New Strategies for Targeting CTLA-4 Emerge

In 2011, the development of ipilimumab (Yervoy), a novel antibody targeting the CTLA-4 immune checkpoint, helped launch the modern era of anticancer immunotherapy.¹ Although immune checkpoint inhibitors (ICIs) directed at the PD-1/PD-L1 checkpoint have multiplied since that milestone, it has taken more than a decade for another therapy aimed at CTLA-4 to reach clinical practice.²

In October 2022, the FDA approved tremelimumab (Imjudo), a CTLA-4 inhibitor, in combination with durvalumab (Imfinzi), a PD-L1–directed ICI, for treating patients with unresectable hepatocellular carcinoma (HCC).³ A month later, the agency gave the go-ahead for a regimen combining the 2 ICIs plus platinum- based chemotherapy for patients with metastatic non–small cell lung cancer (NSCLC).⁴

The development of anti–CTLA-4 ICIs has been challenging because monotherapy has been comparatively less effective with higher rates of more serious immune-related adverse events (AEs) than the PD-1/PD-L1 class of inhibitors. Investigators believe these differences may stem from the distinct roles that the CTLA-4 and PD-1/ PD-L1 checkpoints play in the immune system, including in the response to cancer cells.^5,6

During the past several years, investigators increasingly have turned their attention to incorporating CTLA-4 blockade into combination regimens.⁵ The indications for ipilimumab have grown beyond its initial approval as monotherapy for unresectable or metastatic melanoma to combinations with nivolumab (Opdivo), a PD-1 inhibitor, in clinical settings for renal cell, hepatocellular, colorectal, NSCLC, malignant pleural mesothelioma, and esophageal cancers.^7,8

Recent developments indicate that the trend toward combinatorial approaches involving CTLA-4 inhibition is continuing while investigators also pursue novel drug designs for targeting the checkpoint.^9-20

One of the most advanced emerging agents in terms of clinical development is quavonlimab (MK-1308), an anti−CTLA-4 antibody. Quavonlimab has reached phase 3 testing as part of a coformulation with pembrolizumab (Keytruda), a PD-1 inhibitor. The coformulation, MK-1308A, is being evaluated in combination with lenvatinib (Lenvima), a VEGF receptor 2 inhibitor, in one cohort of a 3-arm trial (NCT04736706) in patients with advanced clear cell renal cell carcinoma.^12,13

Botensilimab (AGEN1181), a multifunctional CTLA-4 antibody, also is advancing in clinical development. Investigators recently reported promising findings for botensilimab in combination with balstilimab (AGEN2034), an anti–PD-1 antibody, in colorectal cancer (CRC) and ovarian cancer.^14,15

The 2023 American Society of Clinical Oncology Annual Meeting (ASCO 2023) in June offered a glimpse of additional emerging approaches. These include the combination of zalifrelimab (AGEN1884), a CTLA-4 inhibitor, plus balstilimab16; gotistobart (ONC-392), a CTLA-4–directed antibody that selectively depletes regulatory T cells (Tregs) in the tumor microenvironment^17,18; XmAb22841, a bispecific antibody targeting the CTLA-4 and LAG3 checkpoints19; and XTX101, a tumor-selective anti–CTLA-4 monoclonal antibody (mAb).²⁰

Establishing the Foundation

The use of immune checkpoint inhibition as an anticancer strategy has been growing since 1995, when James P. Allison, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and colleagues first proposed the concept of CTLA-4 blockade.⁵ Allison, a 2014 Giants of Cancer Care® award winner in the scientific advances category, shared the 2018 Nobel Prize in Physiology or Medicine with Tasuku Honjo, MD, PhD, of Kyoto University in Japan, for discoveries related to inhibition of negative regulation of the immune system.²¹ Allison’s work helped pave the way for the development of ipilimumab, a human IgG1κ anti–CTLA-4 mAb, setting the stage for the exploration of subsequent therapies aimed at other checkpoints such as PD-1. Both CTLA-4 and PD-1 are negative regulators of T-cell activation that modulate the immune response to avoid hyperactivation and protect native body cells. However, the mechanisms of these checkpoints differ.⁶ CTLA-4 inhibits immune responses through multiple processes,⁶ primarily at the initial stage of T-cell activation that usually takes place in the lymph nodes, although findings in mice suggest CTLA-4 may continue to play an important role in self-tolerance during the life span of a T cell.⁵ By contrast, PD-1 is active in maintaining peripheral tolerance, working primarily through intracellular signaling in effector T cells and Tregs during the effector phase.^5,6

