Bispecific immunotherapy MEDI5752 or volrustomig and cervical cancer

Abstract

MEDI5752 is a monovalent bispecific immunotherapy and is strategically unique as it combines both anti programmed cell death 1 and anti cytotoxic T-lymphocyte-associated protein 4 action. This is one of the first of this kind of molecule. The development of this molecule had been very interesting which is not usually described in regular clinical oncology journals thus losing an important piece of history of an upcoming subject. Only some phase I results in such development is published so far and no full report on this is available till now. This effort will try to record the facts and chain of events which actually occurred in inventing and bringing it in phase III trial.

Synopsis

Immunotherapy is the most promising way to fight cancer. Effort is on to increase its response which has remained low. Bispecific immunotherapy is one such way and volrustomig could be pioneering molecule.

Graphical Abstract

INTRODUCTION

The drug, volrustomig, is not yet widely known in literature, hence in PubMed search it produced nil result. So, it had other former name at the preliminary stage of development. In Google search its alternative names was found, which are: MEDI-5752; programmed cell death 1 (PD-1)/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) bispecific monoclonal antibody (mAb); PD-l/CTLA-4 DuetMab. This is a bispecific antibody (BsAb) which has 2 distinct binding domains that can bind to 2 antigens or 2 epitopes (an antigen part) of the same antigen simultaneously whereas BiTes are bispecific T cell engagers with enhanced activity designed to target CD3 of T cell and one tumor-specific antigen simultaneously thus promoting the cytotoxicity of T cells. MEDI-5752 or volrustomig is different as it’s a bispecific immunotherapy or double immune-check inhibitor in a single molecule. Bispecific immunotherapy is in phase III now.

EARLY PHASE TRIALS

A phase I, open-label study (MedImmune LLC, NCT03530397) of MEDI5752 monotherapy 2.25–2,500 mg intravenous every 3 weeks showed encouraging antitumor activity in advanced solid tumors [1]. Maximum tolerated dose was not reached (NR); doses <1,500 mg were better tolerated than doses ≥1,500 mg. overall, 46 renal cell cancer patients were treated: 19 in dose escalation (ESC), 27 in expansion (EXP). In ESC, patients (all immunotherapy-naïve, 73.7% prior nephrectomy, 26.3% 1L, 89.5% clear cell histology) were treated across 3 dose levels: 750 mg (n=1), 2,000 mg (n=16) and 2,500 mg (n=2). Seven patients (36.8%) had objective responses (all partial responses); Grade 3/4 treatment-related adverse events (AEs) were seen in 68.4% of ESC and 74.1% of EXP patients. In EXP, treatment-emergent AEs, particularly hepatotoxicity, were the most common cause of treatment discontinuation. At a median duration of follow-up of 14.6 months, median duration of response (DOR; including in those who discontinued MEDI5752 due to AEs), median progression-free survival (PFS) and overall survival (OS) were NR in 1L EXP patients.

As of 12 July 2022, results in 1L non-small cell lung cancer (NSCLC) from an ongoing phase 1b/2 study (NCT03530397) 105 patients were enrolled. Of the results in 91 patients: 41 patients in the randomized cohort, and the first 50 patients in the single arm cohort with at least 8 weeks of follow-up DOR, PFS and OS were higher in MEDI5752 1,500 mg plus chemotherapy. Among NSCLC patients who had less than 1% PD-1 expression on tumor cells also had good objective response rate, by 55.6% vs. 30.0% over pembrolizumab arm and the median PFS being 13.4 vs. 9.0 months [2]. MEDI5752 750 mg plus chemotherapy also had encouraging result with lowered toxicity and study is under way.

