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Clinical

Karen M. Winkfield, MD, PhD; Narjust Florez, MD, FASCO; Gilberto de Lima Lopes Junior, MD, MBA, FASCO; Coral Olazagasti, MD; Vonetta M. Williams, MD, PhD

 Fighting Disparities and Saving Lives: An Exploration of Challenges and Solutions in Cancer Care

The FDA granted RMAT status to gemogenovatucel-T for maintenance in patients with advanced ovarian cancer.

FDA Grants Gemogenovatucel-T RMAT Status in Advanced Ovarian Cancer

Azenosertib monotherapy showed a 34.9% overall response rate in heavily pretreated, cyclin E1–positive, platinum-resistant ovarian cancer, with a median duration of response of 5.5 months.

Azenosertib Shows Promising Efficacy in Platinum-Resistant Ovarian Cancer

DeepHRD predicted homologous recombination deficiency with greater accuracy than FDA-approved standard molecular tests.

AI Outperforms Standard HRD Tests  for Breast, Ovarian Cancers

The completion of a new drug application for the combination of avutometinib and defactinib in KRAS-mutant ovarian cancer is expected to be finalized with the FDA by the end of the month.

Avutometinib/Defactinib Leads to Positive Response, Survival Data in Ovarian Cancer

The FDA has granted VLS-1488 fast track designation in patients with platinum-resistant high-grade serous ovarian cancer.

VLS-1488 Gains FDA Fast Track Status in Advanced Ovarian Cancer

Mirvetuximab Soravtansine: Delivering Powerful Results in Ovarian Cancer

Mirvetuximab soravtansine (Elahere) is an antibody-drug conjugate designed to treat ovarian cancer. It works by binding to folate receptor-alpha (FRα). This binding delivers a potent anticancer drug to the tumor cells.

The PICCOLO trial (NCT05041257) was a phase 2 study that evaluated the effectiveness and safety of mirvetuximab soravtansine in patients with recurrent platinum-sensitive ovarian cancer. Patients in the trial had high levels of FRα expression and had received at least 2 prior lines of therapy. 

In the study, mirvetuximab soravtansine demonstrated a significant response rate in patients, with over half achieving either a complete or partial response to treatment. The duration of response was also promising, with patients experiencing responses for an average of 8.3 months. While mirvetuximab soravtansine was generally well tolerated, some patients experienced side effects such as blurred vision and dry eye. These side effects were generally manageable.

Overall, the PICCOLO trial results suggest that mirvetuximb soravtansine is a promising treatment option for patients with recurrent platinum-sensitive ovarian cancer who have high levels of FRα expression.

Here, Angeles Alvarez Secord, MD, MHSc, gynecologic oncologist at Duke Cancer Center, discusses the key takeaways from the study presented at the 2024 ESMO Congress.

I hope there are next steps, definitely. The findings from the study are very provocative and really promising in terms of the objective response rate and those individuals who've been heavily pretreated as well as been treated with a PARP inhibitor and progressed on a PARP inhibitor. In that group, the response rate was approximately 46%, which is higher than what we would have anticipated given some of the prior reports of diminished response in that group who gets treated with subsequent therapy. So I think the results are really exciting to explore further in that specific patient population, as well as providing an option for all of our patients who have heavily pretreated platinum-sensitive disease.

It is incredibly important to get testing done on your patients. Understanding the level of the FRα expression will help you in terms of determining what is the next best treatment for them in order for them to have the highest chance of receiving benefit from a therapy, and it really helps me in terms of determining the sequence of therapy.

Videos

Angeles Alvarez Secord, MD, MHSc, discusses key takeaways from the PICCOLO trial. 

Christina Fotopoulou, MD on Individulizing Treatment and Exploring Options in Ovarian Cancer

Individulizing Treatment and Exploring Options in Ovarian Cancer

Christina Fotopoulou, MD, PhD, chair in gynecological cancer surgery in the department of surgery and cancer, faculty of medicine, Imperial College London, discusses recent developments in ovarian cancer and explains how one can individualize treatments when managing patients.

According to Fotopoulou, several new targeted therapies and treatment approaches have emerged in recent years, offering additional options for patients with ovarian cancer. Despite these developments, it often remains difficult to personalize treatment plans as there is a lack of definitive biomarkers and algorithms to guide individual patient decisions.

Further research is needed to develop better tools in this space and to address existing knowledge gaps to optimize patient care in ovarian cancer.

 We have experienced, in the last years especially, a plethora of new agents in ovarian cancer. We have never seen so many positive trials in ovarian cancer with so many new targeted agents and so many new aspects of care that we can explore. However, what I also emphasize is that we still fail to have concrete biomarkers and concrete individualization algorithms of which patient groups will benefit from. Currently, it is like we are in a new playground and we need to put them a bit under perspective and to put them a bit more in order for a more individualized treatment perspective.

