Dr Pal on the Preliminary Efficacy of DFF332 in Advanced ccRCC

Sumanta Kumar Pal, MD, FASCO, chair, Kidney and Bladder Cancer Disease Team; co-director, Kidney Cancer Program; professor, vice chair, Academic Affairs, Department of Medical Oncology & Therapeutics Research, City of Hope, discusses preliminary findings from a phase 1 dose-escalation study (NCT04895748) evaluating the pharmacokinetics and clinical activity of DFF332 in patients with advanced clear cell renal cell carcinoma (ccRCC).

DFF332 is similar to agents such as belzutifan (Welireg) in that it is a HIF2a inhibitor, Pal says. In the phase 1 trial, this agent was administered orally either daily or weekly as part of a dose-escalation design in a relatively large cohort of 40 patients with metastatic ccRCC, Pal notes.

Preliminary results from the dose-escalation portion of the study revealed that patients who received DFF332 did not experience severe levels of hypoxia or anemia, which makes the safety profile of DFF332 relatively unique, Pal explains. Among the entire patient population, 62.5% of patients experienced at least 1 adverse effect (AE). The most common AEs observed in this population include anemia (12.5%), hypercholesterolemia (12.5%), fatigue (12.5%), increased alanine transaminase (10.0%), hypertriglyceridemia (10.0%), increased aspartate aminotransferase (7.5%), dizziness (7.5%), dyspnea (5.0%), hypertension (5.0%), increased lipase (5.0%), nausea (5.0%), and peripheral edema (5.0%).

Notably, the responses observed with the agent were not comparable to those historically seen with belzutifan in patients with ccRCC, Pal emphasizes, noting that this discrepancy may have been due to the heavily pretreated nature of the patients from the phase 1 trial. DFF332 elicited a 52.5% disease control rate, with best responses of partial response and stable disease in 5% and 47.5% of patients, respectively. The best percentage of change in tumor size from baseline per RECIST criteria was 87.5%. Furthermore, at the data cutoff, treatment was ongoing on 27.5% of patients. The median duration of treatment exposure was 17.9 weeks (range, 1.0-75.6).

Going forward, DFF332 may be investigated in combination with immune checkpoint inhibitors or other targeted agents, Pal concludes.

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Sumanta Kumar Pal, MD, FASCO, discusses preliminary findings from a phase 1 dose-escalation study of DFF332 in patients with advanced ccRCC.

Sumanta Kumar Pal, MD, FASCO, discusses key biomarker analyses in renal cell carcinoma that will be presented at the 2024 ASCO Annual Meeting.

Dr Pal Previews ASCO 2024 Data in RCC

Sumanta Kumar Pal, MD, FASCO, chair, Kidney and Bladder Cancer Disease Team, co-director, Kidney Cancer Program, professor, Department of Medical Oncology and Therapeutics Research, City of Hope, discusses key biomarker analyses in renal cell carcinoma (RCC) that will be presented at the 2024 ASCO Annual Meeting, as well as highlights the value of the meeting for oncologists.

Among these highly-anticipated biomarker studies is an analysis of the phase 3 CLEAR trial (NCT02811861) which will present data on lenvatinib (Lenvima) and pembrolizumab (Keytruda) in patients withadvanced RCC, Pal reports. Additionally, biomarker data from the phase 3 KEYNOTE-426 study (NCT02853331) investigating axitinib (Inlyta) combined with pembrolizumab (Keytruda) will be showcased, he details. Another significant presentation will feature a biomarker analysis from the phase 3 IMmotion010 (NCT03024996) trial of adjuvant atezolizumab (Tecentriq), Pal states.

Although the IMmotion010 study did not achieve its co-primary end point of overall survival, it identified the circulating marker KIM-1 as a potential predictor of outcomes with adjuvant therapy, he says. This development is particularly exciting because it offers data not only for predicting responses in metastatic disease but also for guiding the use of adjuvant treatments in localized settings, Pal explains. The anticipated biomarker research in kidney cancer at this year's ASCO is expected to be more extensive than in previous meetings, Pal notes, adding that these studies promise to advance the understanding and management of RCC.

