European Medicines Agency Grants PRIME Access to ADP-A2M4 for Synovial Sarcoma

The European Medicines Agency (EMA) has granted access to the PRIME initiative for the Specific Peptide Enhanced Affinity Receptor (SPEAR) T-cell therapy ADP-A2M4 (MAGE-A4) for the treatment of patients with synovial sarcoma, according to an announcement from Adaptimmune Therapeutics, plc.¹

“We are thrilled that the EMA has acknowledged the potential of ADP-A2M4 to address an unmet medical need for effective treatment options for patients with advanced synovial sarcoma,” Dennis Williams, PharmD, senior vice president of Late Stage Development at Adaptimmune, stated in a recent press release. “Access to the enhanced EMA support and guidance offered in the PRIME scheme will facilitate the development of ADP-A2M4 to ensure this important medicine reaches patients with sarcoma as early as possible.”

The decision was based on phase 1 data, which demonstrated preliminary efficacy, durability, and tolerability with the agent in patients with synovial sarcoma. Out of 14 patients with the disease who had received treatment during the expansion phase of the trial, 7 were reported to have achieved a clinical response per RECIST criteria with ADP-A2M4; this translated to an objective response rate of 50%.²

Moreover, 13 patients experienced clinical benefit with the agent, with best overall responses of partial response (n = 7) or stable disease (SD; n = 6). The disease control rate with ADP-A2M4 was 93%.

Additional data from post-baseline tumor assessments from 2 additional patients showed that both achieved SD at the time of the data cutoff. Notably, a patient who had previously been reported to have an unconfirmed RECIST response in September 2019, had a confirmed response as of November 2019.

Of the 7 patients who experienced overall responses comprised of either confirmed or unconfirmed PRs, 1 patient had died and 6 remain ongoing for follow-up. Of the 6 patients, 4 were reported to have maintained a response to ADP-A2M4 for at least 6 months and 1 patient maintained a response for more than 9 months following the treatment.

With regard to safety, the adverse effects (AEs) reported with the investigational therapy proved to be consistent with what is typically reported by patients with cancer who are receiving cytotoxic chemotherapy or immunotherapeutics.

“This updated data set confirms that ADP-A2M4 continues to deliver clinical benefit, including RECIST responses, to patients with synovial sarcoma. It has also galvanized the support we have received from the sarcoma community, allowing us to rapidly open multiple sites and screen patients for the phase 2 SPEARHEAD-1 trial,” Elliot Norry, acting chief medical officer of Adaptimmune, stated in a press release.³

In the SPEARHEAD-1 trial (NCT04004768), investigators are examining ADP-A2M4 in patients with metastatic or inoperable synovial sarcoma or myxoid/round cell liposarcoma (MRCLS) who have received previous chemotherapy and whose tumors express the MAGE-A4 tumor antigen.⁴

To be eligible for the trial, patients must be aged between 16 years and 75 years, have a diagnosis of advanced synovial sarcoma or MRCLS confirmed via cytogenetics, have received prior treatment with an anthracycline or an ifosfamide-based regimen, have measurable disease per RECIST v.1.1 criteria and an ECOG performance status of 0 or 1, among other criteria.

Patients with a history of autoimmune or immune-mediated disease are ineligible to participate, as are those with leptomeningeal disease, carcinomatous meningitis or symptomatic central nervous system metastases; those with another prior malignancy not considered to be in complete remission; clinically significant cardiovascular disease, or uncontrolled intercurrent illness.

The primary end point is ORR and secondary end points include, the number of treatment-related AEs, including serious AEs, safety of the agent through measurement of Replication-competent Retrovirus in genetically engineered T cells, as well as best OR, time to response, duration of response, progression-free survival, and overall survival, among others.

ADP-A2M4 is a SPEAR T-cell therapy that is directed to a member of the MAGE family of cancer testis antigen, which is expressed in several types of solid tumors.⁵

"This is a T-cell therapy designed to attack cells expressing MAGE4, a cancer testis antigen which is not usually present in normal cells but that is expressed in a good proportion of tumors like synovial sarcoma or myxoid liposarcoma," Claudia Valverde Morales, MD, of Vall d'Hebron Institute of Oncology, told OncLive. "One of the most exciting aspects is that MAGE-A4 is an intracellular antigen, and thus more difficult to target in comparison with surface antigens, which can be targeted with other therapies like monoclonal antibodies or CAR T. This aspect, which may seem trivial, opens a huge field for tumors, like most sarcomas, that lack very specific surface antigens to target."

"Another important aspect is that, although the process is more complex than receiving other traditional treatments like chemotherapy or TKIs, for responding patients the effect of 1 infusion has the potential to last for a long period," added Valverde Morales. "This would be a nice treat for [patients with] synovial sarcoma, who are usually adolescents and young adults, as it would allow them to have a break from treatments to continue with their studies, jobs, hobbies, and their lives at the end."

In September 2019, the FDA granted an orphan drug designation to SPEAR T cells targeting MAGE-A4 for the treatment of patients with soft tissue sarcomas; a Regenerative Medicine Advanced Therapy designation was also granted to this approach for the treatment of patients with synovial sarcoma.

More recently, in April 2020, the EMA’s Committee for Orphan Medicinal Products adopted a positive opinion for the orphan drug designation for ADP-A2M4 for the treatment of patients with soft tissue sarcomas.

References

1. Adaptimmune granted access to PRIority MEdicines (PRIME) regulatory support by the European Medicines Agency for ADP-A2M4 for the treatment of synovial sarcoma. News release. Adaptimmune Therapeutics, plc. July 23, 2020. Accessed July 27, 2020. https://bit.ly/3hJDyYn.
2. Van Tine BA, Butler MO, Araujo D, et al. ADP-A2M4 (MAGE-A4) in patients with synovial sarcoma. Ann Oncol. 2019;30(suppl 5):v684-v685. doi:10.1093/annonc/mdz283.003
3. Updated data from phase 1 ADP-A2M4 trial demonstrating continued clinical benefit for people with synovial sarcoma. News release. Adaptimmune Therapeutics, plc. November 16, 2019. Accessed July 27, 2020. https://bit.ly/3f0abyZ.
4. Spearhead 1 study in subjects with advanced synovial sarcoma or myxoid/round cell liposarcoma. ClinicalTrials.gov. Updated July 10, 2020. Accessed July 27, 2020. https://clinicaltrials.gov/ct2/show/NCT04044768.
5. ADP-A2M4. Adaptimmune Therapeutics, plc. Accessed July 27, 2020. https://bit.ly/2P16uyw.