Investigators believe these mechanistic distinctions contribute to the differences in clinical outcomes observed with ICIs targeting the checkpoints.⁵ Although ipilimumab monotherapy improved overall survival (OS) in patients with previously treated nonresectable melanoma and as adjuvant therapy for resectable melanoma, findings in several other tumor types have not demonstrated similar benefits.⁶ Meanwhile, the development of ICIs directed at the PD-1/PD-L1 pathway has flourished; the FDA has now approved 8 therapies aimed at this checkpoint.^{22, 23}

Tremelimumab's Journey from Dissapointment to Approval

The challenges of targeting CTLA-4 are reflected in the long development arc for tremelimumab, a human IgG2 mAb. Preclinical work on the antibody began in the 1990s, followed by approximately 20 phase 1 and 2 trials in a range of tumor types.²⁴ In 2008, investigators reported that tremelimumab failed to significantly improve median OS compared with the standard of care (temozolomide or dacarbazine) in patients with treatment-naïve, unresectable stage IIIC or IV melanoma in a phase 3 trial (NCT00257205).25 In the final analysis, median OS was 12.6 months (95% CI, 10.8-14.3) for patients treated with tremelimumab vs 10.7 months (95% CI, 9.36-11.96) for participants who received chemotherapy (HR, 0.88; P = .127).²⁶

Some investigators theorized that the disappointing outcome of the study may have resulted from the enrollment of patients with a more favorable prognosis, leading to better-than-expected results in the control group, and in a potentially suboptimal dosing schedule.²⁵ Additionally, standards for evaluating immune-related responses were not introduced until 2009 after most of the tremelimumab studies were designed.²⁴

During the next several years, however, combination regimens incorporating tremelimumab also failed to meet primary end points in pivotal studies in NSCLC, head and neck cancer, urothelial carcinoma, and small cell lung cancer.²⁷

Liver Cancer Success: HIMALAYA Trial

The tide of clinical findings began turning in tremelimumab’s favor when investigators published the results of the phase 3 HIMALAYA trial (NCT03298451) in NEJM Evidence in June 2022. A total of 1171 patients with unresectable HCC and no prior systemic treatment were randomly assigned to receive tremelimumab plus durvalumab (n = 393), durvalumab alone (n = 389), or the angiogenesis inhibitor sorafenib (Nexavar) as monotherapy (n = 389).²⁸

For the tremelimumab-plus-durvalumab cohort, investigators developed the single tremelimumab regular interval durvalumab (STRIDE) infusion regimen, which consisted of a single high priming dose of tremelimumab at 300 mg plus 1500 mg of durvalumab every 4 weeks. Durvalumab monotherapy also was administered at 1500 mg every 4 weeks, and sorafenib was dosed at 400 mg twice daily. (The study initially included a fourth treatment arm that called for dosing tremelimumab at 75 mg every 4 weeks for 4 doses plus 1500 mg of durvalumab every 4 weeks but enrollment in that cohort was closed after phase 2 results failed to support its efficacy²⁸).

The primary end point of the study was OS in the STRIDE cohort compared with the sorafenib group. Noninferiority of durvalumab monotherapy vs sorafenib was a secondary end point.²⁸ After a median follow-up of approximately 33 months, the median OS among patients treated with the STRIDE regimen was 16.43 months (95% CI, 14.16-19.58) compared with 13.77 months (95% CI 12.25-16.13) for sorafenib alone, which translated into an HR favoring the combination of 0.78 (96.02% CI, 0.65-0.93; P = .0035). Durvalumab monotherapy was noninferior to sorafenib (HR, 0.86; 95.67% CI, 0.73-1.03).²⁸

The participants who received the STRIDE regimen also outpaced those for participants who received sorafenib, respectively, at 18 months (48.7% vs 41.5%), 24 months (40.5% vs 32.6%), and 36 months (30.7% vs 20.2%).²⁸

