Vol 18, No 2 2020
Corresponding Author: ThomasEHutson@usoncology.com
The Current and Evolving Landscape of Immunotherapies for Advanced Renal Cell Carcinoma
Allen Jacob, MD
Texas A&M College of Medicine
Ohio Northern University College of Pharmacy
and Urologic Oncology Program
Thomas E. Hutson, DO, PharmD, FACP
Baylor Sammons Cancer Center
Keywords: immune-checkpoint inhibitors, ICI, anti-angiogenics, immunotherapy landscape, immune microenvironment reprogramming, TKI, RCC.
Corresponding Author: ThomasEHutson@usoncology.com
There has been tremendous progress in the treatment landscape of metastatic renal cell carcinoma over the last decade with new, more efficacious strategies emerging and the incorporation of several of these therapies into combinations with even greater benefit to patients. Novel immune checkpoint inhibitors (ICI) have emerged as a primary backbone to many of the most active regimens. However, drawbacks of ICI remain such as lower long-term response rates and the absence of potential biomarkers that will facilitate patient selection. In addition, current data regarding the outcomes of patients including optimal management of patients who progress after ICI are fairly limited. Owing to such limitations, there is an urgent need to identify more reliable biomarkers of immunotherapies for better prediction of treatment response and more efficient stratification of patients. In this review, we provide the current status of the immunotherapy landscape for advanced renal cell carcinoma as well as discuss future directions.
Renal cell carcinoma (RCC) is one of the top ten most frequently diagnosed cancers with an incidence of around 400,000 cases worldwide.1 In United States alone, RCC accounts for 73,820 new cases and 14,770 deaths in 2019. In patients with RCC, about 30% of patients who present with metastatic disease at the time of initial diagnosis typically require systemic therapy and almost 30% of patients who are treated for localized RCC develop recurrent disease during the follow-up.2 RCC is typically known for its resistance to conventional forms of therapies as hormonal and cytotoxic chemotherapeutics have considerably failed to produce remissions and improve overall survival. For the past several years, ongoing clinical trial efforts were aimed at developing targeted therapeutic agents for the management and treatment of metastatic renal cell cancer (mRCC). Until 2005, medical therapies for mRCC were limited to inter-feron‐alpha or interleukin‐2 as cytokine-based therapies which provided only a modest survival benefit of approximately 1 year.3,4 Based on the preliminary data indicating 15% overall response rate (ORR) and a 5% complete response (CR), the high-dose intravenous IL-2 was approved by the US Food and Drug Administration (FDA) for the treatment of RCC in 1992. High-dose IL-2 used in selective patients with metastatic renal cell carcinoma had led to rare complete and durable responses.3 In a follow-up study, CR was 7% and median duration of response was at least 80 months. The scope of IL-2 based therapy is, however, limited by substantial incidence of high-grade adverse events as well as the inability to predict response.
In recent years, multiple targeted therapies predominantly focusing on two major molecular pathways, namely angiogenesis and intracellular signal transduction pathways, have gained increasing attention in RCC landscape. Since 2005, there has been remarkable progress in the treatment of RCC with VEGF inhibitors (sunitinib, sorafenib, axitinib, pazopanib, cabozantinib, bevacizumab, lenvatinib), as well as mammalian target of rapamycin (mTOR) pathway inhibitors (everolimus, temsirolimus). These agents provided considerable survival benefits in pivotal trials as well as gained regulatory approval to become the defacto choice of first-line systemic therapy.5 More recently, key insights obtained in regard to the VHL pathway have profoundly shaped the evolving mutational landscape of mRCC and also provided the basis for the development of the VHL-hypoxia pathway-based therapeutic landscape in renal cancers.6 Despite the significant progress over the past 15 years, there is still room for improvement for targeted therapies as current drug interventions for mRCC have yet to demonstrate the ability to circumvent recurrence and several therapies are accompanied by severe adverse events.3,4 In this review, we summarize recent breakthroughs in the immunotherapy space that remodeled the RCC treatment algorithm and also highlight the novel approaches being evaluated in ongoing clinical trials.