Overall, Pal anticipates that the 2024 ASCO Annual Meeting will be groundbreaking. He adds that this year’s conference will feature a record number of plenary sessions dedicated to lung cancer, a field from which many treatment paradigms are borrowed. Additionally, ASCO is renowned for presenting the latest and most cutting-edge data, Pal says. Beyond the groundbreaking research, ASCO is valued for the opportunity it provides to network with colleagues and meet associates who have leading interests in various diseases, he concludes.

Dr Pal Previews ASCO 2024 Data in Renal Cell Carcinoma

Dr Pal on the Rationale for Investigating Zanzalintinib in Relapsed/Refractory ccRCC

Sumanta Kumar Pal, MD, FASCO, chair, Kidney and Bladder Cancer Disease Team, co-director, Kidney Cancer Program, professor, Department of Medical Oncology and Therapeutics Research, City of Hope, discusses the rationale for treating patients with zanzalintinib (XL092) in relapsed/refractory clear cell renal cell carcinoma (ccRCC).

At the 2023 International Kidney Cancer Symposium, Pal shared a read-out of data from the expansion cohort of the phase 1b STELLAR-001 study (NCT03845166). The STELLAR-001 trial encompasses several cohorts, the first being a dose-escalation portion aimed at determining the optimal dosage for zanzalintinib. This was determined to be a dose of 100 mg, he begins. The focus of his presentation centered on one specific cohort of 32 patients with ccRCC. 

Patients in the dose-expansion cohort exhibited aggressive disease characteristics, with more than 30 patients exhibiting bone and liver metastases, respectively, he expands. A significant portion of these patients had been previously exposed to therapy, with over 40% having received 3 prior treatments, Pal states. This establishes a patient population with notably aggressive disease features. Pal says that zanzalintinib holds promise for patients with RCC in various settings. The agent’s median duration of response (DOR) of 7.4 months, as observed in the cabozantinib (Cabometyx)-naive cohort, is noteworthy, he emphasizes. For patients previously exposed to cabozantinib, the median DOR has not been reached at this point. However, the current survival curves reveal ongoing responses with zanzalintinib in many patients. Notably, most patients’ first response occurred around the time of the initial post-baseline assessment, he explains. Regarding toxicity, the incidence of any-grade treatment-related adverse effects (TRAEs) was 97%, while the rate of grade 3 TRAEs was 44%. No grade 4 or 5 treatment-related AEs were observed.

These promising data support the continued investigation of zanzalintinib alongside nivolumab (Opdivo) in the STELLAR-304 clinical trial (NCT05678673), where it is being validated against sunitinib (Sutent), he continues. Several ongoing studies are evaluating otherzanzalintinib combinations, Pal concludes.

Sumanta Kumar Pal, MD, FASCO, discusses the rationale for treating patients with zanzalintinib in relapsed/refractory clear cell renal cell carcinoma.

Tivozanib (TIVO) is an oral vascular endothelial growth factor tyrosine kinase inhibitor that is approved by the US Food and Drug Administration (FDA) for treatment of patients with relapsed/refractory (R/R) renal cell carcinoma (RCC) following ≥2 prior systemic therapies1,2

Long-term progression-free survival (LT-PFS) is a clinically meaningful outcome for evaluating efficacy in patients with R/R metastatic RCC (mRCC) who received ≥2 prior lines of therapy

The TIVO-3 trial supported FDA approval of TIVO in R/R advanced RCC by demonstrating significantly improved efficacy outcomes over sorafenib (SOR), including:

Significantly longer independent review committee (IRC)–assessed PFS with TIVO vs SOR (unstratified hazard ratio [HR], 0.672; 95% CI, 0.52-0.87; stratified HR, 0.73; 95% CI, 0.56-0.95)

A higher overall response rate with TIVO compared with SOR as evaluated by IRC (18% vs 8%; 

1-year duration of response (DOR) was 71% (95% CI, 53%-88%) with TIVO and 46% (95% CI, 19%-73%) with SOR3

The median DOR by IRC was not reached (NR; 95% CI, 9.8-NR) with TIVO and was 5.7 months (95% CI, 5.6-NR) with SOR1

The median DOR by investigator (INV) assessment was 20.3 months (95% CI, 9.8-29.9) for TIVO and 9.0 months (95% CI, 3.7-16.6) with SOR4

In this analysis, we assessed the proportion of TIVO-3 patients with R/R mRCC who achieved LT-PFS at regular intervals up to 4 years after initiation of TIVO or SOR

TIVO-3 (NCT02627963) is a phase 3, global, open-label, parallel-arm study comparing TIVO with SOR in patients with R/R advanced mRCC.

