ESMO 2019

Barcelona, Spain (UroToday.com) In this discussion of the CARD trial of cabazitaxel as third line therapy in metastatic castration-resistant prostate cancer (mCRPC), Silke Gillessen, MD, began by laying out the therapeutic landscape of mCRPC, using this imagery to highlight what happens after up-front anti-androgen therapy and docetaxel chemotherapy, because it is less clear what the third-line treatment of choice should be.

The CARD study answers this question, showing that the cabazitaxel as third-line therapy is superior with regards to radiographic progression free survival (PFS) in patients who relatively rapidly progress through first-line anti-androgen therapy. This supports the idea that patients who do not have extended responses to anti-androgen therapy need cytotoxic therapy rather than another anti-androgen agent.



Though many providers and patients may have chemophobia, toxicity in the cabazitaxel arm was not markedly worse than the control arm.

There are a few important points to note. Though the PROSELICA trial showed equivalency between 20 mg/m2 and 25 mg/m2 of cabazitaxel, the CARD protocol used the 25 mg/m2 dose and G-CSF prophylaxis, with only a few cases of febrile neutropenia. There is no indication that the US FDA approved dose would be any less effective as to third line therapy. Second, these data do not answer the question of appropriate third line therapy in patients who respond to anti-androgen therapy for longer than a year. Could these patients uniquely benefit from subsequent anti-androgen therapy? Third, could cabazitaxel be moved forward into the castration-sensitive stage based on this data, and would patient outcomes change if it was given prior to docetaxel?

While further study could help understand these lingering questions, Dr. Gillessen believes that this well designed clinical trial clearly identifies cabazitaxel as the third-line treatment of choice in patients who progressed on anti-androgen therapy within 12 months. In light of the PROfound data showing the efficacy of olaparib as a third line therapy in patients with selected DNA damage repair gene defects, further work and discussion is required to understand how to best approach third line therapy in chemofit patients who have these genetic defects and have progressed through anti-androgen therapy in less than 12 months. 

Presented by: Silke Gillessen, MD, senior consultant in the Medical Oncology-Hematology Department at the Kantonsspital St. Gallen, St Gallen, Switzerland and Co-founder of the Advanced Prostate Cancer Consensus Conference (APCCC), previously of the University of Manchester and the NHS Christie Trust, Manchester, United Kingdom

Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct 2019 in Barcelona, Spain

• If patients were eligible for cisplatin chemotherapy - gemcitabine/cisplatin (median overall survival (OS) 12-14 months)
• If patients were ineligible for cisplatin chemotherapy - gemcitabine/carboplatin (median OS 8-12 months)
• If the patients had platinum-refractory disease - taxane or vinflunine (median OS 6-8 months)

As of July 2018, the treatment algorithm is as follows:

• If patients were eligible for cisplatin chemotherapy - gemcitabine/cisplatin (median OS 8-12 months)
• If patients were ineligible for cisplatin chemotherapy, PD-L1 positive - atezolizumab (median OS 12.3 months¹) or pembrolizumab (median OS 18.5 months²)
• If patients were ineligible for cisplatin chemotherapy, PD-L1 negative - gemcitabine/carboplatin (median OS 8-12 months)

The IMvigor130 data showed us that the final progression-free survival (PFS) for atezolizumab + platinum chemotherapy/gemcitabine vs placebo + platinum chemotherapy/gemcitabine favored the atezolizumab combination arm (hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.70-0.96). However, Dr. Powles notes that currently this combination has not quite demonstrated an OS benefit (HR 0.83, 95% CI 0.69-1.00). Furthermore, looking at the subgroup analyses, atezolizumab + platinum chemotherapy/gemcitabine does not improve PFS in the PD-L1 negative patients: ICS0, HR 0.79, 95% CI 0.61-1.03; ICS2/3 HR 0.89, 95% CI 0.70-1.13.

So, do these results for combination therapy change the algorithm proposed above as of July 2018?

