Behind the FDA Approval: Afami-Cel in Synovial Sarcoma

Sandra P. D'Angelo, MD

The FDA approved afamitresgene autoleucel (afami-cel) for the treatment of patients with advanced synovial sarcoma, based on data from the phase 2 SPEARHEAD-1 trial (NCT04044768).¹

SPEARHEAD-1 trial was an open-label, non-randomized trial performed in 23 sites within Canada, the US, and Europe.² Three cohorts were included in the trial. Cohort 1, the main investigational cohort, included patients with HLA-A*02 who were between the ages of 16 to 75 years with metastatic or unresectable synovial sarcoma or myxoid round cell liposarcoma that expressed MAGE-A4. These patients had received at least 1 prior line of anthracycline- or ifosfamide-containing chemotherapy. Once enrolled, these patients received a single dose of afami-cel via intravenous infusion following lymphodepletion.

The primary end point in cohort 1 of the trial was overall response rate (ORR) as assessed by a masked independent review committee using RECIST v1.1 in the modified intention-to-treat population.

A total of 52 patients with cytogenetically confirmed synovial sarcoma (n = 44) and myxoid round cell liposarcoma (n = 8) were enrolled between December 17, 2019, and July 27, 2021. These patients in cohort 1 received afami-cel and were heavily pretreated with a median of 3 prior lines of systemic therapy (IQR, 2-4).

At a median follow-up of 32.6 months (IQR, 29.4-36.1), the overall ORR among all patients was 37% (95%, CI 24%-51%), 39% (95% CI, 24%-55%) for patients with synovial sarcoma and 25% (95% CI, 3%-65%) for patients with myxoid round cell liposarcoma.

Looking at safety, 37 patients (71%) had cytokine release syndrome (CRS). One CRS event was grade 3. The most common grade 3 or greater adverse event was cytopenia, with lymphopenia seen in 96% of patients, neutropenia in 85%, and leukopenia in 81%. Moreover, there were no treatment-related deaths.

Overall, treatment with afami-cel led to durable responses in heavily pretreated patients with HLA-A*02 and MAGE-A4-expressing synovial sarcoma. The SPEARHEAD-1 trial backs the recent FDA approval of afami-cel in this patient population, showing that this type of T-cell receptor therapy can be used to effectively target solid tumors. With these promising results, there is potential to expand this treatment approach to be used in other solid malignancies.

In an interview with Targeted Oncology^TM, Sandra P. D'Angelo, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed the approval and supporting data of afami-cel for the treatment of synovial sarcoma.

Targeted Oncology: Can you discuss the mechanism of afami-cel?

D’Angelo: Afami-cel is a T-cell receptor. The way it works is that it takes a patient's own immune cells and redirects them to the type of protein that is found in the patient's tumor. In this particular case, the protein is called MAGE-A4.

Photorealistic illustration of sarcoma - Generated with Google Gemini AI.jpeg

Can you provide an overview of the clinical trial design for SPEARHEAD-1?

SPEARHEAD-1 was an open-label study where patients with synovial sarcoma were enrolled. This particular trial enrolled patients based on the presence of both a specific blood type called HLA-A*02, and the presence of an expression of the protein in the tumor, MAGE-A4. The first part of enrolling on the trial for patients, when we think about the patient journey, is the screening portion. That is where we look for those particular features. Once we see and learn that the patients qualify, then they go on to the treatment phase of the protocol.

In the treatment phase of protocol, the first part of that is what we call leukapheresis. That is where we remove the blood and send it off to a central manufacturer to genetically modify the T cells to detect the MAGE-A4 protein. That process is called manufacturing. Once that process is completed, the cell is sent back to those specific treatment centers. Then, patients receive chemotherapy, and then they receive the T cells. That is then followed up for the presence of adverse events and determining whether the therapies work with the CAT scans and imaging.

What were the key efficacy results seen in the trial?

In the context of the trial, we saw that the overall response rate was approximately 37%. In the clinical trial, both patients with synovial sarcoma and myxoid round cell liposarcoma were enrolled. When we look more closely at synovial sarcoma, the response rate was 39%. That actually comprised the bulk of the patients that were enrolled, and the duration of response was 11.6 months in synovial sarcoma. We also were able to identify certain features that seem to correlate with improved benefit, namely, those patients that had higher MAGE-A4 expression and lower disease burden, those all were positively correlated with being more likely to benefit.

What significant safety findings were observed?

