Combination Immunotherapy and
Targeted Therapy: Will New Combinations
Raise the Tail of the Survival Curve?

Xin Gao, MD
Medical Oncologist
Claire and John Bertucci Center
    for Genitourinary Cancers
Massachusetts General Hospital
    Cancer Center
Boston, Massachusetts


Keywords: Combination therapy, PD-1/PD-L1, immunotherapy, VEGR/VEGFR, anti-angiogenic therapy

Corresponding Author: Xin Gao, MD, Massachusetts General Hospital Cancer Center, Yawkey Building, Suite 7E, 55 Fruit Street, Boston, MA 02114   Tel: 617-724-4000 Fax: 617-643-1740


Clinical trials investigating combinations of antibodies against the immune checkpoints PD-1 or PD-L1 plus targeted therapies against VEGF/VEGFR have shown promising anti-tumor activity over single-agent therapy in renal cell carcinoma (RCC). In addition to their proven clinical efficacy as single agents, each class of drugs has a distinct and potentially synergistic mechanism of action relevant to RCC biology. Several combinations are now in phase III evaluation in treatment-naïve metastatic RCC patients. This report summarizes the preclinical and clinical rationale under- lying the use of such combination therapies and describes the latest combination trials, which may be transformative for the treatment of advanced RCC. 

The therapeutic landscape for advanced renal cell carcinoma (RCC) has evolved rapidly in recent years, and additional clinical trials investigating combinations of immune checkpoint inhibitors with antiangiogenic therapies are poised to continue to redefine the treatment paradigm. A randomized phase III study of the programmed deathligand 1 (PD-L1) antibody atezolizumab in combination with the vascular endothelial growth factor (VEGF)-targeted antibody bevacizumab has already demonstrated clinical efficacy for a subset of patients with metastatic RCC (mRCC).1 Furthermore, results from four large randomized phase III trials investigating various combinations of monoclonal antibodies against programmed cell death protein 1 (PD-1) or PD-L1 plus small molecule tyrosine kinase inhibitors (TKIs) of VEGF receptor (VEGFR) are highly anticipated as combination approaches work their way through rigorous review toward potentially reshaping the conventional sequential approach in the treatment of mRCC. 

Combined targeting of PD-1/PD-L1 and VEGF/VEGFR is grounded in the basic biology of RCC. The highly immunogenic and vascular nature of RCC are well-known,2,3 and it is logical that immunotherapeutic and anti-angiogenic approaches have yielded clinical success against this remarkably chemo-resistant neoplasm. The predominant histologic subtype – clear cell RCC (ccRCC) – is characterized by high proportions of immunogenic insertion and deletion mutations as well as increased immune infiltration compared to other human cancers.4,5 Furthermore, a mutation in or inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is present in the vast majority of ccRCCs, leading to aberrant signaling via the hypoxia-inducible factor (HIF) transcriptional complex.6,7 Altered expression of a multitude of HIF downstream genes, including VEGF, results in an adaptation to hypoxia through the formation of new blood vessels, increased glycolysis, and enhanced tumor proliferation and survival.8

While immunotherapies and anti-angiogenic therapies have individually become standard-of-care treatments for advanced RCCs, intriguing preclinical data have emerged in recent years to suggest beneficial effects of angiogenesis inhibitors on anti-tumor immunity. Tumor-associated blood and lymphatic vascular formation likely play key roles in promoting an immunosuppressive phenotype by modulating the recruitment, adhesion, trafficking, and function of immune cells in the tumor microenvironment.9

Figure 1. Current Treatment Landscape.

Data from preclinical studies have built a framework for understanding the interaction between angiogenic signaling and anti-cancer immunity, ultimately providing a stronger rationale for the clinical use of combination therapies targeting the VEGF/VEGFR pathway and PD-1/PD-L1 immune checkpoints.10 Due to the known clinical efficacy of separately targeting angiogenesis and immune checkpoints in mRCC, one of the key questions to be addressed by ongoing clinical trials is whether such combination therapies result in synergistic anti-tumor effects and improved clinical outcomes over sequential treatment (Figure 1). 