350 patients were randomized 1:1 to receive TIVO (n=175) or SOR (n=175)

Exploratory analysis of INV-assessed LT-PFS and long-term overall survival (OS) used a data cutoff of May 24, 2021. Unstratified PFS and OS HR for the intent-to-treat (ITT) population and prespecified subgroups (data not shown), as well as landmark values of LT-PFS at 6, 12, 24, 30, 36, 42, and 48 months are reported.

Results include findings from the ITT population, with censoring for missing assessments and discontinuations without progressive disease

Cox proportional hazards and log-rank statistics were used to estimate the HR and 95% CI for INV PFS and OS; odds ratios (ORs) are reported for landmark time points of LT-PFS up to 36 months

Due to low patient numbers at the month 42 and 48 time points (data cutoff), no inferential statistical analyses were conducted. Data are presented descriptively

LT-PFS rates across prespecified subgroups were analyzed descriptively and are presented at 1-year intervals, up to 4 years

The INV PFS HR analyzed with extended follow-up (data cutoff: May 24, 2021) favored TIVO compared with SOR (HR, 0.624; 95% CI, 0.49-0.79), which was comparable to the primary IRC PFS HR reported at the original October 2018 data cutoff (HR, 0.672; 95% CI, 0.52-0.87)

Mature OS was also analyzed, and a nonsignificant trend favoring TIVO continued to emerge with accumulation of events (HR, 0.89; 95% CI, 0.70-1.14)

Landmark INV LT-PFS rates up to 48 months were consistently higher with TIVO vs SOR: 12.3% vs 2.4% (36 months) and 7.6% vs 0% (48 months)

Despite low numbers of patients at risk, subgroups with ≥15% INV LT-PFS at 3 years included International mRCCDatabase Consortium (IMDC) favorable risk, female sex, ECOG PS of 0, age ≥65 years, and geographic region of North America.

Three-year INV LT-PFS rates ≥15% were only observed in the TIVO (and not SOR) arm

INV PFS analyzed with extended follow-up was consistent with the primary IRC PFS

OS continued to mature with longer follow-up, now demonstrating a nonsignificant trend in favor of TIVO

Overall, the rates of INV LT-PFS were higher with TIVO compared with SOR at every time point evaluated

The odds of experiencing LT-PFS at 36 months with TIVO were over 5 times higher than with SOR

The higher LT-PFS rates with TIVO vs SOR were observed across subgroups, with clinically meaningful effects in the TIVO group (defined as ≥15% INV LT-PFS at 36 months) in patients with favorable risk status evaluated by IMDC, female sex, ECOG PS of 0, age ≥65 years, and North American residence

A clinically relevant proportion of patients were alive and progression free at 3 and 4 years after initiating TIVO therapy compared with SOR, and this difference was consistent across all clinical and demographic subgroups evaluated

1. Atkins MB, Verzoni E, Escudier BJ, et al. Long-Term PFS From Tivo-3: Tivozanib (TIVO) Vs Sorafenib (SOR) in Relapsed/Refractory (R/R) Advanced RCC presented at: 2022 American Society of Clinical Oncology Genitourinary, February 17-19,2022; Abstract 362.

Dr. Pal analyzes and reviews the results from long term follow-up data on PFS from the TIVO-3 trial.

Sumanta K. Pal, MD, FASCO

Articles

Dr Pal on the Preliminary Efficacy of DFF332 in Advanced ccRCC

Dr Pal Previews ASCO 2024 Data in Renal Cell Carcinoma

Dr Pal on the Rationale for Investigating Zanzalintinib in Relapsed/Refractory ccRCC

Long-Term PFS From TIVO-3: Tivozanib (TIVO) Vs Sorafenib (SOR) in Relapsed/Refractory (R/R) Advanced RCC