Arguments for:

• Significant delay in PFS
• OS trending the right way
• Complete response rate of 13% (vs 7%)
• No increase in adverse events for the combination therapy

Arguments against:

• PFS HR 0.82, 95% CI 0.70-0.96
• OS is not significant, yet
• Response rates of 47% (vs 44%)
• There is no quality of life/patient-reported outcomes data

In Dr. Powles' opinion, we probably need to wait for the overall survival data from the combination arm before changing the treatment paradigm. Do the results of the monotherapy arm change clinical practice? The OS data versus placebo + platinum chemotherapy/gemcitabine show an encouraging OS with a HR of 0.68 (95% CI 0.43-1.08). However, only 24% of the population was biomarker positive with a response rate of 23% vs 44%. Importantly, there is no subset analysis of the cisplatin population, so in Dr. Powles' opinion, the paradigm does not change yet. This strengthens the case for using atezolizumab in PD-L1 positive patients in platinum ineligible patients, but not in the cisplatin eligible patients yet.

Dr. Powles concluded this discussion of IMvigor130 with several summary statements:

• This is the first positive trial in this setting and underpins the activity of atezolizumab in urothelial carcinoma
• The combination arm is statistically significant but not yet clinically transformative without OS benefit
• The monotherapy arm is clinically meaningful but not statistically robust enough yet
• More detail on the trial design and subset populations is also needed
• This and other trials may be clinically transformative in the future

1. Balar, Arjun V., Matthew D. Galsky, Jonathan E. Rosenberg, Thomas Powles, Daniel P. Petrylak, Joaquim Bellmunt, Yohann Loriot et al. "Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial." The Lancet 389, no. 10064 (2017): 67-76.
2. Balar, Arjun V., Daniel Castellano, Peter H. O'Donnell, Petros Grivas, Jacqueline Vuky, Thomas Powles, Elizabeth R. Plimack et al. "First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study." The Lancet Oncology 18, no. 11 (2017): 1483-1492.

Barcelona, Spain (UroToday.com) At the 2019 European Society for Medical Oncology annual meeting (ESMO), experts gathered from urology, radiation oncology, and medical oncology to discuss the clinical management of pelvic node-positive (cN+) prostate cancer. Dr. Silke Gillessen, discussed the role of chemotherapy and androgen receptor targeted therapy (ARTT) in managing pelvic node-positive prostate cancer.

To summarize, Dr. Efstathiou notes that this is truly a practice-changing study. This is the first assay-specific study in advanced prostate cancer where a validated genomic tissue-based test successfully identified candidates for olaparib treatment. In patients with pretreated mCRPC and DNA damage repair alterations (mainly BRCA2), olaparib provided a statistically significant, clinically meaningful improvement with an acceptable safety profile. This signifies the initiation of the targeted therapy era and we should abandon sequential use of novel androgen signaling inhibitors.

Clinical Trial Information:
NCT02987543

Presented by: Eleni Efstathiou, MD, PhD, Associate Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct, 2019 in Barcelona, Spain 

Barcelona, Spain (UroToday.com) The randomized, phase 3 SPARTAN trial showed that apalutamide offered a metastasis-free survival (MFS) benefit over placebo for patients with non-metastatic (M0) castration-resistant prostate cancer (CRPC) with higher risk characteristics defined as PSA doubling time < or = 10 months prior to entry on the trial.¹  This led to regulatory approval for apalutamide for this patient population with unblinding of the trial by the Independent Data Monitoring Committee (IDMC).  Overall survival was a secondary endpoint, but was not statistically significant (HR 0.70, 95% CI: 0.47-1.04; p=0.07) at the initial interim analysis, with a median of 20.3 months followup, that required 104 (24%) overall survival events.  The O’Brien-Fleming-type alpha spending function would’ve required a p-value <0.000012 at that first interim analysis to reach statistical significance. 