VEGF Signaling and Anti-Tumor Immunity
The central roles of VEGF signaling and anti-tumor immunity in RCC have been well-established in preclinical models and from clinical experience with anti-angiogenic VEGF/VEGFR-targeted therapies, immune checkpoint inhibitors, and cytokine-based therapies. However, recent preclinical work has also suggested important interactions between VEGF signaling and the anti-tumor immune response. Broadly speaking, tumor-associated angiogenesis and lymphangiogenesis facilitate the establishment of an immunosuppressive tumor microenvironment via multiple mechanisms.9 More specifically, VEGF signaling has been shown to inhibit the transcriptional maturation of dendritic cells that serve as antigen presenting cells for tumor-derived neoantigens,11,12 promote the survival and proliferation of myeloid-derived suppressor cells that inhibit effector T cell function and induce regulatory T cell development within the tumor microenvironment,13,14 and promote the expression of PD-1 and other inhibitory checkpoints involved in T cell exhaustion.15 In addition, tumor-associated endothelial cells may induce defective clustering of cell adhesion molecules to inhibit lymphocyte adhesion and extravasation16 and also selectively express the cell death mediator Fas ligand, which binds to Fas-expressing T cells to trigger apoptosis.17 The preclinical data on the interactions between angiogenic signaling and cancer immunity and the clinical efficacy of independently targeting angiogenesis and immune checkpoints in RCC have led to efforts to evaluate whether combination therapy may result in synergistic anti-tumor effects and improved clinical outcomes.

The Landscape of Treatment Combinations
The treatment paradigm for mRCC is evolving from one dominated by single-agent anti-angiogenic agents and immunotherapies toward the adoption of combination regimens geared to achieve enhanced anti-tumor activity. Three combination regimens are already approved for the treatment of mRCC. The immunotherapy and anti-angiogenic therapy combination of interferon-alpha plus bevacizumab has been approved by the United States Food and Drug Administration (FDA) since 2008, though therapeutic efficacy is modest.18,19 More recently, the combination of lenvatinib plus everolimus targeting VEGFR and mechanistic target of rapamycin (mTOR) and the immune checkpoint inhibitor combination of nivolumab plus ipilimumab were granted FDA approval in the second and first-line settings, respectively.20,21

Based on the preclinical rationale discussed previously and the development of multiple VEGF-targeted therapies and immune checkpoint inhibitors that confer improved clinical efficacies over the past decade, multiple combinations of anti-angiogenic agents plus immune checkpoint inhibitors are under investigation in late-phase clinical trials. Such combination strategies may ideally increase the number of long-term survivors and raise the tail of the survival curve, while moderating the additive or synergistic toxicities that may arise with immunotherapy and anti-angiogenic therapy combinations. The combination of atezolizumab plus bevacizumab is furthest into clinical development, having already met one of its co-primary endpoints of improved progression-free survival (PFS) in treatment-naïve mRCC patients with PD-L1-positive (PD-L1+) tumors in the phase III IMmotion151 trial.1

Figure 2. (A) Best percentage change in tumor size in the phase I study of pembrolizumab plus axitinib.22 (B) Percentage change in sum of diameters of target lesions in the phase I study of avelumab plus axitinib.23

Phase I studies of several additional combinations in small numbers of patients have yielded promising early results exceeding what would be expected from anti-PD-1/PD-L1 or VEGFR TKI monotherapy (Figure 2): 

  • Pembrolizumab plus axitinib showed encouraging anti-tumor activity with an objective response rate (ORR) of 73% in previously untreated mRCC patients.22
  • Avelumab plus axitinib showed an ORR of 58% in previously untreated mRCC patients.23
  • Pembrolizumab plus lenvatinib showed an ORR of 63% in mRCC patients, 60% of whom had received prior anticancer therapy.24 
  • Cabozantinib plus nivolumab with or without ipilimumab showed an ORR of 54% in previously treated mRCC patients.25<s/up>

