Role of immune check point inhibitor rechallenge in metastatic renal cell carcinoma

The advent of immune checkpoint inhibitors (ICIs) has transformed the treatment landscape for metastatic renal cell carcinoma (mRCC). Despite these advancements, a substantial proportion of patients experience disease progression during or after ICI therapy, prompting important questions regarding the efficacy of ICI rechallenge strategies.

Sequential approach with response-adaptive escalation has shown limited and clinically non-beneficial activity in OMNIVORE, HCRN GU16-260, and TITAN-RCC trials.^1–3 Although the KEYNOTE-146 trial reported an objective response rate (ORR) of 56% with pembrolizumab and lenvatinib rechallenge, subsequent trials, including FRACTION-RCC, CONTACT-03, and TiNivo-2, demonstrated that ICI rechallenge was ineffective regardless of treatment sequencing.^4–8 Specifically, in CONTACT-03 and TiNivo-2, rechallenge with VEGF TKI and ICI combinations failed to show significant improvements in progression-free survival (PFS) or overall survival (OS) compared to VEGF TKI monotherapy.

The failure of ICI rechallenge highlights the complexity of resistance mechanisms in mRCC, involving alterations in the tumor microenvironment, antigen presentation, and immune regulatory pathways. Although the underlying reasons for the limited efficacy of ICI rechallenge are not fully understood, the available data offers valuable insights that may help elucidate potential reasons. As demonstrated by the OMNIVORE, HCRN GU16-260, and TITAN-RCC studies, introducing another immunotherapy agent targeting a different pathway (such as CTLA-4) after the development of ICI resistance is usually insufficient to overcome established resistance. Similarly, the FRACTION-RCC trial showed a lack of efficacy when ipilimumab (a CTLA-4 inhibitor) and relatlimab (a LAG-3 inhibitor) were added to nivolumab in patients with ICI resistance, reinforcing this observation.^5,6

A potential limitation of the CONTACT-03 trial is the use of atezolizumab, a PD-L1 inhibitor, for rechallenge, as it is not an approved treatment option for mRCC. In the IMmotion151 trial, the combination of the PD-L1 inhibitor atezolizumab with bevacizumab did not improve ORR or OS compared to sunitinib monotherapy in the first-line treatment of mRCC.^9,10 After disease progression on atezolizumab or sunitinib, cross-over to atezolizumab plus bevacizumab was allowed. Overall, 44 patients from the first-line atezolizumab arm received atezolizumab plus bevacizumab following progression. The ORR of second-line atezolizumab and bevacizumab treatment was 25% in patients who previously received atezolizumab and 29% in patients who previously received sunitinib. ¹¹ The combination of another PD-L1 inhibitor, avelumab, with axitinib demonstrated improved PFS vs sunitinib in the first-line, but failed to show an OS benefit. ¹² These results raised questions about the role of PD-L1 inhibitors in the treatment of mRCC. Additionally, after progressing on prior ICIs, patients enrolled in CONTACT-03 underwent immediate rechallenge with ICI therapy. Because some PD-1 inhibitors have long half-lives and prolonged receptor occupancy—such as nivolumab, where over 70% of PD-1 molecules on circulating T cells remain occupied up to two months after the last infusion—anti-PD-L1 therapy may demonstrate limited efficacy due to sustained receptor binding. ¹³ In contrast to the CONTACT-03, the TiNivo-2 study used an anti-PD-1 therapy as the backbone of ICI rechallenge and included patients who have ICI break with different group of treatment (29% of patients with the most recent line of therapy being non-ICI treatment). ⁸ TiNiVo-2 used a lower dose of tivozanib (0.89 mg) in the combination arm vs 1.34 mg in the single-agent control arm, due to increased rate of Grade 3/4 hypertension with the combination at a higher dose. ¹⁴ The reduced dose in the combination arm may explain the failure to observe an improvement in PFS vs tivozanib alone. It is uncertain whether a higher dose of tivozanib would have resulted in improved disease outcomes. Another area of uncertainty is the optimal management of patients who experience disease progression during or after receiving adjuvant pembrolizumab. The proportion of patients who had received prior adjuvant immunotherapy was less than 1% in CONTACT-03 and 14% in TiNivo-2. The underrepresentation of patients receiving adjuvant IO therapy complicates the determination of appropriate strategies for those who progress during adjuvant treatment. Additionally, these studies do not provide guidance on treatment planning for patients who experience progression after completing scheduled IO therapy

