Gavo-cel Elicits Clinical Benefit in Solid Tumors, Including Ovarian Cancer and Mesothelioma

Garry Menzel, PhD

Gavocabtagene autoleucel (gavo-cel; TC-210) demonstrated positive topline results from the phase 1 portion of a phase 1/2 trial (NCT03907852) in patients with mesothelin-expressing solid tumors, according to a press release from TCR2 Therapeutics.

Results showed that gavo-cel led to a disease control rate (DCR) of 77% in all evaluable patients with solid tumors (n = 30). Moreover, 93% of patients evaluable for efficacy experienced tumor regression of their target lesions by blinded independent central review (BICR; range, 4%-80%).

The overall response rate (ORR) among patients who received gavo-cel following lymphodepletion chemotherapy was 22% by BICR and 26% by investigator assessment. By BICR, the ORR was 21% in patients with malignant pleural/peritoneal mesothelioma (MPM) and 29% in those with ovarian cancer.

The median overall survival (OS) and progression-free survival (PFS) for patients with MPM was 11.2 months and 5.6 months, respectively. Among patients with ovarian cancer, the median OS and PFS were 8.1 months and 5.8 months, respectively.

“These are remarkable data in the context of solid tumors where there have been significant challenges with current CAR T-cell therapies. I am particularly excited by this second RECIST response in ovarian cancer as it supports the meaningful clinical activity of gavo-cel in a large patient population. Additionally, we continue to observe consistent tumor regression for heavily pretreated patients with mesothelioma for whom limited options are available,” Garry Menzel, PhD, president and chief executive officer of TCR2 Therapeutics, said in a press release.

“We believe our phase 1 clinical data already position gavo-cel as a first- and best-in-class anti-mesothelin monotherapy with a near-term opportunity during phase 2 to further improve the depth and durability of clinical benefit by using it in combination with immune checkpoint inhibitors and redosing strategies,” Menzel added.

Gavo-cel is a T-cell receptor fusion construct directed against mesothelin under evaluation in patients with mesothelin-expressing non–small cell lung cancer (NSCLC), ovarian cancer, cholangiocarcinoma, and MPM. The phase 1 dose-escalation portion of the trial used a modified 3+3 design with four increasing doses of gavo-cel. At each dose, gavo-cel was tested in two separate dose levels: first without lymphodepletion and then following lymphodepleting chemotherapy.

In the phase 2 portion of the trial, patients will receive gavo-cel at the recommended phase 2 dose (RP2D) of 1 x 108 cells/m2 following lymphodepletion. A total of 75 patients will be treated in the MPM cohort and a total of 20 patients will be treated in each one of the following indications: ovarian, NSCLC and cholangiocarcinoma.

In the MPM cohort, patients will be randomly assigned to receive single-agent gavo-cel, gavo-cel in combination with nivolumab (Opdivo), or gavo-cel in combination with nivolumab and ipilimumab (Yervoy). Patients enrolled in the ovarian cancer, NSCLC, or cholangiocarcinoma cohorts will all receive gavo-cel in combination with nivolumab.

The primary goals of the phase 1 portion of the trial are to establish the safety profile of gavo-cel in patients whose tumors overexpress mesothelin and to determine the RP2D. Secondary end points include ORR and DCR.

To date, 32 patients have received gavo-cel at the following dose levels:

• 0: 5 x 107 cells/m2 without lymphodepletion (mesothelioma, n = 1)
• 1: 5 x 107 cells/m2 following lymphodepletion (mesothelioma, n = 7; ovarian cancer, n = 1)
• 2: 1 x 108 cells/m2 without lymphodepletion (mesothelioma, n = 1)
• 3: 1 x 108 cells/m2 following lymphodepletion (mesothelioma, n = 6; cholangiocarcinoma, n = 1; ovarian cancer, n = 6)
• 3.5: 3 x 108 cells/m2 following lymphodepletion (mesothelioma, n = 4; ovarian cancer, n = 1)
• 4: 5 x 108 cells/m2 without lymphodepletion (mesothelioma, n = 1)
• 5: 5 x 108 cells/m2 following lymphodepletion (mesothelioma, n = 3)

Regarding baseline characteristics, the median patient age was 63 years (range, 28-84), and the median number of prior therapies was 5 (range 1-13); prior treatment included checkpoint inhibitor therapy in 66% of patients and mesothelin directed therapy in 19% of patients.

“The results of the phase 1 trial underscore the potential clinical value of gavo-cel in a very heavily pretreated patient population that are receiving our engineered T cells as their sixth line of therapy on average,” Alfonso Quintás-Cardama, MD, chief medical officer of TCR2 Therapeutics, said.

Regarding safety, gavo-cel was generally well tolerated with a manageable adverse effect (AE) profile up to the fifth dose level. Over the course of the phase 1 portion of the trial, two dose-limiting toxicities occurred, including one case of grade 3 pneumonitis at the first dose level that resolved with anti-cytokine therapy, and one case of grade 5 bronchioalveolar hemorrhage at the fifth dose level.

All three patients treated at the fifth dose level experienced severe cytokine release syndrome (CRS), which prompted a recommendation from the Safety Review Team of de-escalation. The most common grade 3 or higher non-hematologic AEs in patients treated at the RP2D was CRS, which occurred in 15% of patients.

“Gavo-cel has demonstrated a manageable safety profile at the RP2D, induced RECIST responses in every indication studied to date, and has provided a promising survival signal among patients with mesothelioma as well as encouraging preliminary efficacy data in ovarian cancer. These results clearly support the further development of gavo-cel in the phase 2 portion of the study where we believe that the combination with checkpoint inhibitors and the ability to retreat patients with additional doses of gavo-cel will allow us to increase patients’ exposure to gavo-cel, potentially translating into even higher response rates and improved durability of benefit,” Quintás-Cardama added.

“We have already dosed a number of patients in combination with checkpoint inhibitors, including patients with ovarian cancer, in the randomized phase 2 portion of the trial and look forward to providing ongoing progress updates on the various arms of the study as well as following the remaining patients still on the phase 1 portion. We are clearly delighted that patients with various cancers continue to derive meaningful benefit from gavo-cel,” Menzel concluded.

Reference

Gavo-cel continues to demonstrate clinical benefit in solid tumors with additional RECIST reponses in ovarian cancer and mesothelioma. News release. TCR2 Therapeutics. September 28, 2022. Accessed September 28, 2022. https://bit.ly/3CgXKOl