(UroToday.com) The 2024 ESMO annual meeting included a session on kidney and bladder cancer, featuring a discussant presentation by Dr. Jonathan Rosenberg discussing two abstracts including “BL-B01D1-201: BL-B01D1, an EGFR x HER3 Bispecific Antibody-drug Conjugate, in Patients with Locally Advanced or Metastatic Urothelial Carcinoma” presented by Dr. Dingwei Ye, and “NKT2152, a novel oral HIF-2α inhibitor, in participants with previously treated advanced clear cell RCC: Preliminary results of a Phase 1/2 study” presented by Dr. Eric Jonasch.
Dr. Rosenberg started by discussing the bispecific antibody-drug conjugate BL-B01D1 targeting EGFR and HER3 in urothelial carcinoma. Structurally, he notes that the anti-EGFR antibody is derived from cetuximab, which is a high-affinity antibody, with two HER3 single-chain fragments that have lower affinity. The anti-EGFR antibody is fused to anti-HER3 scFv’s with a glycine-serine linker, with a tetrapeptide-based cathepsin cleavable linker. Ed-04 is a camptothecin derivative inhibitor of topoisomerase 1:
Preclinical studies found that BL-B01D1 had enhanced antitumor activity compared to antibody-drug conjugates generated from each parental antibody. Importantly, BL-B01D1 can bind to either EGFR or HER3, with the EGFR family members homo- and heterodimerizing to signal downstream. To activate pathways, HER3 must heterodimerize with another HER RTK to signal. HER3 scfv in BL-B01D1 is “detuned” with lower affinity, and the construct binds EGFR more strongly:
In urothelial cancer, BL-B01D1 has previously been shown in a phase I trial to demonstrate 34% confirmed objective response across solid tumors, and the recommended phase II dose was 2.5 mg/kg IV day 1 and 8 every 3 weeks [1]. There was no relationship between EGFR and HER3 expression observed and nearly all tumors expressed the targets. In the phase 2 study in metastatic urothelial carcinoma presented at ESMO 2024 by Dr. Ye, 34 patients were treated with 2.2 mg/kg dose, with a small number of patients receiving 2.5 mg/kg and 2.75 mg/kg. Very few patients received a prior antibody-drug conjugate (4.9%), but >90% had received an immune checkpoint inhibitor. Furthermore, this was the 3rd line therapy for >50% of patients.
Dr. Rosenberg notes that among these patients treated at 2.2 mg/kg, the majority had tumor reductions, with an objective response rate of 40.7%, and 75% in patients with one prior line of therapy (n = 12). Activity appeared to be higher in the second line population, but with a limited sample size:
Of note, there was no clear relationship between EGFR and HER3 expression and antitumor activity, with responses seen across EGFR and HER3 expression:
Dr. Rosenberg notes that the > 6-month progression-free survival appears promising, but longer follow-up is needed. Moreover, hematologic toxicity predominates, but skin toxicity seems limited.
Dr. Rosenberg concluded his discussant presentation of BL-B01D1 in advanced urothelial cancer by highlighting its strengths and limitations:
- Strengths:
- There is preliminary evidence of significant antitumor activity with an objective response rate of 40.7%
- Nine of 12 patients (75%) with only one prior line of therapy responded
- The treatment was tolerable with hematologic toxicity as the most prominent feature
- There was no interstitial lung disease or severe skin toxicity reported
- There was no neuropathy noted as a treatment-related adverse event
- Limitations:
- There were no patients with prior treatment with enfortumab vedotin + pembrolizumab, thus the utility of a second antibody-drug conjugate following progression on MMAE remains unclear.
- This study had small number of patients, thus further data is required to fully assess the activity and safety profile.