The tumor microenvironment plays a crucial role in determining the therapeutic efficacy of cancer immunotherapies. Tumors have developed multiple mechanisms to evade the immune system, such as enhancement of negative immune regulatory pathways, the disruption of antigen presentation, activation of immunosuppressive signaling pathways and recruitment of tumor-promoting immune cells.^15–17 The use of ICIs promotes a shift in tumor-associated macrophage switch from the M2 to the M1 state, resulting in a reduction of immunosuppressive macrophages, activation of CD8+ T cell responses, and a decrease in regulatory T (Treg) cells. However, there remains a lack of data on the evolution of the tumor microenvironment following ICI exposure. Besides the benefit of ICI varies across cancer types and patients. This variability is likely driven by resistance mechanisms, including downregulation of the HLA antigen presentation complex, alterations in IFN-gamma, RAS/RAF, and PTEN signaling pathways, and changes in the tumor microenvironment, such as T cell exhaustion and increased activity of immunosuppressive cells during treatment.¹⁸ Knowledge about how resistance mechanisms, including those related to the tumor microenvironment or epigenetic modifications, evolve during immunotherapy breaks or after transitioning to another treatment remains limited. Further translational research is required to determine whether a successful ICI rechallenge can effectively restore the immune system after progression on ICI therapy.

Although the available studies show that ICI rechallenge has failed in the treatment of mRCC, research in this area continues. These ongoing studies may help to further clarify and provide insights into this area. The majority of these trials focus on nivolumab- or pembrolizumab- based regimens in combination with anti-VEGF TKIs (NCT06053658, NCT03172754, NCT03149822, NCT04626518, NCT04904302). In addition to anti-VEGF TKIs, several studies are exploring combinations with different molecular targets. MK-3475-03B (NCT04626518) is a phase Ib/II trial investigating pembrolizumab in combination with various agents, including agents targeting CTLA-4 (quavonlimab), LAG-3 (favezelimab), immunoglobulin-like transcript 4 receptor (MK-4830), HIF-2 alpha (belzutifan), and VEGF TKI (lenvatinib) in patients who have progressed on or after PD-(L)1 checkpoint inhibitors. The HCRN GU17-326 (NCT03552380) trial is a pharmacodynamic and efficacy study evaluating entinostat (a histone deacetylase inhibitor) in combination with nivolumab and ipilimumab for patients with mRCC who have progressed on either the nivolumab + ipilimumab regimen or nivolumab monotherapy. A 33% ORR was reported in the safety run-in cohort. ¹⁸ STARLITE 2 (NCT05239533) is a phase II trial evaluating the combination of ¹⁷⁷Lu-girentuximab with nivolumab in patients previously treated with at least one anti-PD-(L)1 antibody. ¹⁹ Additionally, studies investigating the combination of ICIs with recombinant interleukins and T-cell growth factors are also ongoing (NCT03991130, NCT03228667, NCT04374877, NCT05155033).

In conclusion, IO rechallenge studies in the treatment of mRCC have consistently shown limited success, underscoring the necessity for further investigation into the mechanisms driving resistance and treatment failure. Understanding why these approaches fail is critical to developing more effective treatment options and refining therapeutic strategies for patients who progress on initial ICI therapy. Moreover, addressing the ongoing challenge of providing long-term, sustained responses in patients with mRCC after progression on ICI therapy remains scientific priority.