Figure 1. Synergistic effect of immune checkpoint blockade and anti-angiogenesis as a rational for improved targeted therapies. The resistance towards ICI could be alleviated by combination therapy with anti-angiogenesis treatment that not only prunes blood vessel but also reprograms the tumor immune microenvironment. In this sequential and iterative immunity-angiogenesis cycle, the complement interaction between ICI and anti-angiogenics transforms the immunosuppressive tumor microenvironment into immunosupportive microenvironment. PD-1: anti-programmed death receptor 1; PD-L1: anti-programmed death receptor ligand 1; CTLA-4: anti-cytotoxic T lymphocytes antigen-4; APC: antigen-presenting cell; VEGF: vascular endothelial growth factor; CAR: Chimeric antigen receptor; TLR: toll-like receptors.
Rationale for Selection of Immunotherapy
Given that RCC is considered immune-responsive in nature with high numbers of immune cells present in the tumor microenvironment, targeted immunotherapy was explored as a potential therapy in RCC patients who were non-responsive to conventional targeted therapies.7 One immune strategy involved the use of immune checkpoint inhibitors (ICI).8 In particular, the use of sophisticated ICIs, including anti-programmed death receptor 1 (PD-1), anti-programmed death receptor ligand 1 (PD-L1), and anti-cytotoxic T lymphocytes antigen 4 (CTLA-4), have been developed and studied in large international phase III trials demonstrating significant and clinically relevant improvements in efficacy. As such, these new therapies have quickly been integrated into the RCC landscape. PD-1 and PD-L1 antibody- based novel ICIs have been approved by the FDA as the standard second-line treatment for mRCC as well as in the first-line for moderate to high-risk mRCC.9 Notably, the footprints of ICI, expanded across the landscape of oncology with the approval of nivolumab and ipilimumab combination, especially in patients with intermediate to poor-risk renal cell carcinoma (RCC).
Underlying Mechanisms of Action
In-depth understanding of T cell function and associated immunosuppressive molecules have highlighted the central role of the tumor micro-environment. During tumorigenesis, a tumor may trigger certain immune-resistant mechanisms including systemic dysfunction in T cell signaling and exploitation of immune check-points.6-11 By employing such anti-immune mechanisms, tumors can evade specific immune responses.12 Further insights regarding such immune evasive mechanisms in the host-tumor immune environment have led to the development of novel antibody based agents directed against immune checkpoints in tumors.13,14 In many tumors, upregulated programmed death-ligand 1 PD-L1 expression can either be constitutive or induced to evade immune surveillance. PD-1 expressed on activated T cells can bind to its ligand PD-L1 on tumor cells, leads to T cell exhaustion and downregulated immune defense against tumors.10 By blocking or counteracting the tumor mediated inhibition of T‐cell receptor‐activated IL‐2 production and T‐cell proliferation, ICIs can potentially suppress the events that otherwise downregulate a cellular immune response. This counteraction results in a successful anti‐tumor T‐cell mediated immune activity and antibodies raised against such PD-1 and PD-L1 inhibitory axis can unleash activated tumor-reactive T cells to promote durable anti-tumor responses in many tumors. Thus, this biological rationale encouraged the synergistic association of CTLA-4 inhibition, which facilitates active immune response at the level of T-cell proliferation, with PD-1 suppression, which modulates the immune response at the level of the tumor micro-environment. Since the disruption of PD-1–PD-L1 signaling mediated by nivolumab can lead to restored antitumor immunity, PD-L1 expression is associated with improved overall survival in response to nivolumab therapy.11 This anti-PD-1 antibody nivolumab, selectively blocks the interaction of PD-1 (expressed on activated T cells) with its ligands PD-L1 and PD-L2 (expressed on immune cells and tumor cells) and thus counteracting the cellular immune response pathways.12 Such discoveries led to the approval of anti-PD1 antibodies (for example: pembrolizumab and nivolumab) and anti-PD-L1 antibodies (for example: atezolimumab) for the treatment of advanced melanoma, NSCLC, RCC, head and neck squamous carcinoma, Hodgkin’s lymphoma, and bladder cancer.13
Monotherapy or Combinatorial Therapy of Immune Checkpoint Inhibitors