 In ovarian cancer, we have learned in the last year that there are biomarkers. There are new things that we explore. What we are not very good [at] yet is finding the path. For example, in some studies like MIRASOL [NCT04209855], there are different catalogs for the folate receptor alpha, and the HRD scores. Now, even in my institution, we are doing extensive research to see that there is a very big heterogeneity, spatial heterogeneity within the same patient, even for the HRD scores. There are still many things that we don't understand. For example, in more common cancers like breast cancer, [there are] concrete algorithms where this patient with that signature will get this [specific] treatment, but not yet [in ovarian cancer]. And in surgery, it is even less. Currently in surgery, we just operate everybody the same way, which would definitely need to change.

Christina Fotopoulou, MD, PhD, discusses recent developments in ovarian cancer and explains how one can individualize treatments when managing patients.


News

The fourth patient with ovarian cancer has begun receiving treatment with follicle-stimulating hormone receptor (FSHR T)-mediated T cells, a novel chimeric antigen receptor (CAR) T-cell therapy, in the second cohort of an ongoing phase 1 trial (NCT05316129).

The first-in-human study, which is being conducted through a research partnership with Moffitt Cancer Center, includes patients with recurrent/resistant ovarian cancer who have progressed on at least 2 prior therapies. Findings have previously found the CAR T-cell therapy to be both safe and tolerable in the first 3 patients given treatment.

Now, this fourth patient, who is the first to be enrolled in the second cohort of the trial, was given triple the dose of CAR T cells vs those treated in cohort 1.

"First, we have the advantage of a target that is much more specific to our tumor tissue, which should minimize any on-target, off-tumor effect. Additionally, we are administering the engineered T cells directly into the peritoneum, which is the location of most of the ovarian tumor lesions. We hope that this delivery approach will enable direct trafficking of the CER-T-cells to the tumor sites and minimize adverse events such as cytokine release syndrome,” said Robert Wenham, MD, MS, FACOG, FACS, the principal investigator of the trial and the chair of gynecologic oncology at Moffitt, in a press release.

The FSHR-mediated CAR T technology, also known as chimeric endocrine receptor T-cell (CER-T) therapy, is a novel approach to CAR T therapy that differs from traditional methods through the targeting of FSHR. This receptor is found on ovarian cells and in the vasculature of tumors. This innovative approach opens up new avenues for CAR T-cell therapy by targeting hormone receptors, offering potential benefits in treating ovarian cancer and other FSHR-expressing tumors.

The phase 1 trial has an estimated enrollment of 48 patients with a pathologically confirmed diagnosis of high-grade epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube carcinoma that expresses the FSHR antigen.

 Enrollment, in the study is open to patients who have received 1 prior platinum-based chemotherapy regimen, are considered refractory to treatment, and are with measurable disease.

Patients must also have an ECOG performance status of 2 or better; a life expectancy of at least 3 months; and acceptable bone marrow, renal, and hepatic function. If patients have a known germline or somatic 

 pathogenic mutation, they must have been previously treated with a poly-ADP ribose polymerase inhibitor and subsequently experienced disease progression.Moreover, while patients are not required to, they may have received 6 additional previous chemotherapy treatment regimens.

Once enrolled, patients will receive 1 infusion of FSHR T cells intraperitoneally or intravenously at the following dose levels: 1 x 10

The primary end point of the trial is to identify the maximum tolerated dose of the FSH-CER T cells and secondary end points include duration of response, duration of stable disease, and overall survival with this approach. Investigators will also assess the effect of CER-T on pre-existing antitumor immunity.

“With no safety issues observed in the first cohort of patients, we have successfully advanced to the next cohort to evaluate a 3x higher dose. As the trial progresses, we seek to demonstrate efficacy of our cell therapy in solid tumors—a difficult challenge for traditional CAR T therapies that have been shown to be efficacious in hematological tumors and lymphoma," said Amit Kumar, PhD, chairman and chief executive officer of Anixa, in a press release.

1. Anixa Biosciences initiates dosing in second cohort of ovarian cancer CAR-T clinical trial. News release. Anixa Biosciences, Inc. February 12, 2024. Accessed February 13, 2024. 

2. Infusion of autologous T cells engineered to target FSH receptor in recurrent ovarian cancer. ClinicalTrials.gov. Updated January 25, 2025. Accessed February 13, 2024. 

https://clinicaltrials.gov/ct2/show/NCT05316129

A phase 1, first-in-human study is evaluating a novel CAR T-cell therapy in patients with ovarian cancer at Moffitt Cancer Center.

Second Cohort Dosing Underway in Ovarian Cancer CAR T-Cell Trial

Barbara Buttin, MD, a gynecologic oncologist at City of Hope Chicago, discusses the PAOLA-1 clinical trial and it impact on the first-line treatment of ovarian cancer.