Notably, combination thera- pies have also conferred additional toxicities. For example, development of immune checkpoint inhibitor combinations with pazopanib has been limited due to liver toxicity.26,27 Furthermore, grade 3 or worse treatment-related adverse events (AEs) occurred in 65% of patients treated with pembrolizumab plus axitinib,22 58% of patients receiving avelumab plus axitinib,23 70% of patients receiving pembrolizumab plus lenvatinib,24 and 62-71% of patients on cabozantinib plus nivolumab with or without ipilimumab in phase I testing.25 As we move forward into phase III evaluations of these combinations, confirmation of clinical efficacy as well as of safety and tolerability will be eagerly awaited. Here, I describe the five combination regimens currently in randomized phase III clinical trials.

Atezolizumab plus Bevacizumab
IMmotion151 (NCT02420821) is the first randomized phase III trial of a PD-1/PD-L1 pathway inhibitor combined with an anti-VEGF agent in mRCC.1 This trial randomized 915 treatment-naïve patients with predominantly clear cell or sarcomatoid histology advanced or mRCC to atezolizumab 1200 mg IV q3w + bevacizumab 15 mg/kg IV q3w or sunitinib 50 mg PO QD 4 weeks on/2 weeks off. Patients were stratified by PD-L1 status (<1% vs 1% or more expression on tumor-infiltrating immune cells) and prognostic risk groups. Co-primary endpoints included investigator-assessed PFS in PD-L1+ patients and overall survival (OS) in the intention-to-treat (ITT) population.

Results from the first interim analysis were presented at the 2018 Genitourinary Cancers Symposium. The study reached its co-primary endpoint of improved investigator-assessed PFS in the 362 patients with PD-L1+ disease who were treated with atezolizumab plus bevacizumab (HR 0.74, 95% CI 0.57-0.96; P = 0.02). Median PFS was 11.2 months in PD-L1+ patients treated with atezolizumab plus bevacizumab vs 7.7 months in patients treated with sunitinib. In addition, PFS in the ITT population, a secondary endpoint, was also improved with atezolizumab plus bevacizumab vs sunitinib (median 11.2 vs 8.4 months; HR 0.83, 95% CI 0.70-0.97). Of note, an independent radiology committee assessed-PFS was also obtained and differed from the investigator-assessed PFS in the PD-L1+ population (median 8.9 vs 7.2 months). ORRs were not significantly different between atezolizumab plus bevacizumab vs sunitinib in both the PD-L1+ (43% vs 35%) and ITT populations (37% vs 33%). However, complete responses (CRs) were move common with atezolizumab plus bevacizumab vs sunitinib in both the PD-L1+ (9% vs 4%) and ITT populations (5% vs 2%). At the first interim analysis, OS data was immature, but suggestive of an encouraging trend favoring atezolizumab plus bevacizumab in both the PD-L1+ (HR 0.81, 95% CI 0.63-1.03; P = 0.09) and ITT (HR 0.68, 95% CI 0.46-1.00) populations. Follow-up of OS results will likely be crucial in the regulatory review of this regimen.

Atezolizumab plus bevacizumab was relatively well-tolerated compared to sunitinib, with grade 3-4 treatment-related AEs occurring in 40% vs 54% of patients, respectively. The most common grade 3-4 treatment-related AEs with atezolizumab plus bevacizumab included hypertension, proteinuria, and asthenia. Corticosteroids were given to 16% of patients treated with atezolizumab plus bevacizumab within 30 days of an AE of special interest. Treatment-related AEs led to therapy discontinuation in 12% of patients receiving atezolizumab plus bevacizumab and 8% of patients receiving sunitinib. Finally, quality-of life evaluations demonstrated significantly prolonged time to symptom interference with activities of daily living in patients treated with atezolizumab plus bevacizumab as compared to those treated with sunitinib (HR 0.56, 95% CI 0.46-0.68). 

