Sortilin Targeted Peptide-Drug Conjugates: A New Mechanism to Extend Clinical Benefit

Sortilin (SORT1), a transmembrane protein of the vacuolar protein sorting 10 protein (Vsp10p) family, is attracting increasing attention among oncology researchers. Its normal function is to act as a cellular shuttle system to transport proteins across the cell membrane and to rapidly internalize them via the endosomal/lysosomal pathway. SORT1 functions very differently from surface receptors such as HER2 and has a short half-life of approximately 1.25 hours and an internalization rate of its natural ligand of roughly 4 minutes.^1-3 Overall, SORT1 is more highly expressed in cancer cells compared with normal cells,⁴ making it an attractive target for anticancer therapy.

Sudocetaxel zendusortide (formerly TH1902) is a first-in-class peptide-drug conjugate (PDC) consisting of 2 docetaxel molecules conjugated to the SORT1- targeting peptide TH19P01 via a cleavable succinyl linker. PDCs are small, agile chemical entities with short half-lives and rapid internalization from cell membrane to lysosome.^5,6 The rapid internalization of sudocetaxel zendusortide via SORT1 facilitates access to the cancer cell interior, where the conjugate is cleaved and delivers its docetaxel payload directly to the microtubules (Figure 1).

Preclinical models suggest rapid internalization allows the PDC to bypass the multidrug resistance 1 (MDR1) efflux pump. In addition, the current PDC has demonstrated ability to induce cancer stem cell apoptosis, inhibit vasculogenic mimicry, and activate the innate immune system by stimulating significant immune infiltration of tumor-infiltrating CD8+ lymphocytes. This multidimensional mechanism leads to strong and sustained tumor regression, even after treatment discontinuation.^7-11

Phase 1 Results With Sudocetaxel Zendusortide

At the National Cancer Institute–designated cancer center Karmanos Cancer Institute, we participated in the first-in-human phase 1 trial of sudocetaxel zendusortide (TH1902; Theratechnologies). In a presentation at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, we reported preliminary signs of antitumor activity in a heavily pretreated population.

Part 1 (dose escalation) of the study enrolled 18 adults with a confirmed diagnosis of a metastatic or advanced-stage solid tumor that was refractory to standard therapies (average of 8 prior lines of therapies). We selected a starting dose of 30 mg/m² every 3 weeks (Q3W) based on sudocetaxel zendusortide’s preclinical data. Among participants in part 1, 1 patient with endometrial cancer experienced stable disease (SD) for 233 days (33 weeks), a second patient with prostate cancer had SD that lasted for 119 days (17 weeks), and a third patient with ovarian cancer experienced SD for 295 days (42 weeks).¹²

Sudocetaxel doses below 300 mg/m² were well tolerated in part 1 of the trial, which established the maximum tolerated dose and dose-limiting toxicities at 360 mg/m² and 420 mg/m², respectively. Those results informed the selection of a 300 mg/m2 Q3W dose for part 2 (dose expansion) of the study, to determine the safety and efficacy of sudocetaxel zendusortide in 18 additional patients with multiple tumor types with known high expression of SORT1. An interim efficacy and safety analysis of the 300 mg/m2 dose cohort from parts 1 and 2 (n = 25) showed encouraging signs of efficacy in 9 (36%) heavily pretreated patients,including 2 participants—1 with prostate cancer and 1 with ovarian cancer—who experienced RECIST confirmed partial responses (PRs); the patient with ovarian cancer had a complete response (CR) in her target lesion.

Additionally, 7 participants achieved prolonged clinical benefit (including SD) over 4 or more cycles. Five of 6 patients (83%) with ovarian cancer had a best overall response (BOR) of either PR (n = 1) or SD (n = 4). Three of 4 patients (75%) with triple-negative breast cancer (TNBC) had a BOR of SD, with 1 patient experiencing SD for at least 4 cycles and continued clinical benefit up to at least 24 weeks (Figure 2).¹²

At 300 mg/m², the most common treatment-related adverse events (TRAEs; > 20%) were ocular changes, neuropathy, gastrointestinal disturbances, and musculoskeletal complaints, with grade 3 or greater (Table). The neuropathy appeared to be associated with cumulative exposure of circulating docetaxel based on pharmacokinetic/pharmacodynamic data. Further, eye toxicity is likely linked to accumulation of the PDC in the anterior chamber of the eye, similar to that seen with antibody-drug conjugates (ADCs); these ocular changes are reversible and unlikely to be target specific. Both neuropathy and the ocular changes can be mitigated with weekly administration and weightbased dosing, and in the case of eye toxicity, ocular prophylaxis, which was instituted.¹²

Prolonged Antitumor Effects

Consistent with preclinical data, several phase 1 trial participants with high SORT1-expressing tumors experienced prolonged clinical benefit after discontinuing sudocetaxel zendusortide therapy. One patient with endometrial cancer progressed after 2 platinum regimens; her disease rapidly progressed on immunotherapy and additional investigational therapies. She experienced significant neuropathy within 2 cycles of sudocetaxel zendusortide and discontinued treatment in mid-2022. Notably, even after treatment discontinuation, her disease has remained stable over 12 months since initiation of sudocetaxel zendusortide therapy, similar to the prolonged tumor regressions observed in the preclinical setting (this patient remains under observation).