At the 2019 European Society of Medical Oncology (ESMO) Congress, Dr. Matthew Smith presented the final MFS analysis and the second interim analysis for overall survival.  Not surprisingly, the MFS benefit was sustained.  However, this second interim analysis for overall survival with 285 (67%) overall survival events, with a median 41.0 months followup, also did not yet reach the O’Brien-Fleming boundary.  A p-value of <0.0121 would have been required.  Although a 25% reduction in the risk of death was noted with apalutamide, with HR 0.75 (95% CI, 0.59-0.96); p=0.0197, it was not able to meet the bar for statistical significance.  It is important to note that since the initial IDMC unblinding, 76 (~19%) of patients in the placebo arm have crossed over to receive apalutamide.  The 3^rd and final overall survival analysis will occur ~2022 at 427 (100%) of events.



There were multiple other updates presented that were consistent with the original findings.  For instance, the forest plots showed treatment effect of apalutamide to be consistent across all evaluated subgroups, with all subgroups falling to the left of the HR 1.0, although the 95% CI almost all crossed 1.0.  Time to initiation of chemotherapy was also superior with apalutamide HR 0.60 (95% CI, 0.45-0.80); however, there has not been formal statistical testing and that will not occur unless the overall survival results become statistically significant. 



The exploratory progression-free survival 2 (PFS2) analysis, where patients were followed from randomization beyond the initial progression on either apalutamide or placebo until the second progression, confirmed a HR 0.55 (95% CI, 0.45-0.68); p <0.0001.  This second progression most commonly occurred on abiraterone acetate.  Finally, the safety profile of apalutamide remained consistent with prior reports.



In summary, although the overall survival data is not statistically significant at this time, we need to continue to follow the patients on the trial.  Regardless of the ultimate results from the future final overall survival analysis, we need to consider that some patients in the placebo arm have crossed over to receive apalutamide, which has the potential to slightly damper the survival benefit from the therapeutic arm.  This data should not discourage us from continuing to treat patients with high risk M0 CRPC with apalutamide, given the confirmed MFS benefit from the primary endpoint analysis.

Presented by: Matthew R. Smith, MD, Ph.D., Director of the Genitourinary Oncology Program at Massachusetts General Hospital Cancer Center and an Associate Professor of Medicine at Harvard Medical School, Boston, Massachusetts, USA 

Written by: Evan Yu, MD, Professor, Department of Medical Oncology, University of Washington School of Medicine,  Member, Fred Hutchinson Cancer Research Center and Assistant Fellowship Director, Hematology and Oncology Fellowship Training Program, University of Washington and Fred Hutchinson Cancer Research Center at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct, 2019 in Barcelona, Spain 

References:
1. Smith MR et al. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. New England Journal of Medicine. 018; 378:1408-1418 DOI: 10.1056/NEJMoa1715546.

Barcelona, Spain (UroToday.com) Atezolizumab has received regulatory approval for patients with locally advanced or metastatic urothelial carcinoma.  This has occurred for both cisplatin-ineligible patients in the first-line setting and also for those in the post-platinum treated setting.^{1, 2}  In other malignancies, such as lung cancer, major advances have been made in treatment outcomes when cytotoxic chemotherapy has been combined with up front checkpoint inhibition with immune-oncology (IO) agents.  Hence, multiple efforts have been launched with combination chemotherapy and atezolizumab, an anti-PD-L1 antibody as well as pembrolizumab, an anti-PD-1 antibody, in the first-line metastatic urothelial carcinoma setting.

Barcelona, Spain (UroToday.com) Recently, we’ve seen some major advances for patients with locally advanced and metastatic urothelial carcinoma.  For instance, pembrolizumab, an anti-PD-1 antibody has received regulatory approval for both cisplatin ineligible patients in the first-line setting and also in the post-platinum treated population.^{1, 2}  Enfortumab vedotin is a novel antibody drug conjugate, targeting Nectin-4, with 44% overall response rates and 12% complete response rates in the patients previously treated with platinum chemotherapy and anti-PD-(L)1 therapy.³  The United States Food and Drug Administration will consider accelerated approval of enfortumab vedotin for this patient population.  Additionally, novel combinations of enfortumab vedotin with other active agents have ensued.

At the 2019 European Society of Medical Oncology (ESMO) Congress, the initial results from EV-103 trial was presented by Dr. Christopher Hoimes.  

