Advanced Ovarian Cancer Responds to Claudin-Targeted Drug in Preliminary Trial

SAN DIEGO — Half of heavily pretreated patients with platinum-refractory ovarian cancer (PROC) responded to an investigational antibody-drug conjugate (ADC) targeting Claudin 6 (CLDN6), a small study from China showed.

Overall, nine of 18 evaluable patients achieved partial responses with QLS5132, and another eight had stable disease. Five of the nine responses lasted 3 months or longer. Responses occurred in patients with and without CLDN6 expression.

The most common treatment-related adverse events (TRAEs) were gastrointestinal and hematologic in nature, most of which were grade 1/2, reported Tao Zhu, MD, of Zhejiang Cancer Hospital in Hangzhou, at the American Association for Cancer Research annual meeting.

“QLS5132 was well tolerated, especially with the potential recommended phase II dose levels with a wider therapeutic window,” said Zhu. “Only one dose-limiting toxicity occurred [at the highest dose level evaluated], and no treatment-related AEs led to treatment discontinuation or death.”

The drug “showed remarkable antitumor activity in patients with PROC, and patients treated at the 3.2-mg/kg dose level maintained partial response for over 6 months, suggesting that higher dose levels may yield more durable antitumor activity,” he added.

Patient enrollment for the PROC cohort continues, and trials of QLS5132 in lung, gastric, and other cancers are ongoing.

QLS5132 is in an already crowded and still-growing list of ADCs for PROC and other advanced solid tumors, said invited discussant Ramez Eskander, MD, of the University of California San Diego Moores Cancer Center. More than 400 ADCs are currently in development, and three have already been approved for gynecologic malignancies: tisotumab vedotin (Tivdak), mirvetuximab soravtansine (Elahere), and trastuzumab deruxtecan (Enhertu).

Candidates for gynecologic cancers generally have cytotoxic payloads from the same two classes: camptothecins and microtubule toxins. In the current study, the CLDN6 inhibitor demonstrated clinical activity within the range of other ADCs under evaluation for PROC.

Although clinical evaluation begins in advance disease, several competitors have already moved into the first-line maintenance setting. The rapid proliferation of the ADC class has raised multiple questions that have yet to be answered.

“When we talk about the platinum-resistant cohort, what does that mean for sequencing?” Eskander asked. “Are we going to be able to rationally sequence these drugs and show clinical benefit? … Are there novel ADC strategies that are going to improve clinical outcomes for our patients?”

“In the last 1 to 2 years, we have seen an explosion of ADCs across disease settings, but we are obligated to dose optimize,” Eskander continued. “That’s not a problem in platinum-resistant disease, where patients aren’t expected to achieve a meaningful remission, but it’s absolutely our obligation in platinum-sensitive and frontline, where remission is anticipated. How are we going to sequence these agents, and do biomarkers matter? Novel ADC constructs will have to be examined carefully. All-comer trials may not provide us with the information needed to inform scientifically rational directions for drug development.”

CLDN6 has a key role in differentiation of stem cells into epithelial cells. Several types of cancer, including ovarian, overexpress CLDN6, which is associated with poor prognosis. QLS5132 is highly selective for CLDN6 and demonstrated an expanded therapeutic window and potent antitumor activity in preclinical studies.

Zhu reported initial findings from a first-in-human trial to evaluate multiple doses of QLS5132 in multiple patient cohorts with different types of advanced solid tumors, including PROC. Eligible patients had not benefited from prior therapy or had no standard therapy.

The PROC cohort comprised 28 patients who had received a median of three prior lines of therapy. Almost all of the patients had prior exposure to bevacizumab (Avastin) and a PARP inhibitor. Across the five dose levels evaluated, median follow-up ranged from 2 to 6 months. Zhu said pretreatment CLDN6 positivity was not a requirement for enrollment, and 12 of 28 were positive by immunohistochemistry.

The safety analysis showed nine grade ≥3 TRAEs, including six of 18 patients treated at two recommended phase II dose levels. None of the patients developed interstitial lung disease, ocular toxicity, or febrile neutropenia.

The efficacy analysis showed that the nine responses occurred at three dose levels, including five at the potential recommended phase II dose of 4.8 mg/kg. Patients that received ≥3.2 mg/kg (four dose levels) had a disease control rate (response plus stable disease) of 100%. Five of the nine responses have been confirmed. Median relative dose intensity was 99.8% across all dose levels.