The ICI field is evolving rapidly with many clinical trials already completed studying several checkpoint inhibitors alone, in combination, or with other targeted therapies. Since the approval of the CTLA-4 antibody ipilimumab in patients with melanoma in 2011, several PD-1/PD-L1 inhibitors including nivolumab, pembro-lizumab, atezolizumab, durvalumab, and avelumab as well as the CTLA-4 inhibitor ipilimumab were investigated for their anti-tumor efficacy.23 Nivolumab, a fully humanized IgG4 anti-PD-1 that was developed in the form of a monoclonal antibody directed at PD-1, became the first ICI approved by FDA in 2015 for the treatment of refractory mRCC. In a randomized, open-label, phase III study CheckMate-025 (NCT01668784), a total of 821 advanced ccRCC patients who had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned either nivolumab or everolimus.8 The primary end point was overall survival and the secondary end points included the objective response rate and safety. Results showed that the objective response rate (ORR) was greater with nivolumab than with everolimus (25% vs. 5%; p < 0.001) and median PFS was better with nivolumab than with everolimus (4.6 months vs 4.4 months; p = 0.11).8 Results indicated that the nivolumab arm had 25.0 months median overall survival (95% CI, 21.8 to not estimable), longer as compared to only 19.6 months (95% CI, 17.6 to 23.1) in the everolimus arm. Nivolumab’s overall survival benefit was evident across prespecified subgroups, including subgroups defined per region, MSKCC prognostic score, and number of previous regimens of antiangiogenic therapy. Only 19% of the patients receiving nivolumab experienced grade 3 or 4 treatment-related adverse events as compared to 37% of the patients receiving everolimus, and only 8% requiring treatment discontinuation because of toxicity. Altogether, this pivotal clinical trial demonstrated that nivolumab delivers better PFS, overall response rate and overall survival, paving the way for the use of nivolumab as a preferred second line monotherapy option after progression on anti-vegf therapies in international guidelines.8 Interestingly, although over- expression of PD-L1 has been shown to be associated with poor prognosis and pathological features in RCC, its expression pattern in primary tumors failed to predict whether inhibition of PD-1/PD-L1 axis can provide survival benefit in patients in clinical trials.19 Overall, PD-L1 status is not clinically useful for making treatment decisions in mRCC.
Studies indicate that anti-CTLA4 and anti-PD1 antibodies possess non-overlapping mechanisms, and combination of these two classes of ICIs in a double-blind, phase III study showed improved clinical response (up to 60%) in melanoma at the expense of significantly increased frequency of toxicities.14 The dual ICI of nivolumab/ipilimumab is one of the preferred first-line therapies in poor-risk and intermediate-risk patients. In RCC, CheckMate-214 (NCT02231749) was the first trial to evaluate the CTLA-4 and PD-1 inhibitor combination with the co-primary endpoints included ORR, progression free survival (PFS), and OS in the IMDC intermediate or high risk population.9 Results from CheckMate 214 validated the concept that combination therapy using a PD-1 inhibitor (nivolumab) and a CTLA-4 blocker (ipilimumab) can deliver at least additive benefit versus the anti-vegf tki sunitinib in first line metastatic RCC. Results show that the addition of ipilimumab to nivolumab resulted in significantly better overall survival (HR, 0.63; P < 0.001) and improved objective response rate (42% vs. 27%; p < 0.001) as compared to sunitinib in intermediate and poor-risk patients. In addition, the safety of nivolumab and ipilimumab was reasonable and secured this combination regimen within the first-line treatment algorithm in intermediate- and poor-risk patients with RCC.15
Given such encouraging efficacy of ICIs in the metastatic setting, there is huge interest in exploring their potential role in the adjuvant/neo-adjuvant setting to reduce or prevent recurrence. Currently, a number of phase III trials evaluating the efficacy of ICI treatment in the adjuvant setting are ongoing. In phase III CheckMate-914 multinational study (NCT03138512) the efficacy of adjuvant nivolumab plus ipilimumab vs placebo was evaluated in patients with localized RCC with a high risk of RCC relapse after nephrectomy. Similarly, other agents such as pembrolizumab (Keynote 564; NCT03142334), and atezolizumab (IMmotion010; NCT03024996), nivol-umab (Prosper RCC; NCT03055013) are also currently being evaluated.