Although the trial is designed with multiple cohorts with various combinations of enfortumab vedotin in first and second line, the ESMO presentation focused on Cohort A, which was comprised of first-line treated, cisplatin-ineligible patients with combination enfortumab vedotin with pembrolizumab.  Enfortumab vedotin was dosed at 1.25 mg/kg on days 1 and 8 of 3-week cycles while pembrolizumab was administered at 200 mg on day 1 of 3-week cycles.  A 5-patient dose escalation cohort led into an additional 40 patient expansion.  The primary endpoint of adverse events revealed 7 (16%) patients with treatment-related serious adverse events.  There were 4 (9%) patients who discontinued study treatment due to adverse events, with peripheral neuropathy being the cause for 2 of those patients.  Peripheral neuropathy occurred in 22 (49%) patients with 2 (4%) having a grade 3 or greater event.  Rash occurred in 21 (47%) patients with 5 (11%) have a grade 3 or greater event.  There was 1 treatment-related death due to multiorgan dysfunction.


Most impressive was the fact that 32 (71%) patients have a confirmed objective response rate, and 6 (13%) experienced a complete response.  Responses occurred in PD-L1 high and low patients defined with the cutoff of CPS of 10 as the delineating factor.  All but 3 patients on trial had some degree of tumor shrinkage, translating into 93% of patients with some level of tumor reduction on trial.  Responses were rapid and durable, with 91% of responses occurring at the first assessment at 9 weeks.


In summary, Enfortumab vedotin with pembrolizumab has significant antitumor activity in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma with an acceptable safety profile.  Further exploration of this synergistic-appearing combination should be considered not only in the advanced disease setting but also in earlier disease states where the potential for improving upon curative treatment outcomes should not be ignored.

Presented by: Christopher J. Hoimes, DO,  Assistant Professor, Department of Medicine Division of Hematology and Oncology, School of Medicine Member, GU Malignancies Program, Case Comprehensive Cancer Center, Case Western Reserve University/University Hospitals, Cleveland, Ohio

Written by: Evan Yu, MD Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine  at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct 2019 in Barcelona, Spain

References

1. Bellmunt J et al.  Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017; 376:1015-26.
2. Balar AV et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol 2017; 18:1483-92.
3. Rosenberg JE et al. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol 2019:JCO1901140 [Epub ahead of print].

Barcelona, Spain (UroToday.com) Dr. Christian Kollmannsberger from the British Columbia Cancer Agency discussed three abstracts at the ESMO 2019 poster discussion: 913PD - APACHE: an open label, randomized, phase 2 study of Durvalumab, alone or in combination with Tremelimumab, in patients with refractory germ cell tumors: results from the expanded combination therapy cohort, 914PD - Prognostic factors in metastatic seminomatous germ cell tumors and elevated HCG – a study of the G3; 915PD - Diagnosis, Management, and Burden of Renal Cell Carcinomas: Results from a Global Patient Survey in 43 countries.

Barcelona, Spain (UroToday.com) Seminomas do not express specific tumor markers, but in ∼20% of patients, serum HCG levels are elevated. The prognostic role of different marker levels at first diagnosis has not been thoroughly assessed. The objective of the current study was to assess prognostic factors in HCG positive seminoma patients. A presentation from Dr. Christoph Seidel and colleagues at the 2019 European Society for Medical Oncology annual meeting, (ESMO).

Barcelona, Spain (UroToday.com) At the 2019 European Society for Medical Oncology annual meeting (ESMO), experts gathered from urology, radiation oncology, and medical oncology to discuss the clinical management of pelvic node-positive (cN+) prostate cancer. Dr. Gert De Meerleer, discussed the role for radiotherapy (RT) in managing pelvic node-positive prostate cancer.

Barcelona, Spain (UroToday.com) At the ESMO Congress 2019 meeting, experts gathered from urology, radiation oncology, and medical oncology to discuss clinical management of pelvic node-positive (cN+) prostate cancer. Dr. Alberto Briganti, discussed the role for radical surgery in managing pelvic node-positive prostate cancer.

