TUB-040 Represents Novel ADC Approach in Platinum-Resistant Ovarian Cancer

As research behind antibody-drug conjugates (ADCs) continues in the platinum-resistant ovarian cancer realm, TUB-040—featuring an exatecan payload and targeting NaPi2b— could represent an active treatment approach this patient population, according to Antonio González-Martín, MD, PhD.

In the phase 1/2a NAPISTAR-01 trial (NCT06303505), data from which were presented at the 2025 ESMO Congress, patients with histologically confirmed platinum-resistant ovarian cancer who were heavily pretreated but had no prior exposure to an ADC with a topoisomerase I inhibitor payload, received TUB-040. Patients who were administered the ADC at doses ranging from 1.67 mg/kg to 3.3 mg/kg (n = 46) experienced a confirmed objective response rate (ORR) of 59%, a confirmed ORR of 50%, and a disease control rate (DCR) of 96%. González-Martín explained that no patients discontinued treatment due to AEs, and no clinically relevant pneumonitis, ocular toxicity, stomatitis, neuropathy, or bleeding was observed.

“TUB-040 is a nice ADC because of the design of the molecule. It makes the payload extremely stable to the linker, which could make the difference in terms of safety and activity. We are in the early process of development for [TUB-040], but our first data in ORR, safety, and suggested durability of response look extremely promising. It could be very good for patients in the future,” González-Martín, MD, PhD, head of the Department of Medical Oncology and director of the Cancer Center Clinica at Universidad de Navarra in Pamplona, Spain, and an associate professor of medicine at Francisco de Vitoria University, said in an interview with OncLive®.

González-Martín elaborated on TUB-040’s unique properties and potential in the world of ADC treatment in addition to the trial results that have been collected thus far, which indicate the drug’s strong efficacy and safety.

Onclive: What was the rationale behind targeting NaPi2b with an ADC in platinum-resistant ovarian cancer, and how does this approach differ from existing ADCs?

González-Martín: [Patients with] platinum-resistant ovarian cancer have a high unmet need because we do not have sufficiently active treatments. One of the most important [current] strategies is to explore the ADC concept. TUB-040 is a new ADC with an exatecan payload and a stable linker that provides a drug:antibody ratio of 8 [and] targets NaPi2b. NaPi2b is a very interesting target in ovarian cancer because it is highly expressed transporter in ovarian cancer.

What was the design of the NAPISTAR 1-01 trial?

[NAPISTAR 1-01] was a first-in-human, phase 1/2a study. Dose escalation started at 0.5 mg/kg [of TUB-040] and escalated up to 5.3 mg/kg. The focus of our presentation [at ESMO 2025] was the dose range from 1.67 mg/kg to 3.3 mg/kg. Essentially, we included patients with high-grade platinum-resistant ovarian cancer who received a maximum of 7 prior lines of therapy, including 5 prior platinum[-based regimens] and 2 [prior] non-platinum regimens.

The primary end point of this study was safety and tolerability in addition to the determination of the maximum tolerated dose [MTD]. [There were] also some secondary end points, including ORR, duration of response [DOR], and DCR.

What were the efficacy results from the trial?

[We included] 67 patients, with the data cutoff being on September 1, 2025. This [patient population] was heavily pretreated with a median of 4 prior lines of therapy [range, 1-7], and patients had already received current standard of care, including bevacizumab [Avastin] in 83.6% of patients and PARP inhibitors in 76.1% of patients.

In this heavily pretreated patient population, we have observed an unconfirmed ORR of 59% and a confirmed ORR of 50% [at doses ranging from 1.67 mg/kg to 3.3 mg/kg], including 1 complete response. Interestingly, we have started to see responses from the 1.67 mg/kg dose, and the responses across the highlighted doses ranged from 50% to 67%, indicating that TUB-040 is a drug that produced high response rates even with a lower dose in the dose escalation.

Ninety-three percent of patients who responded are still in treatment; globally, 80% of patients are still receiving treatment, which indicates the effects [of TUB-040] are durable. The DCR was [96% at the specified dose range], and the CA125 response rate was 81%; therefore, [TUB-040] is an active ADC in a patient population that was heavily pretreated.

What is the safety profile of TUB-040?

Regarding safety, we have determined the MTD at 4.4 mg/kg. If we focus on the dosage range from 1.67 mg/kg to 3.3 mg/kg, we can say this ADC is safe with a manageable toxicity across the globe. In particular, 20% of patients [in this dose range] had dose reductions [due to AEs], but no patients discontinued the treatment due to AEs. Grade 3 or higher AEs were observed in 35% of patients; most AEs were grade 1 or 2, [including] nausea in 78% of patients and asthenia in 48% of patients. It is important to remark that prophylactic antiemetics were not required in cycle 1.

Regarding hematological safety in the range of doses from 1.67 mg/kg to 3.3 mg/kg, [these AEs] were essentially low grade and manageable. Grade 3 or higher neutropenia [occurred] in 22% of patients, anemia in 9% of patients, and thrombocytopenia in 4% of patients.

There were only 2 cases of patients with grade 1 pneumonitis. Both cases were resolved without any problems, and treatment was continued in those patients. It is remarkable that there have not been any significant ocular toxicities, stomatitis, pneumonitis, bleeding, or neuropathy, which could differentiate [TUB-040] from other ADCs.

What do the trial's results suggest about the potential predictive value of NaPi2b expression, and will there be further biomarker analysis to refine patient selection?

For inclusion in the trial, [patients were] not required to have expression of NaPi2b, thus we have not selected the patients according to biomarkers. However, we are analyzing the ORR associated with [patients’] expression of NaPi2b. To be honest, as most of the patients [in the trial] had expressed NaPi2b, we do not anticipate that there will be a cutoff that will significantly change things, but it is something that we are now exploring.

What are the next steps for TUB-040?

We are now starting the dose-optimization, randomized phase of the study, which is important to select the best dosage for patients. TUB-040 has a lot of opportunities for development in different ovarian cancer settings, not only in the platinum-resistant setting but also in earlier lines. We are also waiting for data from the cohort of patients with lung cancer that this trial included to figure out if [TUB-040] is an interesting ADC for non–small cell lung cancer, as it is for ovarian cancer.

References

1. González-Martín A, Sehouli J, Braicu E, et al. NAPISTAR 1-01: a phase 1 dose escalation study of TUB-040, a novel NaPi2b-targeting exatecan antibody-drug conjugate (ADC) in patients with platinum-resistant ovarian (PROC) high grade serous carcinoma (HGSC). Presentation presented at: 2025 ESMO Congress; October 17-21; 2025; Berlin, Germany. Accessed December 1, 2025.
2. Inman S. TUB-040 yields responses across dose levels in platinum-resistant high-grade serous ovarian cancer. Onclive.com. October 19, 2025. Accessed December 1, 2025. https://www.onclive.com/view/tub-040-yields-responses-across-dose-levels-in-platinum-resistant-high-grade-serous-ovarian-cancer