PHASE III TRIAL FOR LOCALLY ADVANCED CERVICAL CANCER (LACC)

Volrustomig is in phase III trial for LACC (eVOLVECervical, NCT06079671) [3]. It is also being tried in gastric cancer, hepatobiliary cancer, NSCLC etc. which is however beyond the scope of present discussion. eVOLVECervical is a phase III, global study is recently started in high risk LACC (International Federation of Gynecology and Obstetrics [FIGO] 2018 stage IIIC to IVA cervical cancer with lymph node involvement) who have not progressed following platinum-based, concurrent chemoradiation therapy. Sponsors of this trial is AstraZeneca in Collaborators WAS Gynecologic Oncology Group Foundation (GOG-3092) & European Network for Gynaecological Oncological Trial groups (ENGOT-cx19/GEICO). It was first submitted on 2023-09-04. Important inclusion criteria is histologically documented FIGO 2018 stage IIIC to IVA cervical adenocarcinoma, cervical squamous carcinoma, or cervical adenosquamous carcinoma, with lymph node involvement, initial staging procedures performed no more than 42 days prior to the first dose of concurrent chemoradiotherapy (CCRT), should have provision of tumor sample to assess the programmed death-ligand 1 (PD-L1) expression, must not have progressed following CCRT, participants with persistent disease after definitive CCRT must not be amenable to other available therapies with curative intent. There should not be diagnosis of small cell (neuroendocrine) or mucinous adenocarcinoma of cervical cancer, evidence of metastatic disease, intent to administer a fertility-sparing treatment regimen, history of organ transplant, active or prior documented autoimmune or inflammatory disorders, uncontrolled intercurrent illness, history of another primary malignancy except for a) malignancy treated with curative intent with no known active disease ≥2 years before the first dose of study intervention; b) adequately treated nonmelanoma skin cancer or lentigo maligna, or carcinoma in situ without evidence of disease. A total of 88 sites are planned, 52 in Asian countries (China, Russia, Japan, South Korea and Taiwan), 17 site in Europe, 15 sites in USA & Canada and 4 sites in South America. The trial is just starting with recruitment is already started in Taiwan, Japan and South Korea.

It is worthwhile to mention here that in this category efficacy study of pembrolizumab (Keytruda, Merck) with chemoradiotherapy (CRT) was based on KEYNOTE-A18 (NCT04221945), a multicenter, randomized, double-blind, placebo-controlled trial enrolling 1,060 patients with cervical cancer (596 patients with FIGO 2014 stage III–IVA disease and 462 patients with FIGO 2014 stage IB2–IIB, node-positive disease). They had not previously received definitive surgery, radiation, or systemic therapy for patients with FIGO 2014 stage III–IVA cervical cancer. The Food and Drug Administration (FDA) has already approved this combination in January 12, 2024. At 24 months, the PFS rates in these arms were 67.8% (95% confidence interval [CI]=61.8%–73.0%) vs. 57.3% (95% CI=51.2%–62.9%), respectively. The most common adverse reactions (≥10%) occurring in patients who received pembrolizumab with CRT were nausea, diarrhoea, vomiting, urinary tract infection, fatigue, hypothyroidism, constipation, decreased appetite, weight loss, abdominal pain, pyrexia, hyperthyroidism, dysuria, rash, and pelvic pain. Thus, it might be true that eVOLVECervical though set in same design, needs to show superiority in head on comparison with pembrolizumab. However, such comparison is already being done in other indication (NCT05984277, A Global Study of Volrustomig (MEDI5752) Plus Chemotherapy Versus Pembrolizumab Plus Chemotherapy for Participants With Metastatic Non-small Cell Lung Cancer). Interim data analysis may take care of such decision of continuation and assessment of prospect.

In contrast, MEDI5752 was developed to address the challenge of delivering greater CTLA-4 inhibition without adding toxicity. This is the strengths of the eVOLVE study compared to the KEYNOTE-A18 trial. The most common side effects were dermatitis and elevated liver enzymes. Diarrhoea and colitis occurred less than typically expected with conventional CTLA-4 blockade.

IMMUNOLOGICAL PRINCIPLE

T cell activation requires 2 signals. First, major histocompatibility complex guided antigenic recognition by T cell receptor is inherently weak. It leads T cells to anergy. Positive signal transmitted by B7 (CD80/86) binding to CD28 balanced by a negative signal transmitted by B7 binding to CTLA-4 is central the mechanism where immunotherapy works. Drugs acting on this directly or through a host of co-inhibitory and co-stimulatory pathways/molecules constitutes immunotherapy [4].

BsAb in immunotherapy will necessarily mean 2 antibodies or immune check inhibitors having effect in above pathways. They are tugged on a single immunoglobulin by bioengineering.

LITERATURE SURVEY

When searched in PubMed MEDI5752 had only 3 entries, all in AACR’s Cancer Discovery; one review and a case report is in a single issue (May 2021) while the third one, a news in brief by Alissa Poh [5] is in June 2022 issue.

