Updated findings from Stage 1 of the multicenter, international, two-stage phase III PRESERVE-003 trial showed that, among patients with metastatic squamous non–small cell lung cancer (NSCLC) whose disease had progressed following anti–PD-(L)1 therapy, treatment with the investigational anti–CTLA-4 monoclonal antibody gotistobart nearly doubled median overall survival vs docetaxel. Clinical pharmacology data also appeared to support the selected dosing regimen, according to findings presented at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer.

Given the limited role of targeted therapies and the failure of multiple trials to improve outcomes in this setting, an unmet medical need remains. Gotistobart is being investigated as a potential approach to address this treatment gap, using a pH-sensitive anti–CTLA-4 mechanism and an optimized Fc domain designed to enhance intratumoral regulatory T-cell depletion with minimal peripheral immune activation, the investigators reported.

The updated survival findings reinforce the potential of gotistobart to provide a meaningful new treatment option….

— RAMA BALARAMAN, MD

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The nonpivotal first stage enrolled 217 patients with metastatic NSCLC who had previously received anti–PD-(L)1 therapy and platinum-based chemotherapy. Among these patients, 87 with squamous disease were randomly assigned to receive gotistobart at 6 mg/kg every 3 weeks following two 10-mg/kg loading doses (n = 45) or docetaxel at 75 mg/m² every 3 weeks (n = 42). A total of 80.5% had received chemotherapy concurrently with anti–PD-(L)1 therapy, and nearly three-quarters of patients in each treatment arm were Asian. Dr. Balaraman also noted that a higher proportion of patients in the gotistobart arm than in the docetaxel arm had liver and brain metastases at baseline.

Previous findings from Stage 1 demonstrated a clinically meaningful overall survival benefit and durable antitumor activity with gotistobart vs docetaxel in this patient population.^2,3

“The updated survival findings reinforce the potential of gotistobart to provide a meaningful new treatment option for patients with metastatic squamous NSCLC whose disease has progressed following PD-(L)1 therapy,” presenting author Rama Balaraman, MD, of Ocala Oncology Center, Florida, commented in a press release issued by IASLC.

Updated Efficacy Data

After a median follow-up of 25.4 months, median overall survival, the primary endpoint, was 18.5 months with gotistobart vs 10.0 months with docetaxel (hazard ratio [HR] = 0.56; nominal two-sided P = .0295). Overall survival rates were 63.1% with gotistobart vs 33.3% with docetaxel at 12 months and 40.9% vs 19.0% at 24 months.

Mark A. Socinski, MD

To put the overall survival findings into context, study author Mark A. Socinski, MD, of AdventHealth Cancer Institute, Orlando, Florida, told The ASCO Post that outcomes in the control arm appeared consistent with historical experience. “Gotistobart doesn’t look good because docetaxel looked bad,” he said. “Docetaxel looks like docetaxel in this early experience, and gotistobart looks better.” Acknowledging the small patient population and noting that he typically uses docetaxel plus ramucirumab rather than docetaxel alone in this setting, he added that, if this benefit holds up in Stage 2—the ongoing pivotal portion of the trial—“maybe [it’s] not a home run, maybe a triple with an error at third base, and the runner scores.”

Other efficacy outcomes—assessed by investigators as secondary endpoints at a median follow-up of 20.0 months—included median progression-free survival of 2.4 with gotistobart vs 2.6 months with docetaxel (HR = 0.688, 95% confidence interval [CI] = 0.417–1.135). Confirmed objective response rates were 20.0% vs 4.8%, and median durations of response were 11.3 vs 3.8 months, respectively.

Exploratory Pharmacology Data

The exposure-response analysis of the regimen consisting of two 10-mg/kg loading doses followed by 6 mg/kg every 3 weeks found that higher gotistobart exposure was associated with improved overall survival, with the relationship remaining nominally significant after adjusting for covariates. According to the investigators, these findings supported advancement of the dosing regimen into Stage 2.

Population pharmacokinetic modeling, incorporating published data on ipilimumab, showed higher exposure over time and smaller peak-to-trough fluctuations with gotistobart when both agents were modeled using the same dosing regimen (6 mg/kg every 3 weeks).⁴ At steady state, gotistobart achieved an approximately twofold higher maximum plasma concentration and approximately threefold higher trough concentration and area under the curve, according to the investigators.

The investigators also reported that the two 10-mg/kg loading doses achieved exposure during the early treatment cycles comparable to that achieved during later cycles. The regimen incorporating loading doses provided higher and more consistent exposure than ipilimumab, which the investigators said supported reliable drug coverage from the start of treatment.

Safety Summary

The safety findings were generally consistent with the known safety profiles of immunotherapy and chemotherapy, with no new or unexpected toxicities. Grade 3 or higher treatment-related adverse events occurred in 44.4% of patients treated with gotistobart and 48.8% of those who received docetaxel. According to the investigators, these events were largely nonoverlapping between treatment arms, with grade 3 or higher events generally immune-related or inflammatory with gotistobart and predominantly hematologic with docetaxel.

Serious treatment-related adverse events occurred in 44.4% and 29.3% of patients treated with gotistobart and docetaxel, respectively, and treatment-related adverse events led to discontinuation in 15.6% and 4.9%. No treatment-related adverse events resulted in death in either arm.

Looking Ahead

Taken together, these updated Stage 1 findings support further evaluation of gotistobart vs docetaxel in a larger population of patients with squamous NSCLC during Stage 2, the investigators concluded. Dr. Balaraman told The ASCO Post that Stage 2 will seek to confirm the observed overall survival benefit and further assess its durability and the overall benefit–risk profile, helping to define the potential role of gotistobart in this setting.

“If confirmed in the pivotal portion of the phase III trial, we believe gotistobart has the potential to transform the standard of care in a setting where new treatment options are urgently needed,” she added.

However, Dr. Socinski cautioned, “If you look at the oncologic highway in lung cancer, it’s littered with positive phase II trials that never made it in phase III. That obviously is a possibility here, but we are feeling good about these early observations and hoping that they hold up.” 

DISCLOSURE: The study is sponsored by OncoC4 and is conducted in collaboration with BioNTech. Dr. Balaraman reported no conflicts of interest. Dr. Socinski has received institutional grant or research support from BeOne Medicines, Cullinan, Elephas, Enliven, Florida Department of Health, Loxo Oncology, Mirati, Nuvalent, Nuvation, OncoC4, Pfizer, Roche (Genentech), and Summit; has served as a consultant or advisor for AbbVie, AstraZeneca, Akumin, Avistone, Bayer, BioNTech, BeOne Medicines, Blueprint Medicines, Coherus, COR2ED, Daiichi Sankyo, EMD Serono, Foundation Medicine, G1 Therapeutics, Gilead, Gritstone, GSK, Merck, Novartis, Nuvalent, Nuvation, Novocure, OncoC4, Partner Therapeutics, Pfizer, Takeda, Taiho, Veracyte, and Verastem; has served on a data safety monitoring board or steering committee for BMS, Summit, Genentech, BeOne Medicines, Lilly, and Spectrum; and has served on a speaker’s bureau for AstraZeneca, Blueprint Medicines, Genentech, Guardant, Janssen, Jazz, Genentech, Lilly, Nuvation, Pharmacosmos, and Regeneron.

REFERENCES

1. Balaraman R, Cho BC, Chen H-J, et al: Gotistobart vs docetaxel in metastatic squamous NSCLC after PD-(L)1 progression: Updated overall survival of the stage 1 of PRESERVE-003. 2026 World Conference on Lung Cancer. Abstract 627. Presented September 15, 2026.

2. He K, Cho BC, Balaraman R, et al: 3O Anti-tumor activity of gotistobart compared to docetaxel in patients with metastatic squamous non-small cell lung cancer (sqNSCLC) progressing on PD-(L)1 inhibitors: Stage 1 PRESERVE-003 phase III trial. ESMO Open 11(suppl 3):106310, 2026.

3. Cho BC, Balaraman R, Chen H-J, et al: Gotistobart or docetaxel in metastatic squamous non-small cell lung cancer: Stage 1 of the randomized phase 3 PRESERVE-003 trial. Nat Med 32:2245-2253, 2026.

4. Feng Y, Masson E, Dai D, et al: Model-based clinical pharmacology profiling of ipilimumab in patients with advanced melanoma. Br J Clin Pharmacol 78:106-117, 2014.

EXPERT POINT OF VIEW 

In an exclusive interview with The ASCO Post, International Association for the Study of Lung Cancer (IASLC) CEO Karen Kelly, MD, FASCO, highlighted updated findings from Stage 1 of the multicenter, international, two-stage phase III PRESERVE-003 trial as one of the notable scientific presentations at the 2026 World Conference on Lung Cancer. She expressed particular interest in the overall survival difference observed with the investigational anti–CTLA-4 monoclonal antibody gotistobart vs docetaxel among patients with metastatic squamous non–small cell lung cancer (NSCLC) following disease progression on anti–PD-(L)1 therapy.¹

Karen Kelly, MD, FASCO

“When we now see the 24-month overall survival data showing that the distribution of those curves remains widely separated, along with the plateau at the tail, it gives us hope that Stage 2 will look similar to this,” Dr. Kelly said. If confirmed, she added, the findings could represent “a monumental step forward” for this patient population.

Dr. Kelly also considered the overall survival findings in the context of the current second-line treatment landscape. “Docetaxel is not an easy drug to tolerate, so if we can provide a less toxic, noncytotoxic regimen, I believe that is also a step forward,” she said. “We do have high hopes that we can move away from docetaxel, at least in the squamous cell space.”

Despite her optimism, Dr. Kelly emphasized that the efficacy analysis remains exploratory and is based on a small number of patients. “Cautiously,” she said when asked how the current data should be interpreted. “We have seen these smaller randomized phase II studies that do not then translate into the overall survival benefit when it comes to the phase III.”

Questions for the Pivotal Stage

Asked what else she hopes to see in Stage 2, beyond continued separation of the overall survival curves, Dr. Kelly said, “We need to see more geographic balance.” A total of 71% of patients in each treatment arm in the current analysis were Asian, despite the international nature of the study.

Dr. Kelly will also be interested in outcomes by PD-L1 expression, particularly among patients with PD-L1–negative disease. She noted that prior studies have shown that the addition of CTLA-4 blockade with ipilimumab provides durable efficacy in this population, despite their generally poorer outcomes. Whether a similar pattern emerges with gotistobart remains to be seen.

“I’m anxious to see what that group looks like,” she said, adding that “it would also be great to see [consistent efficacy] across all of the PD-L1 scores.”

Another subgroup of interest is patients previously treated with dual immune checkpoint blockade (ie, ipilimumab plus nivolumab), either alone or with chemotherapy, according to Dr. Kelly. She noted that such patients may be small in number who are enrolling in the pivotal portion of the trial, but their outcomes would provide intriguing insight into gotistobart’s ability to overcome dual checkpoint inhibitor resistance. With those questions remaining unanswered, Dr. Kelly concluded: “I’m going to be optimistic that we will see a positive outcome.” 

DISCLOSURE: Dr. Kelly has served on data and safety monitoring boards for Merck.

REFERENCE

1. Balaraman R, Cho BC, Chen H-J, et al: Gotistobart vs docetaxel in metastatic squamous NSCLC after PD-(L)1 progression: Updated overall survival of the stage 1 of PRESERVE-003. 2026 World Conference on Lung Cancer. Abstract 627. Presented September 15, 2026.