In the safety analysis, the rates of treatment- emergent AEs (TEAEs) of grade 3 or 4 severity were 50.5% in the STRIDE arm, 37.1% with durvalumab monotherapy, and 52.4% with sorafenib monotherapy. The rates of TEAEs leading to discontinuation in the 3 trial arms were 13.7%, 8.2%, and 16.8%, respectively.²⁸

The most common TEAEs of any grade with the STRIDE regimen included diarrhea (26.5%), pruritus (22.9%), and rash (22.4%). Immunemediated TEAEs were observed in 35.8% of patients in the STRIDE arm compared with 16.5% of participants who received durvalumab monotherapy and 8.0% of patients treated with sorafenib.²⁸

Based on the results of the HIMALAYA trial, the FDA approved the combination of tremelimumab plus durvalumab for adult patients with unresectable HCC in October 2022, with the STRIDE regimen as the recommended dose for patients weighing 30 kg or more. The dosages of both ICIs are adjusted for patients weighing less than 30 kg.

Lung Cancer Win: POSEIDON Trial

Less than a month after approving the HCC indication, the FDA granted approval for tremelimumab in combination with durvalumab and platinum-based chemotherapy for adult patients with metastatic NSCLC without sensitizing EGFR mutations or ALK alterations.⁴

The phase 3 POSEIDON study (NCT03164616) included 1013 patients with metastatic NSCLC who had not received prior systemic treatment. Participants were randomly assigned to 1 of 3 treatment arms: tremelimumab at 75 mg plus durvalumab at 1500 mg plus platinum-based chemotherapy for up to four 21-day cycles, followed by durvalumab once every 4 weeks and 1 additional dose of tremelimumab; durvalumab at 1500 mg plus platinum-based chemotherapy for up to four 21-day cycles, followed by durvalumab every 4 weeks; or platinum-based chemotherapy for up to six 21-day cycles. Participants in each arm also were eligible for maintenance chemotherapy.^4,29

The FDA based its decision on a comparison of OS and progression-free survival (PFS) outcomes among patients treated with the tremelimumab- containing regimen (n = 338) vs chemotherapy alone (n = 337). The median OS was 14.0 months (95% CI, 11.7-16.1) in the tremelimumab cohort vs 11.7 months (95% CI, 10.5-13.1) in the chemotherapy group, for an HR of 0.77 (95% CI, 0.65-0.92; 2-sided P = .0030). Median PFS also favored the use of tremelimumab at 6.2 months (95% CI, 5.0-6.5) vs 4.8 months (95% CI, 4.6-5.8) with chemotherapy (HR, 0.72; 95% CI, 0.60-0.86; 2-sided P = .0003).²⁹

Investigators also reported in the Journal of Clinical Oncology that the combination of durvalumab plus chemotherapy significantly improved PFS compared with chemotherapy alone (HR, 0.74; 95% CI, 0.62-0.89; P = .0009) but that a trend toward improved OS did not reach statistical significance (HR, 0.86; 95% CI, 0.72-1.02; P = .0758).²⁹ The addition of tremelimumab to durvalumab plus chemotherapy resulted in a higher rate of treatment-related AEs (TRAEs) of grade 3 or 4 severity (51.8%) compared with either durvalumab plus chemotherapy (44.6%) or chemotherapy alone (44.4%).

The most frequently observed TRAEs across all arms were those usually associated with chemotherapy, such as anemia and neutropenia, investigators said. They concluded that although immune-mediated TRAEs were more common in the cohort treated with tremelimumab, the effects were typically low-grade and manageable.²⁹

New Data on Tap

A growing body of clinical data points to a potentially promising future for targeting CTLA-4. Investigators recently reported findings for several new agents moving forward in the development cycle.

Botensilimab

Botensilimab, a CTLA-4 inhibitor, is being developed through the FDA’s fast track program as combination therapy with balstilimab, an investigational PD-1 inhibitor, for patients with microsatellite-stable (MSS) metastatic CRC.³⁰ The agent is an IgG1 antibody designed with an Fc-enhanced structure intended to improve T-cell priming, expansion, and memory while downregulating Tregs to amplify an immune response and decrease complement-mediated toxicity.^14,30