PAOLA-1 was a randomized, double-blind, phase 3 study of the PARP inhibitor with chemotherapy and bevacizumab compared with placebo in patients with advanced FIGO stage IIIb-IV high-grade serous or endometrioid ovarian, fallopian tube, or peritoneal cancer. In 2020, results from this study led to the FDA approval of olaparib plus bevacizumab for the treatment of ovarian, fallopian tube, or primary peritoneal cancers.

Initial results from PAOLA-1 were published in the New England Journal of Medicine and showed that 

olaparib and bevacizumab achieved 41% reduction in the risk of disease progression or death 

compared with placebo (HR, 0.59; 95% CI, 0.49-0.72; 

 <.001). The median progression-free survival (PFS) observed with olaparib plus bevacizumab was 22.1 months versus 16.6 months with bevacizumab.

 The PAOLA-1 trial was the international trial that showed us the benefit of using the combination of PARP and bevacizumab, specifically in the population of ovarian cancer patients with HRD. Again, we you know that our BRCA-positive patients have the best prognosis, and our BRCA-negative/HRD-negative patients have the worst prognosis in terms of progression-free and overall survival. PAOLA-1 showed us that PARP with bevacizumab improves outcomes in both groups, most importantly for the HRD-positive population, and that's where the indication was made.

The post hoc analysis showed us that basically, progression while on olaparib, the PARP inhibitor and bevacizumab is a core prognostic sign, which of course, makes sense in that population. The from first to second progression in the patients who received PRAP vs placebo was significantly different in that group. It is worth pushing these patients towards the doublet in in terms of maintenance therapy to prolong that disease-free survival between recurrences as much as possible, and that's kind of what the takeaway was here.

Barbara Buttin, MD, discusses the PAOLA-1 clinical trial and it impact on the first-line treatment of ovarian cancer. 

Buttin Reviews Results From PAOLA-1 in Ovarian Cancer

Barbara Buttin, MD, a gynecologic oncologist at City of Hope Chicago, discusses the interim analysis findings from the phase 3 DUO-O trial (NCT03737643) of bevacizumab (Avastin) plus olaparib (Lynparza), and durvalumab (Imfinzi) as maintenance therapy for patients with newly-diagnosed advanced ovarian cancer and non 

We tend to look at patients with advanced ovarian cancer patients right now in terms of stratifying everyone based on biomarker status. So, we're looking at mutation status first, do they have 

-related genes? That’s only going to cover about 25% or so of all patients. If they don't, then we're going to do genomic analysis of the tumor to see if they have homologous recombination deficient [HRD], and we treat them based on that as far as whether they're a candidate for PARP inhibition in remission. If they're neither one of those things then we have the patients who are 

-negative, HRD-negative ovarian cancer patients and they still have the toughest prognosis. These stage 3 and 4 patients still have the toughest prognosis. Right now, the standard of care for them is chemotherapy plus bevacizumab and, of course, surgery. Then once patients are in remission, we give bevacizumab maintenance and bevacizumab alone has never really achieved an overall survival benefit.

So, we've never seen an overall survival benefit in this group of patients. We've had a PFS benefit with use of bevacizumab over placebo but never an overall survival benefit. So, now suddenly, we have the addition of durvalumab [Imfinzi] and then a PARP inhibitor added into the maintenance for that group of patients. And, we have a significant improvement in PFS and looks like overall survival hopefully, once that's finalized, is also going to be significant. So that's going to be a first that's going to happen for this group of patients.

Barbara Buttin, MD, provided insight on the phase 3 DUO-O trial and what it implies for the future of ovarian cancer treatment. 

Implications of the DUO-O Trial in Ovarian Cancer

Christina Fotopoulou, MD, PhD, chair in gynaecological cancer surgery in the department of surgery and cancer, faculty of medicine, Imperial College London, discusses the results of the DUO-O trial (NCT03737643) in patients with newly diagnosed ovarian cancer.

The large multicenter phase 3 DUO-O trial randomly assigned patients into 3 arms to receive platinum-based chemotherapy plus bevacizumab (Avastin) and durvalumab (Imfinzi) followed by maintenance bevacizumab, durvalumab, and olaparib (Lynparza); chemotherapy in combination with bevacizumab and durvalumab followed by maintenance bevacizumab and durvalumab; or chemotherapy plus bevacizumab followed by maintenance bevacizumab. The primary end point was progression-free survival (PFS) in the intent-to-treat (ITT) population and in the homologous recombination deficiency (HRD)–positive group.

