Matulonis’ Passion Drives Gynecologic Cancer Research Into the Next Era

Specialization in oncology research affords investigators the opportunity to dive into tumor biology and uncover unique approaches to care. But specialization does not mean siloed approaches. Cross-functional team collaboration coupled with insights gained from patient interactions in the clinic and input from external collaborators are all vital to contributing to the rapidly changing treatment landscape, according to Ursula A. Matulonis, MD, a pillar of gynecologic cancer research and the embodiment of collaborative spirit.

From her start in gynecologic oncology drug development to her present-day position as chief of the Division of Gynecologic Oncology at the Dana-Farber Cancer Institute (Dana-Farber), coleader of the Gynecologic Cancer Program within the Dana-Farber/Harvard Cancer Center, and professor of medicine at Harvard Medical School in Boston, Massachusetts, Matulonis’ career has been built on the foundation of fostering and developing collaborative environments and programs to push the unmet needs of patients with gynecologic cancers into the research spotlight.

In an in-depth discussion with OncologyLive^®, as Matulonis reflected on her research achievements and what lies ahead in her career, she always came back to highlight 1 key factor: her collaborators. “Team science is important. Being open minded, thinking outside the box, [and] working hard—collaboration is critical. No one can operate singularly, it just doesn’t work that way,” Matulonis said.

There is no better way to highlight the collaborative spirit at work than through her latest achievement, securing a Specialized Program of Research Excellence (SPORE) grant from the National Cancer Institute.1 The Ovarian Cancer SPORE will focus on the development of combination drugs for low-grade serous cancers, the initiation of trials to evaluate combination therapies to overcome PARP inhibitor resistance, and the development of novel neoantigen vaccine development to enhance immune response to checkpoint inhibitors for patients with ovarian cancer.^1,2

“This is something I’ve worked for years to develop and something I’ve worked really hard to get off the ground with others,” Matulonis said. “I’m not the sole person here, but a lot of hard work finally came to fruition in 2020. I colead [the program] with my basic science colleagues, Alan D. D’Andrea, MD, and David Spriggs, MD, at Massachusetts General Hospital,” she said. D’Andrea is the director of the Susan F. Smith Center for Women’s Cancers at Dana-Farber. Spriggs is the director of the Gynecologic Oncology Program at Massachusetts General Hospital Cancer Center.

“I’ve certainly learned, from [the] SPORE grant and from the gynecologic program within Dana-Farber, that many individuals need to be incorporated from an expert standpoint— surgeons, oncologists, medical oncologists, radiation oncologists, pathologists, basic scientists—everyone [must] have a seat at the table,” Matulonis said.

In her roles, Matulonis noted that she is coleader of the administrative corps with D’Andrea and Spriggs, as well as the developmental research program with D’Andrea and Kevin M. Elias, MD, who is director of the Gynecologic Oncology Laboratory at Brigham and Women’s Hospital and an assistant professor of obstetrics, gynecology, and reproductive biology at Harvard Medical School.² “The [developmental program] provides grants to fledgling new projects that may eventually serve as a different project within the SPORE grant. It’s been super fun, [and] it is a 5-year grant, so we’re busy at work at the moment.”

In addition to her ongoing leadership and investigative efforts at Dana-Farber, Matulonis will return as the cochair of the upcoming 13th Annual International Symposium on Ovarian Cancer and Other Gynecologic Malignancies™, a 1-day program to be hosted by Physicians’ Education Resource^®, LLC (PER^®), on May 14, 2022.

“I’ve cochaired [the symposium] for a number of years now, [and it] really [is] a group effort,” Matulonis said. “[The agenda] is very fun to put together, and it changes over time. You truly have the experts in the field talking about their cancer [specialties, and] it’s going to be interesting [this year] because we’ve got the world’s experts presenting.”

International presenters at this year’s meeting include Nicoletta Colombo, MD, PhD; Philipp Harter, MD, PhD; Susana Banerjee, MBBS, PhD, MA, FRCP; Domenica Lorusso, MD, PhD; and Ana Oaknin, MD, PhD. The assembled faculty will approach an agenda that has undergone a shift in recent years, moving away from an ovarian cancer–dominated agenda to one that reflects the trends in the field of subspecialties of gynecologic malignancies.

“I remember a few years ago, our focus was on the use of PARP inhibitors [in ovarian cancer], the adverse effects, when to use a PARP inhibitor, which PARP inhibitor to use, and so on,” Matulonis said. “This year, the top billing goes to cervical cancer because of what’s happened in the past year—the leap frogging of immuno- oncology agents into [the treatment paradigm for] patients with newly diagnosed advanced cancer or those with recurrent cervical cancer.”

Laying the Foundation for Research and Innovation

Matulonis graduated from Albany Medical College in 1987 during what she referred to as “the dark ages of oncology.” Her first interest was hematologic malignancies, a field she thought she would pursue as she was drawn to the underlying biology. “I realized there was a whole world of solid tumors out there,” Matulonis said, noting that her interest in breast and gynecologic cancers was fostered during her fellowship at Dana-Farber.

“I was doing both breast and gynecologic cancers at Dana-Farber in the late 1990s, early 2000s, and no one was running a gynecologic program. I found women’s cancers compelling because they’re incredible cancers from a biology standpoint. There was not much drug development happening and we had limited therapies, so that propelled me to want to do a better job for our patients.”