Barcelona, Spain (UroToday.com) Inhibition of angiogenesis using either tyrosine kinase inhibitors against the VEGF receptor (e.g. pazopanib, axitinib, cabozantinib) or antibodies against circulating VEGF (e.g. bevacizumab) have been effective therapies in advanced renal cell carcinoma. Preclinical data has previously implicated endoglin, a receptor on the surface of endothelial cells, as a resistance mechanism for VEGF/VEGFR targeted therapy. Targeting endoglin with the monoclonal antibody TRC105 has been shown to potentiate VEGF/VEGFR inhibition in preclinical models. A phase 1b dose-escalation trial¹ of TRC105 recently showed a 29% partial-response rate in heavily pre-treated metastatic renal cell carcinoma (mRCC) patients.

In this poster, Dr. Toni Choueiri and colleagues present data from the phase II TRAXAR study (NCT01806064) that randomized mRCC patients who had progressed after at least 1 VEGF inhibitor in a 1:1 fashion to receive either axitinib 5 mg BID or axitinib plus TRC105 10 mg/kg weekly. The primary endpoint of this study was progression-free survival by RECIST criteria, and secondary endpoints were overall response rate and safety.

Patients were well-balanced between the cohorts. Approximately 90% of patients had undergone prior nephrectomy, ~10% had received prior immunotherapy, and ~60% had received just one prior cancer therapy.

Regarding the primary endpoint, treatment with axitinib plus TRC105 did not provide any benefit for progression-free survival relative to axitinib monotherapy (HR 1.42, 95% CI: 0.88-2.30, P = 0.15). There was no benefit for combination therapy with regards to overall response rate.
Subgroup analysis by clinical parameters did not reveal any particular patient group that uniquely benefitted from the addition of endoglin inhibition.
Combination therapy was tolerated relative to axitinib, with 20% of patients in the combination arm discontinuing therapy due to treatment-related adverse effects, and 13% of axitinib patients discontinuing therapy for the same reason. Side effects were more frequent with TRC105 + axitinib therapy, most notably with regards to grade 3 anemia and diarrhea. Therapy was on target, as all patients receiving TRC105 developed symptoms of Osler-Weber-Rendu syndrome.

In summary, the combination of the endoglin-targeting agent TRC105 in combination with axitinib did not improve mRCC progression-free survival in this randomized phase 2 study. In the setting of prior data showing no improvement in patient outcomes with TRC105 plus bevacizumab and a hazard ratio in this study favoring axitinib monotherapy, further work is required to understand if endoglin remains a targetable resistance mechanism to VEGF/VEGFR therapy in mRCC.

Presented by: Toni Choueiri, MD, Professor of Medicine and Director of Genitourinary Oncology at the Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA

Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct 2019 in Barcelona, Spain 

Barcelona, Spain (UroToday.com) Interim results from APACHE have been published, with the monotherapy (durvalumab) arm stopped for futility among patients with refractory germ cell tumors¹. The evidence from the durvalumab monotherapy arm were even more negative than that reported for monotherapy pembrolizumab amongst similar patients². At the European Society of Medical Oncology (ESMO) 2019 Annual Congress, Dr. Fare and colleagues presented updated results of APACHE with the expanded combination therapy cohort.

Barcelona, Spain (UroToday.com) Given that targeted therapies and immunotherapy have different mechanisms of action, it is reasonable to consider that the combination of targeted therapy with immunotherapy would achieve superior clinical outcomes relative to either modality alone. At a special symposium of the immune-oncology landscape for first-line treatment of metastatic urothelial cancer, Dr. Yohann Loriot summarized the available data on combinations of immunotherapy with molecular targeted therapy.

There are data to suggest that targeted therapy may induce immunogenic cell death, leading to upregulation of MHC class I, increased antigen presentation and T lymphocyte proliferation, as well as a compensatory increase in PD-L1 expression. These changes within the tumor microenvironment may suggest an induced susceptibility to checkpoint blockade immunotherapy.

