Durvalumab Plus Tremelimumab and Hypofractionated Radiotherapy Shows Early Promise in Gynecologic Cancers

The combination of durvalumab, tremelimumab, and hypofractionated radiotherapy demonstrated early tolerability in patients with gynecologic malignancies and elicited objective responses in those with PD-L1–high tumors.

The combination of durvalumab (Imfinzi), tremelimumab (Imjudo), and hypofractionated radiotherapy demonstrated early tolerability in patients with gynecologic malignancies and elicited objective responses in those with PD-L1–high tumors, according to data from a phase 1 trial presented during the 2023 SGO Annual Meeting on Women’s Cancer.1

All 18 patients experienced at least one grade 1 adverse effect (AE), with more than half (55%) experiencing toxicities that were grade 3 or 4 in severity. Two patients had immune-related AEs in the form of grade 2 hypothyroidism and grade 3 conjunctivitis/dermatitis. No patients discontinued the study because of treatment-related AEs.

The regimen induced an overall objective response rate (ORR) of 16%, which was comprised of two complete responses (CRs) and one partial response (PR). The median progression-free survival (PFS) was 3.7 months, according to lead author Lilie L. Lin, MD, professor in the Department of Gynecologic Oncology and Reproductive Medicine of the Division of Radiation Oncology at The University of Texas MD Anderson Cancer Center in Houston.

“The combination of durvalumab, tremelimumab, and hyperfractionated radiotherapy was tolerable, and clinical benefit was observed despite multiple prior lines of therapy, prior pelvic radiotherapy, and PD-L1 low [status],” Lin said in a presentation of the data. “However, objective responses [were] only observed in patients with PD-L1–high tumors.”

Radiation is a local treatment. “We don’t expect to see effects outside of the radiation field,” Lin noted. “Furthermore, we’re taught that [although] metastatic progression is treatable, we are [hesitant] to use the word ‘cure.’ The introduction of immunotherapy…has [had] a transformational impact not only on many patients with cancer, but it has also caused us to rethink some of these conventional teachings.”

Lin shared a case report published in the New England Journal of Medicine which highlighted the details of a patient with metastatic melanoma who received treatment at Memorial Sloan Kettering Cancer Center.2 This patient had received ipilimumab (Yervoy) for approximately 1 year and received palliative radiotherapy to the right paraspinal mass for symptomatic progression. The patient then received ipilimumab again “presumably because she could not receive any other therapies,” Lin noted.

“A CT scan a couple of months later showed regression not only in the mass that was treated, which was expected, but also in lesions in the mediastinum and in the spleen,” Lin underscored. “This is thought to be due to an abscopal effect, [which] is an effect of radiation outside of the field that was treated, because she had progressed on ipilimumab before.”

This report, coupled with other anecdotal reports, according to Lin, inspired the hypothesis that hyperfractionated radiotherapy and checkpoint inhibitors could reinvigorate the exhausted T cells and elicit an abscopal effect.

She added that Andy J. Minn, MD, PhD, of the University of Pennsylvania, evaluated this hypothesis in mouse models of melanoma.3 “[He put] tumors on bilateral hind legs and [treated] one with radiation and [left] the other one unirradiated, while also giving these mice anti–PD-L1, anti–CTLA-4 blockade, or a combination of both.

He found that the mice that received checkpoint blockade and radiation experienced regression of the unirradiated hind leg tumors, as well. Moreover, in the mice, dual checkpoint blockade and hypofractionated radiotherapy conferred better survival vs radiation alone, checkpoint inhibitor alone, or other combinations, according to Lin.

“How is hypofractionated radiotherapy and immunotherapy thought to work synergistically?” Lin asked. “Well, hypofractionated radiation—which is large doses of radiation, 5 Gy to 8 Gy, delivered in 3 to 5 fractions—is thought to elicit a tumor antigen burst and these antigens are then picked up by dendritic cells to elicit a T-cell–mediated immune response. Then, they go throughout the body [to] other metastatic sites to elicit a response.

The phase 1 trial conducted at UT Southwestern and MD Anderson enrolled patients with a histological diagnosis of recurrent or metastatic cervical, vaginal, or vulvar cancer. Patients were required to have metastatic disease in at least 2 distinct lesions that was evaluable by irRECIST criteria. They also needed to have previously received at least 1 line of platinum-based systemic chemotherapy.

