Batiraxcept Plus Cabozantinib Has Tolerable Safety Profile in Metastatic Clear Cell RCC

Neil J. Shah, MD

The combination of batiraxcept (AVB-S6-500) and cabozantinib (Cabometyx) is safe and generated early evidence of efficacy in pretreated patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC), according to findings from the phase 1b part of a phase 1b/2 trial (NCT04300140) that were presented at the 2023 Genitourinary Cancers Symposium.

At a median follow-up of 13.5 months (range, 3.7-20.7), all 26 patients had experienced all-grade batiraxcept-related adverse effects (AEs), with 19% of patients (n = 5) having grade 3/4 treatment-related AEs (TRAEs) and 1 patient having an all-grade treatment-related serious AE. Additionally, 46.2% of patients (n = 12) had received cabozantinib dose reductions, and the median cabozantinib dose intensity was 40.2 mg/day (range, 15.6-60).

“A recommended phase 2 dose of batiraxcept [at] 15 mg/kg with cabozantinib [at] 60 mg maintains an acceptable safety profile and encouraging efficacy in [patients with] previously treated ccRCC,” lead study author Neil J. Shah, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, and colleagues, wrote in a poster of the data.

Batiraxcept, a recombinant fusion protein, is a highly potent and specific first-in-class AXL inhibitor. TKIs, AXL inhibitors, and GAS6 inhibitors have limited inhibitory effects on the AXL/GAS6 pathway and have several potential competitors. In comparison, batiraxcept mimics AXL receptors to bind and isolate the GAS6 ligand and prevent signaling. It binds to GAS6 more tightly than the wild-type AXL receptor does, providing complete target coverage with no expected off-target toxicity.

Previously, the single-arm, phase 2 BREAKPOINT trial (NCT03463681), which evaluated the efficacy and safety of cabozantinib in patients with metastatic renal cell carcinoma who progressed on PD-1/PD-L1–based therapy alone or in combination with a TKI or CLTA-4 inhibitor, showed that at a median follow-up of 7.2 months, the median progression-free survival (PFS) was 7.2 months. Additionally, 27.2% (n = 6) of patients achieved a partial response (PR), and 22.7% (n = 5) of patients achieved stable disease (SD).²

The phase 1b portion of the phase 1b/2 trial (NCT04300140) used a 3+3 dose escalation design, where patients received intravenous batiraxcept at either 15 mg/kg (n = 16) or 20 mg/kg (n = 10) every 2 weeks plus oral cabozantinib at 60 mg daily.1 Patients were eligible for this trial if they had advanced or metastatic ccRCC and had progressed on or after at least 1 prior line of therapy. Patients with prior cabozantinib exposure were excluded.

The primary end points of this trial were safety, tolerability, and the determination of the recommended phase 2 dose. Antitumor activity assessment was a secondary end point. The exploratory end point was a retrospective evaluation of the correlation between the biomarker baseline serum soluble AXL (sAXL)/GAS6 and objective response rate (ORR).

As of January 17, 2023, the phase 1b part of this trial completed enrollment with 26 patients. At the data cutoff, 6 patients were still receiving the study treatment, 12 patients had discontinued the treatment, and 8 patients had died.

Batiraxcept administered every 2 weeks showed pharmacokinetic/pharmacodynamic and exposure-response relationships. Post-dose serum GAS6 levels were suppressed below quantitation levels in all patients with post-dose results (n = 25). The minimally efficacious concentration of batiraxcept was identified as greater than 12.2 mg/L, and the investigators determined no difference between 15 mg/kg and 20 mg/kg of batiraxcept.

In all patients, the median age was 60 years (range, 40-81), 85% of patients (n = 22) were male, 92% of patients (n = 24) were Caucasian, 50% of patients (n = 13) had an ECOG performance score (PS) of 0, and 50% of patients had an ECOG PS of 1. Additionally, 19% (n = 5), 62% (n = 16), and 19% of patients had favorable-, intermediate-, or poor-risk disease per the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). A total of 65% (n = 17), 19% (n = 5), and 16% (n = 4) of patients had received 1, 2, or at least 3 prior lines of therapy, respectively, including 54% of patients (n = 14) with prior VEGF TKI exposure. In addition, 54% (n = 14), 8% (n = 2), and 31% (n = 8) of patients had received prior nivolumab (Opdivo)/ipilimumab (Yervoy), nivolumab monotherapy, and pembrolizumab (Keytruda)/axitinib (Inlyta), respectively.

In the cohort of patients who received batiraxcept at 15 mg/kg (n = 16), the median age was 61 years (range, 40-76), 81% of patients (n = 13) were male, 88% of patients (n = 14) were Caucasian, 63% of patients (n = 10) had an ECOG PS of 0, and 38% of patients (n = 6) had an ECOG PS of 1. Additionally, 19% (n = 3), 69% (n = 11), and 13% (n = 2) of patients had favorable-, intermediate-, or poor-risk disease per the IMDC. A total of 63% (n = 10), 19% (n = 3), and 19% of patients had received 1, 2, or at least 3 prior lines of therapy, respectively, including 56% of patients (n = 9) with prior VEGF TKI exposure. In addition, 56% (n = 8), 13% (n = 2), and 31% (n = 5) of patients had received prior nivolumab/ipilimumab, nivolumab monotherapy, and pembrolizumab/axitinib, respectively.