Dr. Loriot moved on to highlight ways in which targeted therapies are known to leverage the native antineoplastic immune response. Just as cytotoxic chemotherapy and radiation are able to induce immunogenic cell death, so too are molecularly targeted therapies. Specifically, targeted therapy has been shown to alter the immune landscape of the microenvironment so as to increase the frequency of CD8+ T lymphocytes and decrease the frequency of myeloid-derived suppressor cells and regulatory T cells.

Dr. Loriot used available data from BRAF and MEK inhibition in melanoma to identify mechanisms by which targeted therapy alters the composition of the tumor microenvironment in such a way as to prime the tumor for an immune response. Data suggest that BRAF monotherapy is associated with an increase in antigen expression and CD8+ T cell infiltration. However, MEK inhibition has been associated with impairment of the antineoplastic T cell response, and triplet combinations with BRAF and MEK inhibition plus an immune checkpoint inhibitor have been plagued by high rates of toxicity. Fortunately, more recent data on the combination of vemurafenib plus cobimetinib with the PD-L1 antibody atezolizumab was able to mitigate much of this toxicity while preserving efficacy primarily by administering these agents in sequence rather than concomitantly.

Dr. Loriot then moved on to discuss immune-oncology combinations specific to metastatic urothelial cancer. Given the luminal-papillary molecular subtype which is enriched for FGFR3 alterations and exhibits an immunologically “cold” phenotype, there is much interest in combining FGFR blocking agents with immune checkpoint inhibition. FIERCE-22 is a phase I/II study of the FGFR3 antibody vofatamab in combination with the PD-1 antibody pembrolizumab in unselected patients with platinum-refractory metastatic urothelial cancer. The combination achieved a 36% objective response rate, and interestingly, among 7 patients harboring FGFR3 mutations or fusions, 3 (43%) had an objective response.

Furthermore, on-treatment biopsies from FIERCE-22 demonstrated that vofatamab was capable of inducing an immune gene expression signature, lending support to the underlying biologic rationale.

Given the recent accelerated FDA approval of the pan-FGFR inhibitor erdafitinib, a number of trials are underway to investigate the safety and efficacy of combining erdafitinib and other FGFR antibodies with immunotherapy. Specifically, NORSE is a phase Ib/II study of FGFR2/3 altered cisplatin-ineligible metastatic urothelial cancer investigating erdafitinib with or without the PD-1 antibody cetrelimab.

Still, other trials are exploring the combination of antiangiogenic agents, PARP inhibitors, and HER2 directed therapy with checkpoint blockade.

In conclusion, a number of novel immune-oncology combinations are exploring the efficacy of various targeted therapies and checkpoint blockade immunotherapy in metastatic urothelial carcinoma. Future work will focus on identifying the most effective targeted agents to combine with immunotherapy and defining the optimal sequencing of therapies to augment the immune response and mitigate toxicity associated with combination regimens.

Presented by: Yohann Loriot, MD, PhD, Medical Oncologist, Gustave Roussy Institute, Villejuif, France

Written by: Michael Lattanzi, MD, Medical Oncology Fellow, Memorial Sloan Kettering Cancer Center, Twitter: @MikeLattanzi at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct 2019 in Barcelona, Spain 

Barcelona, Spain (UroToday.com)  Dr. Viktor Grunwald provided a discussion of two abstracts at the ESMO 2019 annual congress poster discussion: 911PD - A First-in-Human Phase 1/2 Trial of the Oral HIF-2a Inhibitor PT2977 in Patients with Advanced Renal Cell Carcinoma (RCC), and 912PD - Results of the Phase 2 TRAXAR Study: A Randomized Phase 2 Trial of Axitinib and TRC105 versus Axitinib Alone in Patients with Advanced or metastatic (mRCC). Dr. Grunwald notes that dysregulation of the VHL-HIF axis is the basis of the anti-VEGF treatment paradigm in mRCC. So, is there a role for selective HIF inhibition in mRCC? It is important to note that there are different HIF subtype inhibitors available: HIF-1beta and HIF-2alpha. PT2385 is a HIF-2alpha inhibitor, but faced variable and unpredictable metabolism. Thus, PT2977 was developed and optimized the pharmacokinetics and is used for further clinical development.

