR 0.55, 95% CI 0.33–0.90, p<0.0155) in the ipilimumab with nivolumab arm compared to sunitinib. Notably, while there were no CRs in the sunitinib arm, there was a 18.3% CR rate in the ipilimumab with nivolumab arm. More recently, a retrospective review comparing outcomes of immunotherapy versus tyrosine kinase inhibitor therapy in patients with RCC and pure sarcomatoid, pure rhabdoid, or mixed sarcomatoid with rhabdoid features, showed that those treated with immunotherapy had better OS (31.4 vs 17.8 months, p <0.001).39 Given the observed responsiveness of sarcomatoid and/or rhabdoid RCC to immunotherapy,40–44 multiple clinical trials are including this rare subtype.45,46 (NCT 03866382, NCT03793166).

Immunotherapy Refractory Patients

While immunotherapy combination therapies are the preferred front-line treatment for ccRCC, there is limited knowledge of the effectiveness and tolerability of immunotherapy as salvage therapy in patients who previously received CPI therapy. In metastatic melanoma refractory to PD-1 therapy, the addition of ipilimumab to nivolumab improved response rates compared to the use of nivolumab alone (16–21%).47 However, there was minimal difference in one year OS rates (54% vs 55%). More recently, a multi-center series evaluated 30 patients with immunotherapy refractory mRCC who received ipilimumab and nivolumab as salvage therapy. Most of these patients were IMDC intermediate risk (60%) with a median number of 3 prior systemic therapies. At the time of restaging scans, 17% of patients had a partial response and 3% had stable disease.48 Immune-related TRAE occurred in 37% of patients with only 6% of patients having a ≥ grade 3 reaction. There are currently multiple trials looking at whether adding an ipilimumab boost to patients refractory to front-line nivolumab is beneficial (NCT03117309, NCT03297593, NCT03203473).49–51

Unanswered Questions

Best Front-Line Therapy

Currently there are two frontline immunotherapy-antiangiogenic combination therapies approved for advanced ccRCC. The society for Immunotherapy of Cancer consensus found that for patients with good performance statue (ECOG 0) and intermediate/poor IMDC risk group stratification, 78% of panelists would recommend initial treatment with ipilimumab and nivolumab, whereas 17% of panelists would recommend pembrolizumab with axitinib (Pembro/Axi).52 With the analyses available so far, ipilimumab with nivolumab continues has a better CR compared to pembrolizumab with axitinib in the intent to treat population (11% vs 6%).24,43 However, ipilimumab with nivolumab is also considered a more toxic regimen with 35% of patients requiring high dose steroids (≥40 mg/day of prednisone equivalent) for treatment related adverse events and a discontinue rate of 22% because of intolerable side effects.22 Ipilimumab with nivolumab should be considered frontline treatment in those who can tolerate it. A prospective trial comparing the two combinations is needed to clarify this issue; until which either Ipi/Nivo or Pembro/Axi combination therapy is reasonable.

READ FULL ARTICLE Curated publisher From Dovepress