Interestingly, earlier evaluation of the combination of atezolizumab plus bevacizumab in a small number of mRCC patients demonstrated molecular and cellular changes consistent with the pre-clinical data that anti-angiogenic therapy modulates the anti-tumor immune response.28 Tumor and blood based analyses after a 2 to 3 week lead-in of bevacizumab monotherapy demonstrated decreases in vascular markers as well as increases in gene signatures associated with T-helper 1 chemokines involved in lymphocyte trafficking, tumor MHC-I protein expression, and infiltration of tumor-specific T-cell clones. The subsequent addition of atezolizumab to bevacizumab resulted in anti-tumor activity that was associated with further increases in intra-tumor CD8+ T cells and the number of unique T-cell clones within the tumor microenvironment. Furthermore, the randomized phase II IMmotion150 study (NCT01984242) identified gene signatures associated with T-effector and myeloid inflammatory responses in pre-treatment tumor samples to significantly predict for response to atezolizumab plus bevacizumab vs atezolizumab monotherapy vs sunitinib.29 The early studies on atezolizumab plus bevacizumab have provided thought-provoking insights into the pharmacodynamics of immune checkpoint and anti-angiogenic therapy that warrant further investigation.

Pembrolizumab plus Axitinib
While studies combining VEGFR-targeted TKIs with PD-1/PD-L1 checkpoint inhibitors have shown clinical activity in mRCC, some combinations have been limited by unacceptable toxicity, including severe liver function abnormalities and fatigue.26,27 Many of the toxicities are thought to be related to the augmentation of off-target effects of multi-targeted TKIs by immune checkpoint inhibitors. In response, one approach has been to use a more specific inhibitor of VEGFR that may be better tolerated in combination with an anti-PD-1 drug. This was the rationale underlying a phase Ib trial of axitinib—a potent, selective inhibitor of VEGFR 1-3—in combination with pembrolizumab in treatment-naïve patients (n=52) with advanced ccRCC.22

The combination of pembrolizumab plus axitinib demonstrated overall tolerability with fewer incidences of grade 3 or worse liver function abnormalities than was seen with prior combination studies with pazopanib or sunitinib. Dose-limiting toxicities were reported in 3 of 11 patients treated in the dose-finding phase of the study, and the maximum tolerated dose was determined to be pembrolizumab 2 mg/kg every 3 weeks and axitinib 5 mg twice daily. Grade 3 or higher treatment-related AEs were observed in 65% of patients, including hypertension, diarrhea, increased transaminases, hypothyroidism, and fatigue. 

Pembrolizumab plus axitinib demonstrated encouraging anti-tumor activity. The proportion of patients who achieved an objective response was 73% (95% CI 59-84%), including 8% with a CR and 65% with a partial response (PR) at a median follow-up of 20.4 months. An additional 15% of patients had stable disease, and more than 90% of patients experienced some degree of tumor shrinkage. The median PFS was 20.9 months. The anti-tumor activity seen in the phase Ib study was superior to that expected from axitinib or anti-PD-1 monotherapy. A randomized phase III trial (KEYNOTE-426; NCT02853331) comparing the combination of pembrolizumab plus axitinib vs sunitinib monotherapy in treatment-naïve mRCC patients is underway and has reached its enrollment goal. The co-primary endpoints are PFS and OS in the PD-L1 positive population.