They could not have previously received immunotherapy or oncologic vaccine therapy, a history of hepatitis, or active or previously documented autoimmune or inflammatory disorder.

Study participants received the PD-L1 inhibitor durvalumab at 1500 mg plus the CTLA-4 inhibitor tremelimumab at 75 mg every 4 weeks for 4 cycles, followed by an additional 4 cycles of durvalumab. Patients received stereotactic body radiation therapy at 8 Gy three times during week 2 or around day 3 to day 7.

Investigators collected research blood, as well as cervical and rectal swabs. Patients were imaged every 2 cycles.

The primary objective of the research was to understand the safety and tolerability of immune checkpoint blockade plus 3 fractions of hypofractionated radiotherapy in up to 2 metastatic lesions. Key secondary objectives were to examine clinical response rates and toxicities with the regimen, as well as to estimate PFS, overall survival, and time to next treatment.

The mean age of study participants was 43.9 years (range, 25-63), and 56% of patients were Caucasian. Most patients (89%) had a primary tumor site of the cervix; in 11% of patients, the primary tumor site was the vagina.

In terms of histology, 78% of patients had squamous cell carcinoma, 17% had adenocarcinoma, 6% had adenosquamous disease, 6% had clear cell carcinoma, and 6% had high-grade poorly differentiated carcinoma. Regarding PD-L1 status, 67% of patients had PD-L1–high disease, defined as a combined positive score of 1 or higher, and 33% had PD-L1–low disease. Seventy-eight percent of patients received 1 prior line of therapy, and 22% received more than 2 prior lines. Moreover, most patients (72%) previously received radiotherapy.

Investigators examined responses by PD-L1 status. “Of the 3 patients who had an objective response, they all had PD-L1–high tumors,” Lin noted. “Although we did observe clinical benefit in those who had PD-L1–low tumors.”

In those with PD-L1–high disease, the CR rate was 16.7% (n = 2), the PR rate was 8.3% (n = 1), and the stable disease (SD) rate was 25.0% (n = 3). Six patients (50%) progressive disease (PD). Fifty percent of patients experienced clinical benefit and the other half did not. In the PD-L1–low group, no patients achieved a CR or PR with the regimen; 66.7% (n = 4) had SD and 33.3% (n = 2) experienced PD. In this subset, 33.3% of patients did not derive benefit from the regimen and 66.7% did.

They also evaluated response by prior pelvic radiotherapy. Two patients who achieved a CR previously received pelvic radiation. “Although we did observe higher clinical benefit in patients who had no prior radiotherapy,” Lin said.

Specifically, in the group of patients who had prior radiation, 2 patients had a CR (15.4%), and no patients experienced a PR; 3 patients had SD (23.1%) and 8 patients had PD (61.5%).

In the group of patients who did not have prior radiation, no patients had a CR, and 1 patient had a PR (20.0%); 4 patients had SD (80.0%) and no patients experienced PD. All 5 patients in this group derived clinical benefit from the regimen.

“These analyses are all hypothesis-generating, given the small nature of our study,” Lin noted.

The most common toxicities reported with the regimen included gastrointestinal disorders (n = 71); investigations (n = 70); metabolism and nutrition disorders (n = 70); general disorders and administration site conditions (n = 34); musculoskeletal and connective tissue disorders (n = 28); blood and lymphatic system disorders (n = 23); respiratory, thoracic, and mediastinal disorders (n = 23); reproductive system and breast disorders (n = 17), renal and urinary disorders (n = 16), skin and subcutaneous tissue disorders (n = 13), endocrine disorders (n = 12), vascular disorders (n = 10), and eye disorders (n = 8).

References

  1. Lin L, Urbauer D, Fang P, et al. A phase I study of tremelimumab, durvalumab, and hypofractionated radiotherapy for metastatic gynecologic cancers. Presented at: 2023 SGO Annual Meeting on Women’s Cancer; March 25-28, 2023; Tampa, Florida.
  2. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366(10):925-931. doi:10.1056/NEJMoa1112824
  3. Victor CT-S, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520(7547):373-377. doi:10.1038/nature14292