A second patient, with TNBC, had progressive disease (PD) on 4 prior regimens, with rapid progression on the ADC sacituzumab govitecan immediately prior to entering the phase 1 study. She started on sudocetaxel zendusortide in late 2022 and had a temporary dose delay due to recurrence of baseline neutropenia during her second cycle, necessitating a dose reduction to 200 mg/m2 for 7 cycles. As of this writing, the patient has received a total of 9 cycles and continues to experience clinical benefit on therapy with significant improvement in baseline symptoms as well.

A third patient, also with endometrial cancer, had received 2 previous platinum-based regimens, experiencing a PR on the first regimen and PD on the second; she also received aromatase inhibitor therapy for 1 year after the first regimen. She initiated sudocetaxel zendusortide treatment in mid-2021 and withdrew consent for further treatment after her last cycle in late 2021, as she desired a treatment pause. This patient’s dose was escalated from 60 mg/m² to 360 mg/m² Q3W over 11 cycles; she developed mild blurred vision and neuropathy at the highest dose. Her BOR was SD, which has continued for at least 4 months after she withdrew consent for further treatment.

Amended Phase 1 Protocol

The data presented at ASCO, and a recent evaluation of additional preclinical and pharmacokinetic data, informed a recently approved amendment to the phase 1 protocol to improve the therapeutic window of sudocetaxel zendusortide and extend its duration of therapy. For the dose-optimization phase of the study (part 3), the amendment narrows the patient population to focus on those with high-grade serous ovarian cancer, including high-grade peritoneal or fallopian tube cancer, or high-grade endometrioid cancer, based on BORs observed thus far in this group of patients. Additionally, patients will not be as heavily pretreated as in parts 1 and 2 of the study. Under the revised eligibility criteria, participants will be restricted to only 1 prior taxane failure, and to a maximum of 8 prior treatment regimens.

Another aim of the amended protocol is to optimize the sudocetaxel zendusortide dose via weekly administration on days 1, 8, and 15 of a 28-day cycle. The dose will be calculated based on mg/kg instead of mg/m². Two dose levels will be tested sequentially in a 16-patient cohort, including 6 patients who will receive a 1.75-mg/kg dose (similar to 210 mg/m2), and 6 to be treated at 2.50 mg/kg (similar to 300 mg/m2); the latter group will be expanded to 10 patients. All patients in the new schedule are within the expected efficacious dose range of sudocetaxel zendusortide. Amending the dose aligns with the FDA’s Project Optimus, which aims to reform the dose optimization and dose selection paradigm in oncology drug development.¹³

Looking to the Future

Preclinical evidence, augmented by our clinical experience thus far with sudocetaxel zendusortide, appears to bolster the therapeutic rationale for targeting the SORT1 receptor with PDC therapy. As noted above, the rapid internalization of sudocetaxel zendusortide via SORT1 can yield multiple anticancer benefits, including strong and sustained tumor regression, inhibition of mechanisms of cancer resistance, and activation of the innate immune system.

The ongoing phase 1 trial of sudocetaxel zendusortide, under its amended protocol, is expected to add to the growing body of evidence of these effects and to enhance our understanding of the correlation between efficacy and high SORT1 expression.

References

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6. Chavda VP, Solanki HK, Davidson M, Apostolopoulos V, Bojarska J. Peptide-drug conjugates: a new hope for cancer management. Molecules. 2022;27(21):7232. doi:10.3390/molecules27217232

7. Demeule M, Currie JC, Larocque A, et al. Sortilin receptor-mediated novel cancer therapy: a targeted approach to inhibit vasculogenic mimicry in ovarian and breast cancers. Presented at: American Association for Cancer Research Annual Meeting; June 22-24, 2020; virtual. Poster 4335.

8. Taxotere. Prescribing information. Sanofi-Aventis US LLC; 2023. Accessed June 16, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020449s084lbl.pdf

9. Annabi B, Demeule M, Currie JC, et al. TH1901, a novel curcumin-peptide conjugate for the treatment of sortilin-positive (SORT1+) cancer. Presented at: American Association for Cancer Research Annual Meeting; June 22-24, 2020; virtual. Poster 4386.

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11. Currie JC, Charfi C, Demeule M, et al. A novel sortilin-targeted docetaxel peptide conjugate (TH1902), for the treatment of sortilin-positive (SORT1+) triple-negative breast cancer. Presented at American Association for Cancer Research Annual Meeting; June 22-24, 2020; virtual. Poster 4472.

12. Meric-Bernstam F, Shah S, Sharma M, et al. Sudocetaxel zendusortide (TH1902), a novel sortilin-receptor (SORT1)-targeting peptide-drug conjugate (PDC) in patients (pts) with advanced solid tumors: results from part 1 (dose-escalation) of a phase 1, open-label study. Presented at: 2023 ASCO, Chicago, IL; June 2-6, 2023. Abstract 3089.

13. Project Optimus. US Food and Drug Administration. February 14, 2023. Accessed June 12, 2023. https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus