Next-Generation CTLA-4 Targeting Frames Post-Immunotherapy Squamous NSCLC Management

Patients with advanced squamous non–small cell lung cancer (NSCLC) whose disease progresses after PD-(L)1 inhibitor–based therapy and platinum chemotherapy have few options. Docetaxel with or without ramucirumab (Cyramza) remains the standard, and outcomes have changed little in a decade.

At the 2026 IASLC World Conference on Lung Cancer (WCLC 2026), updated data from the phase 3 PRESERVE-003 trial (NCT05671510) investigating the CTLA-4–directed antibody gotistobart (BNT316/ONC-392) in patients with metastatic squamous NSCLC following progression on PD-(L)1 inhibition have sparked renewed interest in a target that has played a complex role in this disease.

During a recent OncLive^® Peer Exchange, lung cancer experts reviewed the post-immunotherapy squamous NSCLC treatment landscape; the evolution of CTLA-4 inhibition in this disease; and approaches to selecting therapies, sequencing tumors, and monitoring for treatment-related adverse effects (TRAEs).

“That gap [in treatment developments for squamous NSCLC] has prompted a broad range of development work, including antibody-drug conjugates [ADCs], bispecific immunomodulators, new immunotherapy combinations, and novel approaches [directed at] CTLA-4, a target with a long and mixed history in lung cancer,” said Jacob Sands, MD, the moderator of the discussion.

Why has treatment development progress been slow for patients with squamous NSCLC after frontline immunotherapy?

“[Docetaxel] is a drug that we all love to hate, but still the one that has preserved benefit in a phase 3 trial,” said Narjust Florez, MD.

That trial is REVEL (NCT01168973), in which adding ramucirumab to docetaxel improved the median overall survival (OS) vs docetaxel alone after platinum-based chemotherapy in patients with stage IV NSCLC.¹ Although REVEL predates frontline checkpoint inhibitors, Florez noted that data from retrospective studies and newer control arms suggest that docetaxel still yields a median OS of approximately 10 to 11 months. She offers ramucirumab plus docetaxel to fit patients who do not have contraindications, such as recent hemoptysis, thromboembolic events, or cavitary lesions.

However, efforts to improve on that backbone have struggled. Findings from the phase 2 Lung-MAP S1800A study (NCT03971474) suggested a benefit with ramucirumab plus pembrolizumab (Keytruda; n = 69), with a median OS of 14.5 months (95% CI, 13.9-16.1) vs 11.6 months (95% CI, 9.9-13.0) with investigator’s choice of standard-of-care therapy (n = 67) in patients with NSCLC who had previously received immunotherapy.² However, the results of the phase 3 Pragmatica-Lung trial (NCT05633602) did not confirm the benefit with this combination in this patient population, although panelists noted that Pragmatica-Lung still advanced community-based trial enrollment through its broad eligibility criteria.³

Edward Kim, MD, MBA, offered context for the slow drug development pace in the squamous NSCLC setting, explaining, “It’s not that we’ve gone slower, it’s just that adenocarcinoma [drug development] has accelerated at a pace that is quicker than any of us could have imagined.”

Which emerging drug mechanisms could reshape squamous NSCLC care after immunotherapy?

Christian Rolfo, MD, PhD, emphasized that the field is moving away from recycling PD-(L)1 blockade and toward new payloads and tumor microenvironment remodeling, outlining 4 types of treatment approaches that align with this shift.

The first approach is TROP2-directed ADCs. In the phase 3 TROPION-Lung01 trial (NCT04656652), datopotamab deruxtecan-dlnk (Datroway) benefited mainly patients with nonsquamous NSCLC, and in the phase 3 EVOKE-01 trial (NCT05089734), sacituzumab govitecan-hziy (Trodelvy) did not meet the primary OS end point vs docetaxel in patients with metastatic NSCLC.^4,5

The second approach pairs a checkpoint inhibitor with an antiangiogenic agent. For instance, in the phase 3 CONTACT-01 study (NCT04471428), atezolizumab (Tecentriq) plus cabozantinib (Cabometyx) missed the trial’s end points, which showed that adding a TKI to PD-(L)1 blockade was not enough, according to Rolfo.⁶

The third approach involves bispecific antibodies, including PD-(L)1/VEGF agents and the PD-1/IL-2 bispecific IBI363. In results from a phase 1 study (NCT05460767) presented at the 2026 ASCO Annual Meeting, patients with immunotherapy-pretreated squamous NSCLC who received IBI363 at 3 mg/kg every 3 weeks (n = 31) had a median progression-free survival (PFS) of 10.1 months (95% CI, 6.0-14.0) and a median OS of 18.2 months (95% CI, 10.7-not evaluable [NE]).⁷

The fourth approach surrounds the potential efficacy of next-generation CTLA-4–directed antibodies.

The panelists also stressed that squamous NSCLC has not benefited from precision oncology as much as nonsquamous disease has, partly because many patients never receive full genomic sequencing. Kim urged comprehensive testing, including RNA sequencing.

“We need to approach [lung cancer management] in a holistic manner [because] we still don’t understand all of the biology of all the different types of lung cancer,” Kim said.

Could re-engineered CTLA-4–directed antibodies overcome the target’s troubled record?

Florez explained that CTLA-4 acts mainly during T-cell priming in the lymph nodes, whereas PD-1 acts in the tumor, and that CTLA-4’s systemic reach drives its toxicity. Combined PD(L)1 and CTLA-4 blockade has shown efficacy in nonsquamous disease, and data from the phase 3 CheckMate 227 (NCT02477826) and CheckMate 9LA (NCT03215706) trials increased the field’s level of comfort with using ipilimumab (Yervoy) in this population.^8,9

Rolfo traced the target’s earlier record, noting that findings from the phase 3 Lung-MAP S1400I study (NCT02785952) found no benefit from adding ipilimumab to nivolumab (Opdivo) after PD-(L)1 inhibitor progression in patients with recurrent stage IV squamous lung cancer.¹⁰ He added that even positive combinations, such as durvalumab (Imfinzi) plus tremelimumab-actl (Imjudo) and chemotherapy, as investigated in the phase 3 POSEIDON trial (NCT03164616) in first-line patients with metastatic NSCLC, were associated with high toxicity burdens.¹¹ Newer molecules aim to separate efficacy from toxicity, and Rolfo described himself as cautiously enthusiastic regarding this approach, noting that no pivotal supportive data have yet emerged.

What do the PRESERVE-003 stage 1 data show?

PRESERVE-003 is a 2-stage, randomized trial investigating gotistobart vs docetaxel in patients with mNSCLC who have progressed on a PD-(L)1 inhibitor and platinum-based chemotherapy.¹² Rolfo explained that stage 1 was a nonpivotal portion that confirmed the optimal gotistobart dose to be 6 mg/kg every 3 weeks after 2, 10-mg/kg loading doses and gathered preliminary signals in 217 patients with disease spanning all histologies. A benefit with this agent emerged in those with squamous disease, so stage 2, which will randomly assign patients with squamous NSCLC with OS as the primary end point, narrowed the population. Rolfo stressed that the squamous analysis included only 87 patients (gotistobart arm, n = 45; docetaxel arm, n = 42) and that its OS findings were nominal, rather than formally tested.

Previously reported data showed that at a median follow-up of 14.5 months (range, 0.1-18.8) showed an objective response rate (ORR) of 20.0% (95% CI, 9.6%-34.6%) with gotistobart vs 4.8% (95% CI, 0.6%-16.2%) with docetaxel, and a median duration of response of 11.0 months (95% CI, 3.5-NE) vs 3.8 months (95% CI, 3.5-NE), respectively. Similar median PFS values were reported between these respective arms (HR, 0.69; 95% CI, 0.42-1.13), and the OS data favored the gotistobart arm (HR, 0.46; 95% CI, 0.25-0.84; nominal P = .0102).

Florez said the OS benefit was “appealing because we haven’t seen that in squamous [NSCLC] in a long time,” but cautioned that “ORR doesn’t mean durability. It all comes to the tail of the curve.”

At WCLC 2026, updated OS data from stage 1 showed that at a data cutoff of July 17, 2026, the median OS was 18.5 months (95% CI, 9.3-NE) with gotistobart vs 10.0 months (95% CI, 6.2-12.0) with docetaxel (HR, 0.56; 95% CI, 0.33-0.95; nominal P = .0295).¹³ Grade 3 or higher TRAEs occurred in 44.4% of patients vs 48.8% of patients, respectively, with a gotistobart safety profile that was consistent with data seen in earlier reports with this agent.

What is important to know about immune-related toxicity associated with CTLA-4–directed therapy?

Kim said the toxicity profile of gotistobart in stage 1 of PRESERVE-003 “has not shown anything outside of the norm” that is expected with CTLA-4 and PD-1 inhibitors. However, the panelists stressed that the gotistobart-related toxicities demand a different mindset that relies on proactive management, rather than reactive strategies that are commonly employed with other types of agents. Kim emphasized that CTLA-4 inhibitor–related events, such as colitis, thyroiditis, and hypophysitis, can arise quickly and call for aggressive management. He recommended routine monitoring of liver enzymes and thyroid function and explained the importance of educating emergency department staff to be aware of these AEs as well.

Rolfo added that immune-related AEs can be unpredictable and can often appear at least 1 year after treatment initiation. He advised giving patients safety cards that name the drug they are receiving and its expected toxicities.

The experts explained that community oncology practices face a steeper learning curve. Kim described ways to close this gap, including regularly updated disease management resources and telehealth links between academic experts and community clinicians.

“The only way we’re going to effectively treat patients is to make sure we have communication lines open,” Kim said, as Rolfo urged community oncologists to “create their own network” of referral partners to strengthen their resources when treating patients with squamous NSCLC.

Jacob Sands, MD, is associate chief of the Lowe Center for Thoracic Oncology and the oncology medical director of the International Patient Center at Dana-Farber Cancer Institute, as well as an assistant professor at Harvard Medical School in Boston, Massachusetts.

Narjust Florez, MD, is the associate medical director of the Cancer Care Access Program at Dana-Farber Cancer Institute, as well as an assistant professor of medicine and a member of the faculty at Harvard Medical School.

Christian Rolfo, MD, PhD, is director of the Division of Medical Oncology in the Department of Internal Medicine at The Ohio State University Comprehensive Cancer Center — James in Columbus.

Edward Kim, MD, MBA, is physician-in-chief of City of Hope Orange County, deputy physician-in-chief of City of Hope National Medical Center, a professor in the Department of Medical Oncology & Therapeutics Research at Construction Industries Alliance City of Hope Orange County, and the system director of the Clinical Trials Office and physician-in-chief chair at City of Hope in Irvine, California.

References

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