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.
As presented by Jonasch and colleagues, PT2977 has clinical activity in previously treated patients with mRCC. Among patients with a median three prior treatments, the median PFS was 11 months (95% CI 7-17 months). Dr. Grunwald highlights that PT2977 stands up well to other trials (METEOR – cabozantinib;1 lenvatinib + everolimus)2 in this disease space of previously treated mRCC with regards to:
- ORR: 24% vs 24% (METEOR) vs 30% (lenvatinib + everolimus)
- Partial response: 24% vs 24% (METEOR) vs 28% (lenvatinib + everolimus)
- Stable disease: 56% vs 63% (METEOR) vs 39% (lenvatinib + everolimus)
- Progressive disease: 16% vs 9% (METEOR) vs 14% (lenvatinib + everolimus)
However, he does note that the median time to response for PT2977 was 6.0 months, compared to 1.9 months for cabozantinib in METEOR. Because of the mechanism of action (HIF inhibitor) we are seeing some different adverse events compared to TKIs: anemia (26% grade 3) and hypoxia (15% grade 3), but essentially no peripheral edema (0% grade 3) and much less diarrhea (22% grade 1/2) compared to cabozantinib (75%) and lenvatinib + everolimus (85%).
Dr. Grunwald’s conclusions from the PT2977 study are as follows:
- This treatment has interesting activity in later lines of therapy
- PT2977 exerts a favorable toxicity profile, with a low incidence of characteristic TKI-related adverse events, such as diarrhea, hand-food-syndrome, and stomatitis
- There is a phase III trial in development
The phase II TRAXAR study assessed TRC105 (a chimeric antibody targeting endoglin) + axitinib. Unfortunately, TRC105 + axitinib failed to improve efficacy with a PFS HR of 1.41 (95% CI 0.95-2.10; p-value 0.09). Furthermore, subgroup analyses failed to identify any particular subgroup that benefited from the combination treatment. Dr. Grunwald notes that a hazard ratio of 1.41 demonstrates that TRC105 may have an adverse effect on progression. As he points out, optimization of anti-angiogenic therapy is prone to failure, as three previous negative trials of different combinations in mRCC delineate: dalantercept (ALK1i) + axitinib, CRLX101 + bevacizumab, and AMG386 (Ang2i) + axitinib.
Dr. Grunwald’s conclusions based on the TRAXAR trial are as follows:
- The dual anti-angiogenic strategy of TRC105 + axitinib failed to improve efficacy
- On the contrary, it may expose patients to risk of disease progression
- The results are in line with previous attempts to broaden anti-angiogenic therapy
- However, TRC105 may serve as a partner for combinations with distinct classes of agents
- Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015;373(19):1814-1823.
- Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: A randomized, phase 2, open-label, multi-centre trial. Lancet Oncol 2015;16(15):1473-1482.
Presented by: Viktor Grunwald, MD, University Hospital Essen Westdeutsches Tumorzentrum, Essen, Germany
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