Barcelona, Spain (UroToday.com) Sarcomatoid differentiation can occur in all subtypes of renal cell carcinoma (RCC) and is associated with an aggressive phenotype. Sarcomatoid RCC (sRCC) is characterized by immunologic infiltration and has with higher PD-1/PD-L1 on tumor cells and tumor-infiltrating immune cells. JAVELIN Renal 101 demonstrated a significant improvement in progression-free survival (PFS) with avelumab plus axitinib (A + Ax) versus sunitinib (median PFS 13.8 vs 8.4 months, HR 0.69, p < 0.001) in patients with previously untreated clear cell mRCC.¹ This abstract reports the efficacy and biomarker results from a post-hoc analysis of patients enrolled in JAVELIN Renal 101 who had sarcomatoid features in their tumor histology.

The study design is shown below. Eligible patients had treatment-naïve unresectable metastatic RCC (mRCC) with measurable disease. All Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic RCC Database Consortium (IMDC) risk groups were eligible. Patients were randomized 1:1 to A + Ax versus sunitinib and stratified by ECOG performance status and geographic region. Co-primary endpoints were progression-free survival (PFS) and overall survival (OS) in the PD-L1 positive cohort. PFS and OS in the overall cohort was a key secondary endpoint.

Of 886 patients with mRCC enrolled in JAVELIN Renal 101, 108 (12.2%) had sarcomatoid components and/or features in their pathology report, 47 in the A + Ax arm and 61 in the sunitinib arm. Baseline characteristics in this subgroup were well-balanced between treatment arms and consistent with the overall trial population. The only notable difference between the two treatment groups in the sRCC population is that the PD-L1 positive status was significantly lower in patients who received A + Ax (72.3%) versus sunitinib (85.2%).

Patients with sRCC had an improved PFS of 7.0 months in the A + Ax arm compared to 4.0 months in the sunitinib arm (stratified HR 0.57, 0.325-1.003).

The 12-month OS rate was 83.0% with the combination and 67.0% with sunitinib. The confirmed objective response rate was higher in the A + Ax arm (46.8%) than the sunitinib arm (21.3%). Further, patients in the combination arm had 2.4 months longer median duration of response than those in the sunitinib arm.

The investigators reported results of multiple biomarker analyses, which revealed that sRCC tumors had an immunosuppressive tumor microenvironment and higher CD274 and CD8A gene expression. Further, they discovered that approximately 50% of sRCC patients in this cohort had m3 tumors based on the subtype-specific mRNA signatures from molecular analysis of clear cell RCC tumors by the TCGA;² m3 is the molecular subset of RCC tumors associated with the poorest survival. Similar to results from the overall population, patients with sRCC who had m3 tumors that were also CD8- or CD8A-positive had longer median PFS with A + Ax (6.2 and 8.3 months) than sunitinib (2.9 and 2.8 months). These characteristics may help explain the poorer prognosis of sRCC patients when treated with VEGF inhibitor alone, but comparable response to the overall cohort when treated with A + Ax.

In conclusion, this study found that patients with sRCC who received A + Ax had PFS and ORR benefit over sunitinib, consistent with the results in the overall trial population. This analysis provides insight into the biology of an aggressive subtype of RCC and suggests a potential new treatment option.

Presented by: Toni K. Choueiri, MD, Director of the Lank Center for Genitourinary Oncology, Director of the Kidney Cancer Center, the Dana-Farber Cancer Institute, Jerome and Nancy Kohlberg Chair, Professor of Medicine, Harvard Medical School, Boston, Massachusetts

Written by: Jacob Berchuck, MD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, Twitter: @jberchuck at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct, 2019 in Barcelona, Spain 

References:

1. Motzer, Robert J., Konstantin Penkov, John Haanen, Brian Rini, Laurence Albiges, Matthew T. Campbell, Balaji Venugopal et al. "Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma." New England Journal of Medicine 380, no. 12 (2019): 1103-1115.
2. Cancer Genome Atlas Research Network. "Comprehensive molecular characterization of clear cell renal cell carcinoma." Nature 499, no. 7456 (2013): 43.