ESMO 2018, IKCS Offer Report Cards on New Hypotheses, Real-World Data in RCC

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ESMO 2018, IKCS Offer Report Cards on New Hypotheses, Real-World Data in RCC

Eric Jonasch, MD Professor
Department of Genitourinary
Medical Oncology
Division of Cancer Medicine
Co-Chair, Renal Cancer Program
MD Anderson Cancer Center
of the University of Texas
Houston, Texas

Two international conferences within the last three months provided a framework to gain new insights on late-breaking clinical data from pivotal trials and to explore hypothesis-generating results on a broad spectrum of potentially transformational work. This report focuses on selected presentations at the European Society for Medical Oncology (ESMO) 2018 Congress held in Munich and the International Kidney Cancer Symposium held in Miami.

ESMO 2018
ESMO 2018 provided a multi-professional platform for oncology education and exchange, and offered immense international visibility for scientific research. This year the Congress also featured a dedicated nursing track through a collaboration with the European Oncology Nursing Society (EONS). ESMO invited a universe of oncology stakeholders: researchers, clinicians, cancer nurses, industry partners, patient advocates and members of the press to join for discussions on securing better patient outcomes through access to high-quality care. In all, more than 1,000 attended this major international meeting.

From posters, abstracts, and presentations, these highlights at ESMO gave attendees a renewed focus on trends from closely watched trials and new data likely to be covered at upcoming international meetings of the American Society of Clinical Oncology (ASCO), including the GU ASCO sessions in San Francisco in February and the main ASCO event in Chicago next June. Among selected presentations, the following abstracts and/or posters suggest several avenues likely to be front and center during 2019.

Highly Selective Inhibitor Aimed at Upstream Target in VHL-Related Disease: An open-label phase 2 study to evaluate PT2977 for the treatment of von Hippel-Lindau disease associated renal cell carcinoma.

Hypoxia inducible factor (HIF-2) has been established as an oncogenic driver in clear cell renal cell carcinoma (ccRCC) RCC, where VHL deficiency is the underlying genomic alteration. In this setting of VHL gene inac-tivation, HIF-2 accumulates under normoxic conditions, driving the expression of genes associated with progression of ccRCC, including vascular endothelial growth factor A (VEGFA), cyclin D1 and other factors that contribute to tumor growth and proliferation. A phase 2 trial is accruing VHL patients over the next year and was described during a poster session.

The open-label Phase 2 study will evaluate the efficacy and safety of PT2977, a highly selective small molecule inhibitor of HIF-2, in patients with VHL disease who have at least one measurable ccRCC (as defined by RECIST 1.1). PT2977 will be administered orally at a dosage of 120 mg once daily. Key inclusion criteria include a germline VHL alteration and at least 1 measurable solid ccRCC but no tumor >3.0 cm that requires immediate surgical intervention. Patients may have VHL disease-associated tumors in other organ systems. Key exclusion criteria include prior systemic therapy for VHL disease, an immediate need for surgical intervention, evidence of metastatic disease, and history of a non-VHL disease-associated invasive malignancy in the past 2 years. The primary efficacy endpoint is objective response rate (ORR) of ccRCC tumors per RECIST 1.1. Secondary efficacy endpoints include duration of response (DOR), time to response (TTR), progression-free survival (PFS), and time to surgery (TTS) for ccRCC tumors as well as efficacy evaluations for non-ccRCC VHL disease-associated tumors. Safety/tolerability and pharmacokinetics of PT2977 in this trial will also be evaluated. Patient recruitment is ongoing.

The trial will seek an answer to whether this up-stream target can be inhibited since HIF-2a is a driver of VEGF. If it can be blocked by using the molecule, perhaps it could reduce the growth of lesions in various manifestations which include eye, kidney, pancreas, brain, and adrenal areas. The phase 1 trial generated excitement because activity was observed in RCC and PT2977 could produce a response in other VHL manifestations. The clinical trial identifier is NCT03401788; EudraCT: 2018-000125-30.