In the cohort of patients who received batiraxcept at 20 mg/kg (n = 10), the median age was 59 years (range, 42-81), 90% of patients (n = 9) were male, 100% of patients were Caucasian, 30% of patients (n = 3) had an ECOG PS of 0, and 70% of patients (n = 7) had an ECOG PS of 1. Additionally, 20% (n = 2), 50% (n = 5), and 30% of patients had favorable-, intermediate-, or poor-risk disease per the IMDC. A total of 70%, 20%, and 10% (n = 1) of patients had received 1, 2, or at least 3 prior lines of therapy, respectively, including 50% of patients with prior VEGF TKI exposure. In addition, 60% (n = 6), 0%, and 30% of patients had received prior nivolumab/ipilimumab, nivolumab monotherapy, and pembrolizumab/axitinib, respectively.

The safety profile between the 15 mg/kg and 20 mg/kg batiraxcept dose levels was consistent with those seen in prior studies. In the 15 mg/kg population, 19% of patients (n = 3) had grade 3/4 TRAEs, and no serious AEs occurred. In the 20 mg/kg population, 20% of patients (n = 2) had grade 3/4 TRAEs, and 1 patient had an all-grade, treatment-related serious AE.

The most common batiraxcept-related AEs of all grades were diarrhea (34.6%), fatigue (30.8%), decreased appetite (26.9%), infusion-related reaction (26.9%), aspartate aminotransferase increase (23.1%), hypophosphatemia (23.1%), alanine aminotransferase increase (19.2%), nausea (19.2%), decreased platelet counts (15.4%), stomatitis (11.5%), palmar-plantar erythrodysesthesia syndrome (7.7%), hyponatramia (7.7%), and dry mouth (7.7%). Additionally, 3.8% of patients had grade 3 or higher diarrhea.

The most common cabozantinib-related AEs of all grades were diarrhea (80.8%), aspartate aminotransferase increase (69.2%), fatigue (53.8%), alanine aminotransferase increase (53.8%), stomatitis (50%), palmar-plantar erythrodysesthesia syndrome (50%), decreased appetite (46.2%), decreased platelet counts (34.6%), hyponatramia (34.6%), nausea (30.8%), and dry mouth (26.9%). Additionally, 11.5%, 3.8%, and 3.8% of patients had grade 3 or higher diarrhea, decreased platelet counts, and hyponatramia, respectively.

At the 8-week response assessment, 85% of all patients (n = 22) had target lesion reductions, and 58% of patients (n = 15) achieved a better response than they did with prior therapy. In total, 42% (n = 11), 39% (n = 10), and 15% (n = 4) of patients achieved best confirmed overall responses of PR, SD, and progressive disease (PD), respectively. One patient was not evaluable (NE) for response. In the overall population, 18 uncensored PFS events occurred, and the median PFS in those patients was 9.3 months (95% CI, 7.3-11.4).

Of the patients who had received a prior VEGF TKI, 57% (n = 8), 29% (n = 4), and 7% (n = 1) achieved best responses of PR, SD, and PD, respectively, and 1 patient was NE. In total, 8 uncensored PFS events occurred, and the median PFS in those patients was 11.4 months (95% CI, 5.8-NE).

Of the patients who had not received a prior VEGF TKI, 25% (n = 3), 50% (n = 6), and 25% (n = 3) achieved best responses of PR, SD, and PD, respectively. In total, 10 uncensored PFS events occurred, and the median PFS in those patients was 9.2 months (95% CI, 3.7-9.3).

The evaluation of the correlation between patients’ sAXL/GAS6 biomarker status and their response to batiraxcept/cabozantinib defined high biomarker status as biomarker-to-response ratio of over 2.1. In total, 55% (n = 11) of patients with high biomarker status (n = 20) and 0% of those with low biomarker status (n = 5) achieved a PR, indicating the potential predictive value of the presence of sAXL/GAS6.

In all 25 patients with available biomarker ratio values, the 9-month PFS rate was 65%. The 9-month PFS rates in patients with high biomarker status and those with high biomarker status and prior VEGF TKI exposure (n = 12) were 69% and 75%, respectively.

“Overall, batiraxcept in combination with cabozantinib is well tolerated. The efficacy data from the phase 1b portion of the study are very encouraging. The data from the phase 2 portion of the study will be presented at the 2023 ASCO Annual Meeting,” Shah said to OncLive^®.

References

1. Shah NJ, Campbell MT, Mao SS, et al. A phase 1b/2 study of batiraxcept (AVB-S6-500) in combination with cabozantinib in patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC). J Clin Oncol. 2023;41(6):666. doi:10.1200/JCO.2023.41.6_suppl.666
2. Procopio G, Pircher C, Claps M, et al. A phase II open-label study of cabozantinib after first-line treatment including an immune-checkpoint combination in patients with advanced or unresectable renal cell carcinoma: the BREAKPOINT trial (MeetUro trial 03 – EudraCT number 2018-000582-36). J Clin Oncol. 2021;39(6):326. doi:10.1200/JCO.2021.39.6_suppl.326