The most common [adverse] effect that we tend to see with T-cell therapy is something called cytokine release syndrome, which is essentially inflammation in the body. This occurred in about 70% of patients, but it was mostly grade 1 or 2. About 37% of patients received the drug tocilizumab [Actemra], which is an effective way to treat cytokine release syndrome. The other common [adverse] effects that we see is what we refer to as cytopenia, which we think is mostly related to the cytoreductive chemotherapy that patients receive prior to receiving the T-cell therapy.

[Overall,] the data that we saw sort of duplicated what had been seen in the phase 1 [NCT03132922] data. It was quite similar. There were really no unexpected findings, both with regards to benefit, duration of benefit, and [adverse] effects.

You discussed the CRS and cytopenias. How are these managed? What kind of advice do you have for oncologists treating this patient population in the clinic?

Cytokine release syndrome, if managed correctly and swiftly, is something that is easily addressed. I think the field of T-cell therapy, adoptive cell therapy, and even CAR T-cell therapy, has become more aggressive with the integration and identification of cytokine release syndrome and its management. The mainstay of management right now is with tocilizumab, which is an [interleukin-6] monoclonal antibody. It effectively treats, almost universally, rare instances where cytokine release syndrome becomes more complex, and at times, you need to use other alternative agents such as steroids and other immunomodulatory agents for that. But that is quite rare. I would say that it is important to be aggressive with the identification of CRS and to be aggressive with this management, mainly with tocilizumab.

What lessons were learned from the trial that could inform future research and the development of similar therapies?

What we have learned is that this form of therapy is an effective therapy for immunologically cold tumors. Synovial sarcoma sort of is a prototype of a type of cancer that has limited immune cells. Other drugs, such as checkpoint inhibitors, have been shown to be relatively ineffective. I think the fact that we can effectively stimulate the immune system with this exogenous administration of a patient's own immune cell that has been effectively genetically engineered holds promise that this can probably be expanded to other solid tumors that express this protein. It also highlights that the field of T-cell therapy is probably at its infancy.

This is just laying the foundation for future efforts. There is a clear need to expand applicability and improve duration, but I do think this is the beginning of many more efforts, both in sarcoma and beyond, because checkpoint inhibitors obviously have formed the backbone of immunotherapy development over the last 10 years in our solid tumor space. However, the reality is that those drugs are beneficial for about 20% to 30% of patients. There remains an unmet need across the field of oncology to improve those numbers and those outcomes.

What does this potential approval for afami-cel mean for this patient population?

For synovial sarcoma, this is super important and a practice-changing approval. To give a little bit perspective about synovial sarcoma, there are about 500 to 1000 cases of synovial sarcoma diagnosed in the United States each year, so it falls into the category of a rare malignancy. This is a disease where peak incidence is for patients in their 30s, so young patients are affected with this diagnosis. The standard –of care for synovial sarcoma is typically surgery with or without radiation and with or without adjuvant chemotherapy, but unfortunately, 50% of patients develop metastases and, obviously in the setting of metastatic disease, the disease is no longer curable. Standard therapy has consisted of cytotoxic chemotherapy with drugs like doxorubicin, ifosfamide, a combination of doxorubicin and ifosfamide, where response rates range from 20% to 30%, and the duration of benefit is about a year or a year and a half. When you go to the second and third line, those outcomes become even worse.

The last FDA-approved drug in synovial sarcoma was an oral tyrosine kinase inhibitor called pazopanib, which [was approved in] 2012. That drug offers response rates of about 5% to 10%, and the duration of responses is about 5 months. Afami-cel offers a remarkable improvement upon the standard –of care, so it is a promising and exciting option for our patients. It also provides a lot of hope and excitement for patients with rare cancers as it shows the ability of our sarcoma community to work together to identify these patients, treat these patients, and bring this drug over the finish line. I think it is an exciting time. Obviously, the limitation is the eligibility criteria, because not every patient with synovial sarcoma will be eligible based on the requirements of the specific blood type, but that will require us to expand that applicability and think of other alternative ways to target those particular patients.

T-cell therapy is generally limited to specific sites within the United States that are able to administer this therapy. I imagine that we are going to be working together as a community to identify those sites and allow patients to have access to these particular drugs.

REFERENCE:

1. Adaptimmune receives U.S. FDA accelerated approval of TECELRA® (afamitresgene autoleucel), the first approved engineered cell therapy for a solid tumor. News release. Adaptimmune. August 1, 2024. Accessed August 1, 2024. https://tinyurl.com/tch2emrw

2. D'Angelo SP, Araujo DM, Abdul Razak AR, et al. Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial. Lancet. 2024;403(10435):1460-1471. doi:10.1016/S0140-6736(24)00319-2