Dr. Rosenberg then discussed NKT2152 in previously treated clear-cell RCC patients. Clear cell RCC is characterized by VHL loss or inactivation in 90% of tumors, which leads to constitutive upregulation of HIF-2α, a transcription factor that regulates the expression of multiple genes critical for RCC growth and metastasis. HIF-2α contains a binding pocket that can be blocked, disrupting heterodimerization and target gene expression. Belzutifan led to the first-in-class US FDA approval for metastatic clear cell RCC in patients previously treated with an immune checkpoint inhibitor and VEGFR TKI. In LITESPARK-005 [2], belzutifan showed clinical benefit versus everolimus with an improvement in progression-free survival (HR 0.75, 95% CI 0.63-0.90), and an objective response rate of 22.7% (3.5% complete responses). However, there was no overall survival benefit, and treatment was well tolerated (grade 3-4 hypoxia – 10%; grade 3-4 anemia – 29%).
NKT2152 is a small molecular inhibitor of HIF-2α, which disrupts the HIF-2α/ HIF-2beta complex, thus suppressing the expression of genes downstream of HIF-2α, including VEGF, CCND1, and GLUT1. Two dose levels were selected for dose expansion phase II to determine the recommended phase II dose for further development:
Erythropoietin production as pharmacodynamic measure consistently showed suppression across dose levels:
Dr. Rosenberg notes that expected toxicities of fatigue and hypoxia were observed, including anemia in >70% of patients (17.7% grade 3) and grade 3+ hypoxia in 16% of patients. Fatigue and hypoxia were dose-limiting toxicities:
The aforementioned toxicities are similar to belzutifan, though the duration of hypoxia after cessation or dose reduction is unclear in the context of the longer half-life of NKT2152 (38 days). Among the 100 evaluable patients (all heavily pre-treated), there was anti-tumor activity associated with NKT2152. Overall, 59.3% of patients had 3-4 prior lines of therapy (median of 3), and 28% had prior mTOR inhibitor therapy. Most patients were IMDC intermediate and poor risk, and antitumor activity was noted across dosing levels and regardless of line of therapy. An objective response rate of 20% in this ongoing trial is worthy of further investigation and additional antitumor activity may evolve with longer following (among 57 patients with longer follow-up, the objective response rate was 26.3% and progression-free survival was 9.2 months). Dr. Rosenberg does note that progression-free survival in an early phase trial is difficult to interpret, but these results are promising.
NKT2152 is being evaluated further beyond phase I in hepatocellular carcinoma in the MORPHEUS-LIVER trial of atezolizumab + bevacizumab + NKT2152. Additionally, preclinical data supports the combination with CDK4/6 inhibitors, and a randomized phase II study is evaluating the combination of NKT2151 + palbociclib +/- sasanlimab in RCC.
Dr. Rosenberg concluded his discussion of the NKT2152 trial by highlighting where it may fit in the landscape of advanced RCC:
- Belzutifan refractory disease may represent an opportunity: there are different PK properties that may lead to more steady inhibition of HIF-2α target genes
- The neoadjuvant setting in combination with checkpoint inhibition may provide an avenue: would the long half-life of NKT2512 pose a challenge in patients with hypoxia?
- NKT2152 represents an active agent and further evaluation is worthwhile
Presented by: Jonathan E. Rosenberg, MD, Chief, Genitourinary Oncology Service, Division of Solid Tumor Oncology, Enno W. Ercklentz Chair, Memorial Sloan Kettering Cancer Center, New York, NY
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 European Society of Medical Oncology (ESMO) Annual Meeting, Barcelona, Spain, Fri, Sept 13 – Tues, Sept 17, 2024.
Related content: New Dual-Target Drug Shows Promise Against Bladder Cancer - Jonathan Rosenberg
References:
- Ma Y, Huang Y, Zhao Y, et al. BL-B01D1, a first-in-class EGFR-HER3 bispecific antibody-drug conjugate, in patients with locally advanced or metastatic solid tumours: A first-in-human, open-label, multicenter, phase 1 study. Lancet Oncol. 2024 Jul;25(7):901-911.
- Choueiri TK, Powles T, Peltola K, et al. Belzutifan versus Everolimus for Advanced Renal-Cell Carcinoma. N Engl J Med. 2024 Aug 22;391(8):710-721.