Duration of Therapy

It remains unclear how long patients should remain on therapy in order to obtain and sustain optimal clinical benefit. In general, patients continue on treatment until toxicity or progression. Clinical trials of CPI in melanoma have showed durable responses in patients who discontinued therapy for reasons other than disease progression. Updates from Keynote 006 showed that 78.4% of patients who completed 2 years of pembrolizumab therapy continued to have disease control at 5 years.53 The estimated risk for progression or death nearly 10 months after completing pembrolizumab was 9% and did not differ by best response to pembrolizumab. Similarly, the long term update of the phase III Checkmate 067 trial, showed that 71% of patients with advanced melanoma who received ipilimumab with nivolumab did not need subsequent therapy at 4 years.18

Similar trends have been seen in RCC as well. In the extended follow up analysis of CheckMate 214, 52% of patients with intermediate to poor risk disease who were treated with nivolumab/ipilimumab had a response duration ≥18 months with a median time to response of 2.8 months (range 2.7–3.1 months).54 Of those who responded but discontinued therapy for reasons other than progression, more patients who were treated with the combination therapy were able to remain off of therapy compared to those treated with sunitinib (38% vs 26%). Further studies into the biology of the tumor and biomarkers of response are needed to help predict who will not only benefit from therapy but also sustain a response once therapy is discontinued.

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Likewise, studies looking into intermittent immunotherapy dosing have begun. In a small prospective phase II trial of intermittent nivolumab monotherapy in 14 VEGFR TKI refractory aRCC, demonstrated that 80% of eligible patients were able to sustain a response at 48 weeks post treatment suspension.55 Currently, there are two phase trials investigating this question. (Table 2) One trial includes patients with treatment-naïve mRCC who will be treated with ipilimumab and nivolumab followed by 24 weeks of nivolumab maintenance, at which point patients with a CR or PR will enter an observation phase until progression (NCT03126331).56 In another trial, treatment-naïve mRCC patients with advanced RCC will receive nivolumab monotherapy with a transition to either therapy suspension (arm A) for those with a persistent CR/PR versus a N3I1 boost (arm B) for those with PD. (NCT03203473).50 Novel dosing schedules, early discontinuation considerations, and biomarkers of response are all sorely needed to identify patients who can sustain disease regression while off of therapy.

Table 2

Restarting Therapy in Patients Who Developed Immune-Related Adverse Events

A host of data suggests that the development of immune-related adverse events (irAEs) are associated with improved response to CPI therapy. A meta-analysis of 48 clinical trials using ipilimumab and nivolumab in various solid tumors found that the ORR of combination therapy was positively correlated with irAE of the skin (r=0.54, p=0.04) and GI tract (r=0.60, p=0.02).57 Specifically, in RCC, the NIVOREN GETUG AFU trial found that those who had a grade ≥ 3 TRAE (18%) had a longer PFS (HR 0.69, 95% CI 0.56–0.86) than those who did not.16

IrAEs usually occur within 3–6 months of CTLA-4 or PD-L1 initiation, however they can occur at any time during treatment.58 Severity is determined by the common terminology criteria for adverse events grading system.59 Across ASCO60 and NCCN guidelines,61 grade 2–3 irAEs can be managed with temporary discontinuation of therapy until symptoms resolve below grade 1 or patients are on a maximum of prednisone 10 mg daily. Grade 4 irAEs should lead to permanent discontinuation of combination therapy.

In CheckMate 214, 47% of patients experienced a TRAE on ipilimumab and nivolumab therapy, with diarrhea (4%) and hepatitis (4%) being the most common.22 Twenty two percent of these patients discontinued therapy secondary to AE intolerability. While patients who experienced a severe irAE on protocol were not allowed to continue with nivolumab monotherapy, the NCCN guidelines suggest that patient can be restarted on PD-1 or PD-L1 monotherapy after symptoms secondary to combination therapy resolve.61 Currently, the Phase 3b/4 CheckMate 920 trial is looking to answer this question by evaluating the incidence of high grade irAEs with patients treated with both ipilimumab and nivolumab (NCT02982954).62 Additional data is needed to guide therapy resumption in patients who develop severe irAEs.

Treating Patients with Underlying Autoimmune Conditions

Patients with active autoimmune conditions have been excluded from the ipilimumab and nivolumab trials, given the theoretical exacerbation of their underlying disorder when the CTLA-4 and PD-1 receptors are blocked. In a retrospective study of PD-1 blockers (pembrolizumab or nivolumab) for advanced melanoma, 52 patients with underlying autoimmune conditions had 33% response rates and 38% had a flare of their pre-existing disease requiring immunosuppression.63 Of note, only 2 patients had to discontinue treatment due to their flare. However, 29% developed other iRAEs, with 8% of these patients discontinuing treatment. Similarly, in a retrospective study of 30 patients with advanced melanoma and a pre-existing autoimmune condition (43% of which were on immunosuppressive therapy) were treated with ipilimumab, there were 20% response rates with 27% exacerbation of their underlying condition requiring steroid management.64 There have been no large series published in renal cell carcinoma or with the combination of ipilimumab with nivolumab. However, the Society of Immunotherapy of Cancer consensus recommends that patients with aRCC can be considered for ipilimumab nivolumab combination therapy if they do not have a life threatening autoimmune condition or require immunosuppressive treatments.52

Identifying Patients for Nivolumab Monotherapy in Treatment-Naïve mRCC

While the combination of ipilimumab and nivolumab has proven survival benefits, the tolerability of the regimen has been a concern in clinical practice. A metanalysis using the World Health Organization pharmacovigilance database showed that combination therapy (CTLA-4 plus anti PD-1 therapy) is associated with more iRAE compared to anti-PD-1 monotherapy (55–60% vs 10–20%) across multiple tumor types.65 Thus, investigations into nivolumab monotherapy upfront is warranted.

In the phase II TITAN-RCC trial, treatment-naïve (cohort 1) and VEGF-refractory (cohort 2) patients were induced with nivolumab 240 mg IV every 2 weeks for 4 doses, at which point they either received a N3I1 boost for early progression or continued on nivolumab 240 mg IV every 2 week maintenance. This reassessment was repeated again after the 8th dose. Specifically, in cohort 1, the ORR was worse in the nivolumab monotherapy arm compared to those who received an N3I1 boost (29% vs 37%). Of those who had a N3I1 boost, 29.8% of patients had improvement after the combination was given. Of those who responded with a PR (27%) or CR (2%) at 4 weeks, median PFS was not reached at analysis. OS data remains immature. This study highlights that there is a small subset of patients that may not need combination therapy upfront and can respond when ipilimumab is added later. There are currently multiple trials investigating this question (Table 2).51

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