Burton and Tawbi [6] in their review predicted “precision Immunotherapy” in tune with the mechanism of MEDI5752 where engineered competitive targeting occurs in the T cells expressing both PD-1 and CTLA-4. It theoretically achieves the goal of higher “dose,” to get best outcome with least AEs due to less non-tumor infiltrating lymphocyte (TIL) activation and subsequently fewer immune-related AEs. Internalization and degradation of PD-1 receptors also occur causing more stable and prolonged PD-1 inhibition.

The second paper is a preclinical study with preliminary case study at the beginning of phase I study by Dovedi et al. [7]. It showed PD-1/CTLA-4 co-expression in 80%–90% of TIL. Manageable toxicity was shown in their phase I study evaluating the safety of MEDI5752 (NCT03530397). However, they inferred that there may not be sufficient response in cases with low tumor mutational burden and/or lack of appropriate and potent antigen-presenting cells in so called ‘immunologically cold tumors’ or ‘immune desert.’

DRUG DEVELOPMENT & PATENT

Most important and reportable incidence that happened by this time is that the Chinese regulatory approved cadonilimab (AK 204) [8] from Akseo, Inc. in June 2022. It is globally first dual immune checkpoint inhibitor BsAb approved for marketing. This molecule does same thing and is already equipped with approval from Chinese drug regulatory authority in recurrent cervical cancer. They started trial in 2017 and already got orphan drug designation in FDA in 2021.

Volrustomig started its development at least by 2015. It is actually the pioneer in this PD-1 × CTLA-4 categories. Market impression is while famous pembrolizumab has become one of the most watched in oncology there is craze in industry to have a share of the drug’s gushing multibillion-dollar revenue stream. MEDI5752 or volrustomig (C₆₅₂₈H₁₀₀₀₆N_1736O2029S₄₇) could be one such molecule, though there is still some issue with dose. It’s a monovalent bispecific immunotherapy and is strategically unique as it combines anti PD-1 and anti CTLA-4 action. In gastric carcinoma it has a 30% phase transition success rate which indicates benchmark for progressing into phase III. GlobalData’s reported its Likelihood of Approval & probability of success to be very high. Studies for post second-line therapies do better than first-line therapy. OS is inferior to PFS or response rate as primary end point. Studies for which there is strong prior evidence are disadvantageous for success. Studies for lead indication succeed more than non-lead indication.

First AstraZeneca immunotherapy durvalumab came in May 2017 when only one bispecific molecule was proposed from Pieris Pharmaceuticals [4]. Most recent scenario on bispecific molecule in immunotherapy is well described by this team of Sichuan University, Chengdu, China. They eventually presented their Phase 1 Data for 4-1BB/HER2 bispecific ‘PRS-343’ using anticalin protein technology using natural lipocalins [9] but they got their patent for PRS-343 only in 2021. It was surprising that patent came later than publication. Though by 2017 2 BsAb, i.e., blinatumomab (2014) and emicizumab-kxwh (2017) were approved PRS-343 was the first immune checkpoint blocker containing BsAb though it was not double immune checkpoint blockers.

Other such molecules of same dual combination [10] PD-1 × CTLA-4 in development are bispecific DART molecule (MGD019, lorigerlimab of MacroGenics), XmbAb20717 from Xencor, SI-B003 of Sichuan Baili Pharmaceutical Co. and KN046 of Alphamab Oncology. Three more PD-L1 × 4.1BB (CD137) combinations beyond PRS-343 (ABL503, FS222, MCLA-145), 2 PD-1 × LAG-3 (EMB-02, RO7247669), 2 PD-L1 × LAG-3 (ABL501, FS118), 2 PD-1 × TIM-3 (AZD7789, RO7121661), one PD-1 × TIGIT (AZD2936) and one PD-1 × PD-L1 (IBI318) have been reported so far.