Combining Immune Checkpoint Inhibitors and Tyrosine Kinase Inhibitors
Given the recent discoveries of the effectiveness of immune resistance blockade in tumors, ICI agents in combination with either multikinase inhibitors or other monoclonal antibodies (CTLA4 and PD-1) have been or are currently being studied in previously untreated patients with advanced RCC. Recently reported and FDA approved combinations of ICI or ICI with TKI therapy have been rapidly integrated into the first line treatment setting based upon international phase III trials. The recently completed and ongoing trials proposed antiangiogenics be used in association with targeted immuno- therapy to overcome resistance by emphasizing the role of the tumor microenvironment (TME).16,17 Moreover, inhibition of the VEGF pathway has been shown to facilitate access of T-cell population into the TME and also decreases the activity of T-regulatory cells and myeloid-derived suppressor cells, thereby enhancing responsiveness to immunotherapy.18
Similar clinical trials in mRCC are currently ongoing. In another randomized phase II trial (NCT03075423), the combination of axitinib and pembrolizumab was evaluated versus sunitinib in untreated advanced or metastatic RCC. Results revealed that the combination of axitinib and pembrolizumab significantly reduced the risk of death (HR for death, 0.53; p < 0.0001) and disease progression (HR for disease progression or death, 0.69; p < 0.001). In the combination arm, the ORR was 59.3% (p < 0.001) compared to 35.7% in the sunitinib group. These favorable outcomes were observed across all risk groups and regardless of PD-L1 expression.16 Similarly, pembrolizumab is also being evaluated in the cohort B of the KEYNOTE 427 phase II trial. In pRCC, durvalumab is being evaluated in combination with savolitinib, a highly selective MET tyrosine kinase inhibitor, in the CALYPSO phase II trial (NCT02819596).
The Phase III trial IMmotion 151 (NCT02420821) used the combination of PD-L1/PD-1 pathway inhibitor with an anti-VEGF agent in untreated mRCC.20 This study investigated the combination of atezolizumab, an anti-PD-L1 antibody, with bevacizumab, as compared to sunitinib monotherapy in mRCC. Based on PD-L1 expression level on tumor-infiltrating immune cells, patients were stratified by PD-L1 status. Results indicated longer PFS (11.2 months) in the combination arm vs. 7.7 months in the sunitinib arm (HR, 0.74; p= 0.02) in the PD-L1+ patients. Improved PFS was also observed in ITT patients. The ORR in the PD-L1+ patients was 43% in the combination arm as compared to 35% in the sunitinib arm. The CR rate in the PD-L1+ patients was 9% in the combination arm as compared to 4% in the sunitinib arm. In the bevacizumab–atezolizumab arm, grade 3 or 4 toxicities occurred in 40% of patients group and in 54% of patients in the sunitinib group.20
In another randomized phase III trial known as JAVELIN Renal 101 (NCT02684006), Motzer et al investigated the combination of axitinib and avelumab in treatment-naive RCC patients with metastatic or advanced disease.17 In the axitinib and avelumab combination arm, median PFS in the combination arm was 13.8 months versus 8.4 months in sunitinib arm (HR, 0.69; p< 0.001). The ORR and CR rate were 55% and 4% were in the combination arm as compared to 26% and 2% in the sunitinib arm. When PD-L1+ patients were assessed, the median PFS was 13.8 months in axitinib and avelumab combination arm, versus 7.2 months in the sunitinib arm (HR, 0.61; p < 0.001).17 This study demonstrated that patients who received a combination of avelumab plus axitinib had longer PFS and a higher objective response rate than those who received sunitinib monotherapy. KEYNOTE 426 phase III trial (NCT0285-3331) evaluated the efficacy and safety of pembrolizumab (MK-3475) in combination with axitinib versus sunitinib monotherapy