Avelumab plus Axitinib
JAVELIN Renal 100 was a phase Ib trial investigating the combination of the anti-PD-L1 antibody avelumab with axitinib in treatment-naïve patients (n=55) with advanced ccRCC.23 Avelumab is a human IgG1 monoclonal antibody that not only targets the immune checkpoint protein PD-L1 but also mediates antibody-dependent cell-mediated cytotoxicity of cancer cells.30

The safety profile of avelumab plus axitinib was consistent with the known profiles of single-agent avelumab and axitinib. A dose-limiting toxicity of proteinuria was reported in 1 of 6 patients treated in the dose-finding phase. The maximum tolerated dose for the combination was determined to be avelumab 10 mg/kg every 2 weeks and axitinib 5 mg twice daily. Grade 3 or higher treatment-related AEs were reported in 58% of patients, most commonly hypertension, palmar-plantar erythrodysesthesia, and increases in transaminase, lipase, and amylase.

The combination of avelumab plus axitinib also dem-onstrated encouraging anti-tumor activity. Objective response was reported in 58% (95% CI 44-71%) of patients, including CR in 5% and PR in 53%. An additional 20% of patients experienced stable disease, resulting in a disease control rate of 78%. A majority of patients experienced early and durable responses. The anti-tumor activity of the combination in JAVELIN Renal 100 was superior to the expected activity of single-agent axitinib or anti-PD-L1 therapy. The randomized phase III trial JAVELIN Renal 101 (NCT02684006) is comparing avelumab plus axitinib against sunitinib monotherapy in treatment-naïve mRCC patients and has reached its accrual target. The co-primary endpoints are PFS and OS between the treatment arms. 

Pembrolizumab plus Lenvatinib
The combination of pembrolizumab plus the multikinase TKI lenvatinib was evaluated in a phase Ib/II study in patients with selected solid tumors. Updated preliminary results from the ccRCC cohort (n=30) were reported at the 2018 ASCO Annual Meeting.24 Unlike the phase Ib studies of pembrolizumab plus axitinib and avelumab plus axitinib in treatment-naïve patients, the early evaluation of pembrolizumab plus lenvatinib allowed for patients who previously received systemic therapies. Treatment-experienced patients accounted for 60% of the mRCC cohort. Pembrolizumab was administered at 200 mg every 3 weeks and lenvatinib administered at either 24 mg daily or 20 mg daily.

Grade 3 or higher AEs occurred in 73% of patients treated with the combination. The most common grade 3 or higher AEs included proteinuria, elevated lipase, hypertension, diarrhea, and fatigue. Dose adjustment or discontinuation due to AEs was common. Lenvatinib dose was reduced in 73% of patients, lenvatinib discontinuation in 20%, and pembrolizumab discontinuation in 27%.

The primary endpoint of ORR at 24 weeks was 63% (95% CI 44-80%) in the phase Ib/II study. Twenty-nine of the 30 patients experienced tumor shrinkage. Median PFS was 17.7 months. Anti-tumor activity appeared to be similar regardless of prior therapy or PD-L1 status. The phase III CLEAR trial (NCT02811861) is currently enrolling patients with treatment-naïve advanced ccRCC with randomization to pembrolizumab plus lenvatinib vs lenvatinib plus everolimus vs sunitinib. The dosing regimen of pembrolizumab 200 mg every 3 weeks and lenvatinib 20 mg daily was selected for the phase III study. The primary endpoint is to compare the PFS of pembrolizumab plus lenvatinib or lenvatinib plus everolimus vs sunitinib.

Nivolumab plus Cabozantinib
The combination of cabozantinib plus nivolumab with or without ipilimumab was evaluated in a phase I study that enrolled patients with a variety of metastatic genitourinary cancers.25 Preliminary results were presented at the 2018 Genitourinary Cancers Symposium. A total of 75 patients were enrolled, including 14 patients with previously treated mRCC. Seven RCC patients accrued to the nivolumab plus cabozantinib cohort and 7 RCC patients accrued to the nivolumab plus ipilimumab plus cabozantinib cohort. A total of 7 dose levels were included in the study. All 7 RCC patients in the nivolumab plus cabozantinib combination received nivolumab 3 mg/kg every 2 weeks plus cabozantinib 40 mg daily, which was ultimately determined to be the recommended phase II dose for the doublet combination. All 7 RCC patients in the triplet combination received nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab 3 mg/kg every 2 weeks, with 6 patients concurrently receiving cabozantinib 40 mg daily and 1 patient receiving cabozantinib 60 mg daily. 