The combination of botensilimab plus balstilimab elicited an objective response rate (ORR) of 23% (95% CI, 14%-34%) in a cohort of 70 patients with MSS CRC who were treated during a multicohort first-inhuman trial (C-800-01; NCT03860272) in advanced cancers, according to findings reported at the 2023 ASCO Gastrointestinal Cancers Symposium in January. One complete response was reported (1%), 15 patients had partial responses (21%), and most (53%) had stable disease. The disease control rate was 76% (95% CI, 64%-85%). At the time of analysis, median OS had not been reached, and median PFS was 4.1 months (95% CI, 2.8-5.5). The 12-month OS rate was 63% (95% CI, 46%-76%).¹⁴

In ovarian cancer, the dual ICI therapies demonstrated an ORR of 33% (95% CI, 15.6%-55.3%) in 24 patients treated in one of the trial cohorts, investigators reported at the 2023 Society of Gynecologic Oncology Annual Meeting on Women’s Cancers in March. The responses included 1 (4%) complete response and 7 (29%) partial responses. Eight patients achieved stable disease, and 8 others experienced disease progression. At a median follow-up of 6.9 months (range, 1.7-29.2), the median duration of response was not reached (95% CI, 4.2-not reached). The disease control rate was 67% (95% CI, 44.7%-84.4%).¹⁵

Agenus Inc, the company developing both immunotherapies, is testing botensilimab in several clinical settings, including in phase 2 trials in advanced melanoma (NCT05529316) and in MSS metastatic/recurrent CRC (NCT05608044). The C-800-01 study continues to recruit patients with ovarian and endometrial cancers, and a global phase 3 study in MSS CRC is planned for 2023.^14,15

Zalifrelimab

Zalifrelimab, another CTLA-4 inhibitor, also is being explored in several therapeutic combinations. In a phase 2 trial (NCT04028063), the combination of zalifrelimab, balstilimab, and doxorubicin is being tested as first- or secondline therapy in patients with advanced/metastatic soft tissue sarcoma. The concurrent use of doxorubicin may improve tumor immunogenicity and boost the efficacy of the dual ICI regimen, investigators said during an abstract presentation at ASCO 2023.¹⁶

The combination showed a 6-month PFS rate of 46.4% (95% CI, 28%-66%) in 28 evaluable patients and an ORR of 33.3% (95% CI, 17%-53%) in 30 efficacy-evaluable patients. Responses were observed in several sarcoma subtypes in which antitumor activity with ICI or doxorubicin monotherapy is unlikely. The study is continuing with a cohort of patients treated with botensilimab in combination with doxorubicin with and without balstilimab.¹⁶

Zalifrelimab also is paired with balstilimab in the phase 2 RaPiDS trial (NCT03894215) for patients with advanced cervical cancer that has relapsed or progressed after first-line platinum-based chemotherapy.

Gotistobart

Unlike first-generation ICIs, gotistobart is an anti–CTLA-4 inhibitor designed to maintain “high-level” CTLA-4 on Tregs through a “recycling mechanism” that improves antibody-dependent cellular toxicity against Tregs in the tumor microenvironment, investigators said in abstracts presented at ASCO 2023. In animal studies, gotistobart also maintained CTLA-4 expression in Tregs in peripheral tissues, which suggests increased antitumor potency with low toxicity.^17,18

At ASCO 2023, investigators presented data from patients with advanced NSCLC resistant to PD-1/PD-L1 inhibitor therapy treated during an expansion portion of the multicohort phase 1 PRESERVE-001 trial (NCT04140526). In the expansion cohort, patients received gotistobart as monotherapy at 10 mg/kg for 2 cycles, followed by gotistobart at 6 mg/kg every 3 weeks.¹⁸

Among 27 evaluable patients, 1 patient had a complete response, 7 exhibited partial responses, and 11 had stable disease, for an ORR of 29.6%. The estimated OS rates were 65% at 6 months and 55% at 12 months, with median OS not yet reached. In all, 43% of patients in the safety population (n = 35) experienced a TRAE of grade 3 or greater severity, which included diarrhea/colitis, an increase in liver enzymes/hepatitis, muscular weakness, nephritis, and adrenal insufficiency.¹⁸

These data have prompted the launch of the phase 3 PRESERVE-003 trial (NCT05671510), in which patients with metastatic NSCLC with disease progression after PD-1/PD-L1 inhibitor therapy will be randomly assigned to treatment with gotistobart or docetaxel. Two different doses of gotistobart will be tested in experimental cohorts. The study has a target enrollment of approximately 600 patients.¹⁷

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