as a first-line treatment for 861 participants with advanced or metastatic renal cell carcinoma.16 The combination therapy arm of pembro-lizumab plus axitinib showed a longer median PFS of 15.1 months compared to 11.1 months of the axitinib arm (HR = 0.69; p < 0.001). The safety profile was comparable to the results of the JAVELIN Renal 101 trial. Interestingly, the benefit of pembrolizumab plus axitinib for OS, PFS, and ORR was observed in the entire population irrespective of the prognostic group and PD-L1 tumor expression. In the KEYNOTE-427 (NCT02853344) trial, pembrolizumab monotherapy for treatment naïve patients has also demonstrated promising efficacy and acceptable tolerability in patients with accRCC. Results indicated that ORR was 38.2 % and CR 2.7% in all treated patients. In PD-L1 negative patients, ORR was found to be 50.0 % as compared with 26.4% and the median PFS was 8.7.
Although the combination of ICI and antiangiogenics has shown encouraging preliminary antitumor activity for advanced or mRCC, clinical trials indicate that toxicity and tolerability may be difficult in some patients. For instance, in the phase I study CheckMate 016 (NCT01472081), the efficacy and safety of nivolumab in combination with antiangiogenic tyrosine kinase inhibitors or ipilimumab for the treatment of mRCC.21 In this study, addition of sunitinib or pazopanib to nivolumab resulted in a high incidence of high-grade toxicities, limiting its scope in future trials.
The remarkable advancement of immunotherapy into the landscape of mRCC has improved the outlook for many patients. In the coming years, emerging targeted and immune therapies, or their combinations, may not only deliver the improved efficacy achieved with overriding immune resistance but also profoundly shape the therapeutic landscape. There remains unmet need for prospective ICI-based immunotherapy data in regard to their ability to be appropriately sequenced as well as selected after ICI. Evidently, successful outcome from ICI plus antiangiogenic combinatorial regimens may be dependent on prudent selection of the specific agents tailored with optimal dose. Most importantly, appropriate therapeutic sequence of combinatorial regimen along with their dosage optimization will need to be ascertained to avoid treatment discontinuation based on intolerable toxicity and also ensure that the remarkable therapeutic outcome will be achieved. The dosage optimization for ICI monotherapy or the combination of ICI with VEGF inhibitor in conjunction with optimal modulation of TME is essential to facilitate the efficacy of ICI. Besides, in the rapidly evolving renal cancer landscape with the prospective of future ICI plus antiangiogenics, efforts should be directed at obtaining consensus from various immunotherapy agents as appropriate control arm. Likewise, since complex immune modulatory responses can be elicited by continuous exposure to ICI combination, the irreversible T cell exhaustion, immune-editing, and antigenic drift like complication should be take into account while considering new therapeutic combination. Currently available trials involving heterogeneous patient populations making cross trial comparisons impossible. Further emphasis is needed on potential biomarkers and prospective validation of biomarkers combinations. The treatment associated toxicities remain a major roadblock hindering the widespread use and applicability of these treatments. Therefore, evidence-based and algorithmic approaches in stratification, treatment sequence, and treatment selection need to be standardized in the management of immune-related toxicities. In addition, due consideration should be given for effective protocol design including endpoint choice, and methods used for treatment response to avoid some pitfalls.
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