Grade 3 or 4 AEs were reported in 57% of all patients receiving doublet therapy and in 72% of all patients receiving triplet therapy. Common grade 3 or 4 treatment-related AEs included diarrhea, hypertension, fatigue, hypophosphatemia, hyponatremia, hypokalemia, lymphopenia, neutropenia, and elevations in transaminases, lipase, and amylase. Immune-related AEs were relatively uncommon with either doublet or triplet therapy. 

At early follow-up (median 5.2 months), objective response was seen in 54% of patients in the RCC cohort. All responding patients experienced a PR. The remaining 46% of patients in the RCC cohort experienced stable disease. Patients with mRCC who experienced disease response appeared to have a prolonged duration of response, with median PFS estimated at 18.4 months (95% CI 6.4-18.4). The study investigators did not present data on RCC responses by doublet vs triplet therapy. The ongoing phase III CheckMate 9ER trial (NCT03141177) is comparing the combination of nivolumab plus cabozantinib vs sunitinib in treatment-naïve patients with advanced ccRCC. The primary endpoint is PFS of the treatment arms.

Combination Therapy vs Monotherapy: Is More Always Better?
The early data from combinations of immune checkpoint inhibitors plus anti-angiogenic therapies indicate that combination treatments may result in improved clinical efficacy as well as the potential for enhanced toxicities. Studies of immune checkpoint inhibitor monotherapy in advanced RCC and other tumors have demonstrated clinical activity in addition to a favorable toxicity profile.31-33 For example, preliminary results from the phase II KEYNOTE-427 study of first-line pembrolizumab mono-therapy in advanced ccRCC patients have shown an ORR of 38%, including 3% with CR and a majority of responding patients having ongoing responses at 12 months of follow-up. Long-term follow-up results from KEYNOTE-427 and data from the ongoing phase III combination studies in RCC may provide additional insights into the additive benefit anti-angiogenic agents to immune checkpoint inhibitor monotherapy. Survival data will be important in assessing the benefits of frontline combination therapy relative to sequential treatment with immune checkpoint inhibitors and VEGFR TKIs. It is possible that some patients may respond well to single-agent treatment and may be spared the additive toxicities of combination therapies, while other patients may require combination approaches to obtain clinical benefit. Biomarker analyses such as PD-L1 expression have been incorporated into all of the ongoing phase III studies. Further development of candidate predictive biomarkers such as angiogenesis- and immune-associated gene expression profiling29 and tumor mutational burden34 may provide guidance on optimizing treatment strategies for mRCC patients.

Combinations of immune checkpoint inhibitors plus anti-angiogenic therapies are advancing rapidly through clinical evaluation in mRCC, supported by preclinical data suggesting biological synergism and by the proven clinical efficacy of each therapeutic approach independently. Multiple early-phase clinical trials have demonstrated favorable anti-tumor activity and manageable safety profiles of combination therapies, and five large randomized phase III studies involving distinct treatment combinations are ongoing in treatment-naïve mRCC patients. The combination of atezolizumab plus bevacizumab has achieved one of its co-primary endpoints of improving PFS in patients with PD-L1+ tumors. With regulatory review of atezolizumab plus bevacizumab expected in the near future, results of survival data in follow-up will be key in further informing the role of this combination in the treatment of mRCC patients. Efficacy and safety results from four additional randomized phase III trials of VEGFR TKI plus anti-PD-1/PD-L1 therapy are also forthcoming. Ultimately, these studies have tremendous potential to transform the standard-of-care treatment for advanced RCC from one of sequential therapies to one of combination regimens that meaningfully improves the lives of kidney cancer patients.

Many thanks to David McDermott, MD for the helpful discussion and comments in the preparation of this manuscript.

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