The study showed a significant improvement in PFS in the ITT and HRD-positive groups with a HR of 0.49 favoring the triplet combination in HRD-positive patients and 0.63 favoring it in the ITT population. It additionally showed a HR of 0.68 in the HRD-negative group favoring the triplet combination arm. Fotopoulou says that no other studies showed a benefit for this group besides the PRIMA study (NCT02655016) of maintenance niraparib (Zejula). That study also had an HR of 0.68, although niraparib was compared with placebo and not an active comparator for maintenance. Fotopoulou says this study shows a role for a maintenance regimen that includes immunotherapy, but the relative toxicity of the DUO-O triplet regimen would also influence the choice to use it.

It's a very large multicenter prospective randomized phase 3 study with durvalumab, a PD-L1 inhibitor, bevacizumab, a VEGF inhibitor, and PARP inhibitors, versus bevacizumab alone. These were the 2 main arms that were the primary analysis there was also a second arm with bevacizumab and durvalumab. The primary end point was to see whether there was a survival benefit in the ITT and HRD-positive population.

This study is the first study in ovarian cancer, the first IO second-line cancer [study], to show a significant prolongation of the PFS with the HR of 0.68 for the HRD-negative population, which has been always a very challenging target group. So far, it is a group where only the PRIMA and the DUO-O study have shown a benefit. Very interestingly, we see that the hazard ratio in both studies is exactly the same with 0.68. It was very interesting to see it; even though the HR is the same, the difference is the triplet. One has a triplet therapy and the other only 1 [drug], meaning of course that there are also different associations with morbidity and toxicity and heterogenic complications, etc.

Christina Fotopoulou, MD, PhD, discusses the results of the DUO-O trial in patients with newly diagnosed ovarian cancer. 

DUO-O Trial Shows Efficacy of Triplet Maintenance for Ovarian Cancer

Bruno Bockorny, MD, a an attending physician for medical oncology/hematology at Beth Israel Deaconess Medical Center, an assistant professor of medicine at Harvard Medical School, and researcher of Cellular Biology at Beth Israel Deaconess Medical Center, discusses the phase 1 C-800 trial of botensilimab (AGEN1181) plus bastilimab (AGEN2034), specifically for patients in the C-800-01 cohort with recurrent platinum refractory/resistant ovarian cancer (NCT03860272).

The trial enrolled patients with platinum-resistant or refractory, metastatic disease and administered them 1 mg/kg (29%) or 2 (71%) mg/kg of botensilimab every 6 weeks plus 3 mg/kg of balstilimab every 2 weeks.

Patients must have had measurable disease on imaging based on RECIST 1.1, a life expectancy of ≥ 3 months, an ECOG performance status of 0-1, adequate hematological, liver, and renal function, and have n history of prior or concomitant malignancy that requires other active treatment. Additionally, patients were allowed to have received prior immunotherapy, and crossover from prior botensilimab monotherapy was allowed.

Primary end points of the trial were incidence of treatment-emergent adverse events, dose-limiting toxicities of botensilimab, and to determine the recommended phase 2 dose of botensilimab. Secondary end points assessed in the trial included objective response rate, duration of response, disease control rate, progression-free survival, overall survival, and pharmacokinetics.

The C-800 trial is a phase 1b clinical trial. It's a very large study that enrolled patients with any solid tumors with disease progression after standard-of-care treatment options including, investigational options and immunotherapy options. This study started with a monotherapy phase with botensilimab at a lower dose, followed by that combination with balstilimab. Now, we are in the final phases with disease specific expansion cohorts.

 At [the Society of Gynecologic Oncology [SGO] 2023 Annual Meeting on Women’s Cancer] this year, we presented data of patients with ovarian cancer who were platinum resistant or refractory.

Fc-engineered anti-CTLA-4 monoclonal antibody in advanced cancer. ClinicalTrials.gov. Updated April 28, 2023. Accessed May 17, 2023. https://clinicaltrials.gov/ct2/show/NCT03860272

Bruno Bockorny, MD, discusses the phase 1 C-800 trial of botensilimab plus bastilimab, specifically for patients in the C-800-01 cohort with recurrent platinum refractory/resistant ovarian cancer.


About the C-800 Trial of Botensilimab/Balstilimab in Ovarian Cancer

Erin Crane, MD, MPH, a gynecological oncologist at the Atrium Health Levine Cancer Institute, discusses the impact of the FDA request to restrict niraparib (Zejula) in the second-line maintenance setting for patients with recurrent ovarian cancer and how, ultimately, this hasn’t vastly changed physicians’ approach.

In 2017, the FDA approved the use of niraparib, a PARP inhibitor, as a maintenance treatment for patients with recurrent epithelial fallopian tube, or primary peritoneal cancer who had a complete or partial response to platinum-based chemotherapy. This was based on early data from the phase 3 ENGOT-OV16/NOVA trial (NCT01847274). 

The approved PARP inhibitor niraparib has been beneficial for patients with recurrent ovarian cancer, but new second-line restrictions for certain patients have led physicians to be more cautious when re-challenging these patients. 

Ovarian Cancer

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