Folate receptor alpha (FolRα) is a folate-binding protein overexpressed on ovarian and several other epithelial malignancies that can be used as a target for imaging and therapeutic strategies.[1] Higher level of FRα expression generally occurs in ovarian epithelial tumors, especially in carcinomas and ovarian serous tumors [2]

According to the American Cancer Society, the incidence and prevalence of ovarian cancer 1 in 78 women born in the United States will develop the disease, and 1 in 108 of women diagnosed will die as a result of the disease.  In real numbers,  the American Cancer Society estimates that in 2022 about 19,880 women will receive a new diagnosis of ovarian cancer and 12,810 women will die from the disease.[3]

Ovarian cancer mainly develops in older women. About half of the women who are diagnosed with ovarian cancer are 63 years or older, although it may occur in younger women (especially those with a family history of the disease). The disease is also more common in white women than African American women.

Scientists continue to study ovarian cancer. to find ways to better treat women diagnosed with the disease. This research is beginning to yield clues leading to results and novel treatment options reaching the clinic.

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The interim data from an ongoing, fully enrolled, dose-expansion Phase 1 study of STRO-002, a folate receptor alpha (FolRα)-targeting antibody-drug conjugate (ADC) for the treatment of patients with advanced ovarian cancer, were recently presented.  The results showed a 33% Objective Response Rate (ORR) in 33 RECIST evaluable patients across all FolRα expression levels. In addition, dose response was observed, with a 47% ORR in 17 patients who started at the 5.2 mg/kg dose level.

“These interim data in the dose-expansion cohort showing deep responders in ovarian cancer patients treated with STRO-002 are compelling,” said R. Wendel Naumann, MD, Professor & Director of Gynecologic Oncology Research, Associate Medical Director of Clinical Trials at Levine Cancer Institute, and an investigator on the STRO-002 study.

“Patients entered the study with progressive disease and were a heavily pre-treated population and had experienced up to three lines of prior treatment. The interim data show that STRO-002 could potentially improve the lives of an underserved ovarian cancer patient population,” Naumann added.

Study design
The dose-expansion cohort for ovarian cancer enrolled 44 patients who had experienced up to three prior lines of therapy. As of the interim data cutoff date of Nov. 8, 2021, 43 patients had been randomized into dose levels starting at 4.3 mg/kg and 5.2 mg/kg, and one patient had not yet been dosed. 81% of the patients were platinum-resistant, and 63% and 65% of the patients had been treated previously with bevacizumab (Avastin®; Genentech/Roche) and PARP inhibitors, respectively. Of the 43 patients, 33 had at least one post-baseline scan and, therefore, were evaluable for RECIST v1.1 responses.

  • As of the November 8, 2021, the interim data cutoff date, the Best Overall Response (BOR) for evaluable patients were as follows (N=33):
    • Seven patients had achieved partial responses (PR), which were confirmed with at least two post-baseline scans.
    • Five patients had unconfirmed partial responses (PRu), based on having received only one post-baseline scan as of the interim data cutoff date. Their next scheduled scan, subsequent to the interim data cutoff date, revealed the following: Four PRs were confirmed and one patient was in stable disease (SD).
    • An ORR of 33% (11 PRs out of 33 patients) was demonstrated in all evaluable patients, unenriched for FolRα-expression levels at both dose levels.
    • 14 total patients experienced SD, and 8 patients had progressive disease (PD).
  • Dose response was observed, with an ORR of 47% (8 PRs out of 17 patients), for patients who started at the 5.2 mg/kg dose level, unenriched for biomarker status.
  • Higher FolRα expression levels using TPS are correlated with higher response rates.
    • TPS has been identified as a potentially appropriate scoring algorithm for STRO-002 with respect to the biomarker enrichment strategy.
    • Based on an exploratory cut-off of TPS > 25%, a 40% ORR (10 PRs out of 25 patients) was observed. TPS ≤ 25% demonstrates 13% ORR.
  • Based on our data, an enrichment approach of TPS > 25% FolRα expression may enable treatment of about 70% of the advanced ovarian cancer patient population.
  • Safety signals from the 43 safety evaluable patients at the 5.2 mg/kg and 4.3 mg/kg starting dose levels were consistent with data from the dose-escalation cohort.
    • No new safety signals were observed in the dose-expansion cohort, including the absence of keratopathy.
    • 85.5% treatment-emergent adverse events (TEAEs) were Grade 1-2.
    • Neutropenia was the leading TEAE, resulting in treatment delay or dose reduction. The majority of the cases of neutropenia were generally asymptomatic and resolved with a one week dose delay or, in other cases, with standard medical treatment, including the use of G-CSF.
    • There were limited observed cases of febrile neutropenia, including one Grade 5 event at the 5.2 mg/kg starting dose level and one Grade 3 event at the 4.3 mg/kg starting dose level. The trial protocol was subsequently updated to require dose reduction for Grade 4 neutropenia.
  • Data from the STRO-002 dose-expansion cohort are expected to provide further information to inform regulatory discussions and a global registration strategy.

“We are encouraged by the investigator interest in STRO-002 in the dose-expansion cohort, with full patient enrollment in under a year. These interim data underscore our confidence in STRO-002 as a potential therapeutic for patients with ovarian cancer, and we will continue to follow the patients who remain on treatment,” said Arturo Molina, Chief Medical Officer of Sutro Biopharma.

“With additional data continuing to mature, we expect to confirm our dosing regimen and our patient selection strategy based on FolRα expression. We plan to advance STRO-002 into the next phase of clinical development and leverage our Fast Track designation for continuous engagement with the FDA.” he added.

More studies
In addition to the STRO-002-GM1 Phase 1 clinical trial, a STRO-002 study for patients with ovarian cancer in combination with bevacizumab and a study for patients with endometrial cancer are both enrolling at sites in the United States and Europe. Nonclinical work to expand STRO-002 to non-small cell lung cancer (NSCLC) and potentially into other FolRα-expressing solid tumors is also ongoing.

Clinical trials
Study of STRO-002, an Anti-Folate Receptor Alpha (FolRα) Antibody Drug Conjugate in Ovarian & Endometrial Cancers – NCT03748186

Highlights of prescribing information
Bevacizumab (Avastin®; Genentech/Roche) (Prescribing Information)

[1] Kalli KR, Oberg AL, Keeney GL, Christianson TJ, Low PS, Knutson KL, Hartmann LC. Folate receptor alpha as a tumor target in epithelial ovarian cancer. Gynecol Oncol. 2008 Mar;108(3):619-26. doi: 10.1016/j.ygyno.2007.11.020. Epub 2008 Jan 28. PMID: 18222534; PMCID: PMC2707764.
[2] Shen DH, Xie JL, Zhang YL, Wang Y. [Expression of folate receptor alpha in ovarian epithelial tumors]. Zhonghua Bing Li Xue Za Zhi. 2010 Nov;39(11):747-51. Chinese. PMID: 21215165.
[3] Key Statistics for Ovarian Cancer.American Cancer Society. Online. Last accesses on January 12, 2022.

Featured image: Teal ribbon awareness to support Ovarian/Cervical Cancer. Photo courtesy: © 2019 – 2021 Fotolia/Adobe. Used with permission.

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