MEDI5752 was lodged in United States. Patent of Kasturirangan et al. for it had provisional application No. 62/332,788 and was filed on May 6, 2016 with Patent No.: US 10,457,732 B2 and Date of Patent: Oct. 29, 2019 for their BISPECIFIC BINDING PROTEINS AND USES THEREOF. Applicant was: MEDIMMUNE, LLC, Gaithersburg, MD, USA. Research took place in the Discovery Centre of MedImmune, LLC. in Biomedical Campus of Cambridge, UK. Just after application for this patent is lodged Dr. Srinath Kasturirangan (Fig. 1) left MedImmune in 2017 and joined Boehringer Ingelheim as chief scientist. Another Indian in this patent was Prakash Manikwar who’s associate director in AstraZeneca now.

Fig. 1. Dr. Srinath Kasturirangan.

PLATFORM

Unlike natural bivalent antibodies, the BsAbs are dual-specicity molecules binding 2 different epitopes simultaneously, hence they require specific platform or format so that they can be genetically altered to abolish antibody-dependent cell-mediated cytotoxicity or complement dependent cytotoxicity while retaining the potential for a lengthy half-life. Many such formats such as, crossmab, nanobody, grabody, sdAB, etc. are used in producing above BsAbs. DuetMab technology is a format for MEDI5752 & was first reported in 2015 by the Department of Antibody Discovery and Protein Engineering of MedImmune [10]. Its patent is same as that of MEDI5752. There are 4 entries for DuetMab in PubMed. In MEDI5752 it acts by fusing an anti-PD-1 mAb and the variable binding domains of Tremelimumab (anti-CTLA-4) onto a DuetMab backbone, optimally designed with triple amino acid mutations of the human IgG1 constant heavy chain to reduce Fc-mediated immune effector functions. Mazor et al. [11] created this novel DuetMab design by 2015. Dovedi et al. [7] discovered that this engineered molecule preferentially localizes and inhibits CTLA-4 on PD-1 + T cells and rapidly induces internalization and degradation of PD-1. Yariv Mazor is also one of the patent holders of MEDI5752. This platform uses knobs-into-holes technology for heterodimerization of 2 distinct heavy chains. It increases the efficiency of pairing of heavy and light chain by replacing the disulfide in one of the CH1:CL interfaces with an engineered disulfide bond. Thus it appears that Medimmune invented MEDI5752 between January 2015 to May 2016.

NOMENCLATURE

If one tries to search about how MEDI5752 became volrustomig there will be no direct or easy reference. After cancer discovery paper MEDI5752 is presented in multiple conferences including Society for Immunotherapy of Cancer, European Society for Medical Oncology and American Society of Clinical Oncology. In ESMO Congress of September 2022 it was MEDI5752. This naming scheme followed both the World Health Organization’s International Nonproprietary Names (INN) [12], and the United States Adopted Names (USAN) for pharmaceuticals. It was proposed in INN proposed list 127 dated 21 July 2022 (WHO Drug Information Vol. 36 No. 2, 2022). New word stem ‘mig’ is multi-immunoglobulin and substems ‘sto’ is immunostimulatory. Sometimes substems are erroneously called infixes, even by the USAN Council itself. Volru could be company or proprietary name. Recently PD-1 × TIGIT bispecific (AZD2936, AstraZeneca) got the name Rilvegostomig which showed promise following prior immunotherapy resistance for advanced PD-L1+ NSCLC.

Dr. Wayne T. Hockmeyer & MEDIMMUNE

It appears from above discussion that invention of MEDI5752 occurred long after Medimmune was sold to AstraZeneca. Dr. Wayne T. Hockmeyer was a Vietnam War veteran. He was born in La Crosse, Wis., and raised in Evansville, Indiana. He founded Molecular Vaccines, Inc. in 1988. Dr. James Young joined him as head of research and development. Company’s name was changed to Medimmune, LLC in 1989. With failure of RespiGam in FDA they faced “bet the farm” moment. But the team persevered, and MedImmune won its approval in 1996, got huge successes with the blockbuster flu-fighter FluMist. He was joined in 1993 by David Mott would succeed him as MedImmune's chief executive. He came from banking sector. The company was sold to AstaZeneca in 2007 when they agreed to acquire MedImmune for $15.6 billion (Fig. 2). After 30 years of drug development, MedImmune ceased to exist as an industry name from February 2019 when AstraZeneca decided to retire the brand.

Fig. 2. MedImmune founder Wayne T. Hockmeyer, third from right, with James Young, David Mott and Douglas Swirsky (photo by Larry French).