ASH2020: VelosBio’s ROR1 Targeted Therapy Shines in Safety Trial

On December 7th, VelosBio presented data from its Phase 1 trial at the 62nd American Society of Hematology Meeting that evaluated the safety and efficacy of their lead candidate, VLS-101, in adult patients with previously treated diffuse large B-cell lymphoma and mantle cell lymphoma. The drug showed encouraging clinical efficacy, consistent pharmacokinetics, and a favorable safety profile in the patients.

VelosBio is one of the few companies that is developing a treatment for cancers with high expression of ROR1 protein. The protein is a transmembrane receptor whose expression is minimal in normal tissues but is abundant in many hematological and solid cancers. VelosBio’s drug candidate is a novel antibody-drug conjugate that contains a humanized IgG monoclonal antibody against ROR1 and an anti-microtubule toxin, MMAE. VLS-101 works by binding to ROR1 protein on the cell surface, which causes rapid internalization of the toxin attached with the ADC.

VLS-101’s Efficacy as an Anticancer Agent in vitro

In vitro testing of the drug in the mouse model of MCL and DLBCL revealed some interesting features of the drug. These human tumor models showed ROR1 expression on the surface in 24.5% to 100% of the cells. The growth of these tumors resistant to ibrutinib and venetoclax was completely repressed in the mouse model following treatment with VLS-101. Topping that, the drug showed a remarkable safety profile with no adverse effect on mouse body weight.

Phase 1 Safety Study in Humans

The study enrolled cancer patients with different tumor types. These patients were mostly old and heavily pretreated with a median of four cancer therapies, including CAR-T or NK cell therapy. Treatment with VLS-101 showed expected side effects, including neutropenia (Gr 3: 25%, Gr4: 28%) and neuropathy (Gr2: 22%, Gr 3: 13%, Gr 4: 0%), which could be either controlled by GCSF injections or dose-modifications. However, these adverse side effects caused seven patients to opt-out of the study. Interestingly, VLS-101 did not cause adverse effects attributable to ROR1 non-specific binding or immunogenicity. No occurrences of venous irritation, tumor lysis syndrome, ocular, skin, cardiac, pulmonary, renal, hepatic metabolic toxicities, or prolongation of the cardiac QT interval were observed.

When looked at the properties of the drug inside the body, it was found consistent with the expected profile for MMAE-containing ADCs. Soon after the injection (~30min), the levels of ADC peaked in the body. However, it took 3 days for the levels of cytotoxic MMAE to peak in the body, consistent with the slow release of MMAE from VLS-101.

With a striking safety profile, the drug also showed a good efficacy profile. Almost similar to the response seen in mouse models, VLS-101 made a deep and prolonged negative impact on tumor growth. At the time of cut-off, an objective response rate of 47% (5PRs and 2CRs) in MCL patients and 80% (2PRs and 2CRs) in DLBCL patients was observed. Moreover, responses extended to as long as 67+ weeks in patients with MCL and 47+ weeks in DLBCL affected patients. However, what was surprising was the absence of a correlation between the expression of ROR1 and the efficacy of the drug. CLL cancers have a high expression of ROR1 on the surface, yet they did not respond to the drug. This could be due to differences in the biology of cancer itself, which the company plans to work out in the future.

Nevertheless, the drug worked well with other solid cancers. The drug’s remarkable efficacy was shown visually in a patient who was affected by double-hit DLBCL and had undergone 4 prior therapies, including CAR-T therapy. By the end of cycle 3, there was a complete regression of the lymphoma in both his legs and at the end of the 44th week, he is still responsive to the drug. These results are particularly encouraging for patients whose cancers have failed to respond to other treatments or have relapsed despite the treatment.

Future of the Drug

Well before the data was presented at the conference, the drug was successful at impressing Merck. Last month, the pharma giant announced a merger agreement with VelosBio, giving it control of VLS-101. With good efficacy and safety data and support from Merck, the drug certainly has a bright future. Besides, it is the only one so far that has shown any efficacy in the clinical trials, which might make it the first one to get the FDA’s blessings. Based on the safety data, VelosBio has initiated a Phase 1/2 trial. The drug will be tested as monotherapy and a combination therapy in patients with hematological cancers and solid tumors.

By Ruchi Jhonsa, Ph.D.

Related Article: ASH2020: New Studies Showcase Potential of CAR-T Therapy to Treat More Cancers

References

1. https://ash.confex.com/ash/2020/webprogram/Paper136373.html
2. https://ash.confex.com/ash/2020/webprogram/Paper137660.html
3. https://www.geneonline.com/2020/11/06/hot-pursuit-for-antibody-drug-conjugates-continue-as-merck-acquires-velosbio/

Author

Ruchi Jhonsa