PRINCIPAL Study: Real-World Study Captures Treatment Patterns, Outcomes and Generates Hypotheses
Stratification by prognostic risk informs efficacy for various treatments in patients with advanced RCC. Whether further stratification beyond prognostic risk aids in predicting treatment outcomes is unknown. A post-hoc analysis of real-world data, the PRINCIPAL study (NCT01649778) assessed the effectiveness of pazopanib in patients with intermediate risk in advanced RCC.

In this prospective, observational study, patients with advanced and/or metastatic clear cell RCC were enrolled within 30 days of initiating pazopanib. Data on progression, survival, and safety were collected approximately every 3 months until death. Primary efficacy end points included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). A post-hoc analysis of patients with intermediate risk per Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria was conducted to evaluate effectiveness by number or risk factors (1 vs 2), age (<65 vs ≥ 65 years), and Eastern Cooperative Oncology Group performance status (ECOG PS).

Of the 657 enrolled pts who received ≥1 dose of pazopanib, 363 (55.3%) and 343 (52.2%) had inter-mediate risk per MSKCC and IMDC criteria, respectively. Within the subgroup of patients with intermediate risk MSKCC and IMDC, median PFS and OS was longer in those with 1 vs 2 risk factors, and outcomes were poorer in patients with ECOG PS ≥ 2 (vs < 2) (Table).

The results of the PRINCIPAL study suggest that patients with advanced RCC of intermediate prognostic risk can be further stratified to predict treatment out-comes. This is a hypothesis-generating study and asks whether, in the intermediate risk group, there was a difference in outcomes depending on the number of risk factors—1 or 2. It raises the interesting question that we are struggling with in a timely manner in the immune-oncology era. It is a question of whether or not the intermediate 1 or 2 should be considered as distinct groups. Evidence now supports the use of ipili-mumab-nivolumab in inter-mediate to poor risk patients. But should all patients with intermediate risk undergo such treatment or should some be considered for TKIs? Currently there is no answer to that, but this study raises the idea that all intermediate risk patients should not be considered equivalent.

JAVELIN Renal 101: VEGF Inhibitor + Immunotherapy—Additive or Synergistic?
The premise of combining VEGF inhibitors with immunotherapy stems from the possibility of having not just additive, but synergistic effects with the combination. In particular, VEGF-directed agents are thought to have some immune-related properties: increasing immune cell tumor infiltration and decreasing immune suppressor cells. The JAVELIN Renal 101 trial is important because it addresses this issue, and some observers, including Sumanta Kumar Pal, MD, in his online commentary after the meeting, suggest that it could be the “trial of the year.”

In the JAVELIN 101 clinical trial, patients with treatment-naïve advanced RCC with tumor tissue available for PD-L1 assessment were randomized to the combination of axitinib and avelumab or sunitinib at a dose of 50 mg, 4 weeks on, 2 weeks off. This study had two primary endpoints, including progression-free survival (PFS) by independent review committee in patients with PD-L1–positive disease and overall survival (OS) in the PD-L1–positive group. Key secondary endpoints included PFS in the overall population by independent review as well as OS. The study ultimately enrolled and randomized 886 patients. About 63% of patients were characterized as being PD-L1–positive. The median age and other characteristics were representative of a renal cell carcinoma population, with about 20% of patients considered favorable risk and the remainder considered to be intermediate or poor risk. This was similar in both the PD-L1–positive and overall patient populations. Roughly 80% to 90% of patients had undergone prior nephrectomy.

With respect to the primary endpoint of this study, PFS improvement with axitinib and avelumab was achieved, with a PFS of 13.8 months in the PD-L1–positive group versus just 7.2 months with sunitinib therapy, with a hazard ratio of 0.61 (95% CI). In the overall population, a slightly smaller benefit was observed in PFS, with axitinib and avelumab achieving 13.8 months versus 8.4 months with sunitinib with a hazard ratio of 0.69 (95% CI). There was little discrepancy between this and investigator assessment of PFS. Response rates were higher with the combination of axitinib with avelumab, ranging between 50% and 55% depending on PD-L1 status. This nearly doubled the response rate observed with sunitinib therapy.

One of the biggest questions and challenges that emerge is related to OS. At the time of this interim analysis, without sufficient events for final assessment, there was no significant difference in OS. This lack of maturity in OS data is one of the conundrums associated with the study. To be considered as a more compelling study, JAVELIN 101 needs to (1) demonstrate positive OS data, and (2) demonstrate that there is a higher rate of durable, complete responses. Still to be addressed is the provocative question of whether adding an anti-angiogenic agent to an IO agent is additive or synergistic.

IMotion 151 Confirms Different Gene Expression Profiles for Atezolizumab + Bevacizumab vs Sunitinib
The IMmotion151 (NCT02420821) phase 3 study previously demonstrated improved PFS with combined atezolizumab/ bevacizumab vs sunitinib in treatment-naive patients with metastatic renal cell carcinoma (mRCC). The presentation at ESMO correlated molecular gene expression signatures with clinical outcomes, prog-nostic risk groups, and tumor histology, extending data from the IMotion150 study.

The investigators, led by Brian Rini, MD, noted that biomarker analyses performed in a phase 2 study (IMmotion150) suggested that T effector (Teff) and interferon gamma, as well as angiogenesis gene expression signatures (GEs) were associated with differential out-comes to atezolizumab plus bevacizumab and sunitinib. They subsequently conducted prespecified genomic analyses to validate these GEs with clinical outcomes from 823 patients in IMmotion151 and also evaluated association of GEs with Memorial Sloan Kettering Cancer Centre (MSKCC) risk groups, and sarcomatoid histology.

The IMmotion151 study met its co-primary endpoint of improved PFS with atezolizumab plus bevacizumab over sunitinib in PD-L1-positive patients across all MSKCC risk groups, hazard ratio (HR) 0.74; 95% confidence interval (CI), 0.57 – 0.96 (P = 0.02). Improved PFS was also observed in patients with sarcomatoid histology, HR 0.56; 95% CI, 0.38 – 0.83. Tumor molecular analyses showed that high Teff GE was associated with PD-L1 expression, as evaluated by immunohistochemistry. High Teff GE also associated with longer PFS for atezo-lizumab plus bevacizumab compared to sunitinib, HR 0.76; 95% CI, 0.59 – 0.99.

In patients receiving sunitinib, high angiogenesis GE was associated with improved PFS, HR 0.59, 95% CI, 0.47 – 0.75; however high angiogenesis GE did not differentiate between atezolizumab plus bevacizumab versus suniti- nib clinical activity, HR, 0.95; 95% CI, 0.75 – 1.19. Atezolizumab plus bevacizumab improved PFS vs suni-tinib in the subset of patients with low angiogenesis GE, HR 0.68; 95% CI, 0.52 – 0.89. Angiogenesis GE was found to be higher in favorable versus intermediate-to-poor MSKCC risk groups (P = 4.28e-06).

Prospective evaluation of biomarkers in IMmotion 151 added further evidence molecular signatures that could identify subpopulations of patients more likely to benefit from ther combination immunotherapy plus antiangiogenic therapy versus antiangiogenic monotherapy. These data also demonstrated that sarcomatoid histology is possesses an immune signature that signals a unique sensitivity to immunotherapy. Aside from providing further confirmation of the IMotion150 data, this study is one of the first steps toward resolving an unmet need: development of predictive biomarkers based on an understanding of tumor biology. Ultimately it can inform clinicians as to which treatment should be used for which patient and at what time.

Future Directions
Ironclad evidence is still lacking that the IO-TKI com-bination is the new standard of care. Information from Merck indicates that the combination of pembrolizumab and axitinib met its primary endpoint of OS as well as PFS. Perhaps that could serve as an example of an IO-TKI combination that will soon gain ascendancy. The next 12 months will help determine how various data sets evolve and hopefully will provide a clear signal on how to change the treatment algorithm. This remains one of the overarching challenges as the next round of international meetings present data with which to revisit this issue. KCJ