Around 2004, the programs split into 2 divisions, and Matulonis chose to follow the pathway paved by recent advances with PARP inhibitors for gynecologic cancers. “What really drove the program forward and gave us footing and foundation were PARP inhibitors. I was one of the US principal investigators of Study 19 [NCT00753545], the results of which were published in the New England Journal of Medicine in 2012.”³

The trial evaluated olaparib (Lynparza) as maintenance treatment for patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer, demonstrating a significant progression-free survival (PFS) benefit. “That was a pivotal study. At that moment, there was nothing going on in ovarian cancer. In 2006, there was carboplatin/gemcitabine [for] platinum-sensitive cancer, but there had not been anything [new] since then. It was interesting to use these drugs [and] to see how they worked. They had activity, and Study 19 [illuminated] the concept that patients with BRCA-mutated tumors elicited much more benefit than nonmutated cancers. But even [patients with] nonmutated cancers had activity.”

Investigators solidified olaparib’s role in the treatment landscape with results of the SOLO-1 trial (NCT01844986),⁴ and Matulonis turned her attention to another novel agent, niraparib (Zejula), serving as the US principal investigator of the phase 3 NOVA trial (NCT01847274).⁵ “That was an incredibly exciting time [and] sealed my interest in new drug development for ovarian cancer,” Matulonis said.

At the time that these agents were expanding the treatment landscape, Matulonis had a hand in another area of growth—the gynecologic cancer research team at Dana-Farber. With an influx of investigative efforts under her purview, Matulonis built out a team that would help to support not only the management of the grants and funding but also the processes required to move drug development from bench to bedside, including compliance standards. “I was able to grow the team from 2 or 3 medical oncologists up to 9 and build a team that includes research managers, data managers, research nurses, regulatory individuals, program managers—approximately 40 [team members].”

As a professor at Harvard Medical School, Matulonis said that position places her in a role that is meant to elevate the junior faculty. “I am at a certain point in my career, where my job is to make sure junior faculty are actively doing research, generating their own ideas, [and] writing their own trials,” Matulonis said. “My job is to be incredibly supportive and help them be successful.”

Observations From a Diverging Landscape

The various histologies that fall under the gynecologic cancer umbrella do not respond to a one-size-fits-all approach. For example, patients with cervical cancer represent a significant unmet need in the clinic, as mortality rates worsen rather than improve in these subtypes. Endometrial cancer and ovarian cancer also have their own unique challenges for investigators at various stages.

“Each cancer is its own cancer, and there is a lot to think about individually,” Matulonis said.

Integration of Immuno-oncology Agents

Data for immuno-oncology (IO) agents have shown varying success across the gynecologic landscape, including among those with cervical cancer, ovarian cancer, endometrial cancer, and the tangentially related uterine cancer, according to Matulonis.

Pembrolizumab (Keytruda) has been integrated into the standard of care for patients with cervical cancer in combination and as a single agent based on PD-L1 expression, microsatellite instability–high (MSI-H), and mismatch repair deficient tumors (dMMR), respectively.^6,7

Recently, the addition of pembrolizumab to chemotherapy with or without bevacizumab (Avastin) showed promise among patients with recurrent or metastatic cervical cancer. Data from the KEYNOTE-826 trial (NCT03635567) demonstrated that among patients in the intention-to-treat population, the median PFS among those who received pembrolizumab (n = 308) was 10.4 months (95% CI, 9.1-12.1) vs 8.2 months (95% CI, 6.4-8.4) among those who received placebo (n = 309; HR, 0.65; 95% CI, 0.53-0.79; P < .001).⁸ Specifically for those with a PD-L1 combined positive score of at least 1, the median PFS for those who received pembrolizumab (n = 273) was 10.4 months (95% CI, 9.7-12.3) vs 8.2 months (95% CI, 6.3-8.5) among those who received placebo (n = 275; HR, 0.62; 95% CI, 0.50-0.77; P < .001).⁸

For patients with endometrial cancer, combination IO therapy with tyrosine kinase inhibitor lenvatinib (Lenvima) plus pembrolizumab demonstrated a significant improvement in PFS vs chemotherapy alone for patients treated in the KEYNOTE-775 trial (NCT03517449).⁹ Results were stratified by mismatch repair status at baseline.

Among those who were mismatch repairproficient (pMMR), the median PFS was 6.6 months vs 3.8 months for those who received the combination and chemotherapy alone, respectively (HR, 0.60; 95% CI, 0.50-0.72; P < .001). In the overall population, the median PFS was 7.2 months in the combination group vs 3.8 months in the chemotherapy group (HR, 0.56; 95% CI, 0.47-0.66; P < .001). The median overall survival in the pMMR population was 17.4 months vs 12.0 months (HR, 0.68; 95% CI, 0.56-0.84; P < .001) and 18.3 months vs 11.4 months, respectively, in the overall population (HR, 0.62; 95% CI, 0.51-0.75; P < .001).⁹

“For patients with ovarian cancer, introduction of [IO] agents [are] a different story,” Matulonis said. “The only approval for an IO agent in ovarian cancer is tumor agnostic for those patients with MSI-H or tumor mutational burden–high [TMB-H] disease, but IO does not have any formal indications.”

The tumor agnostic approvals for patients with solid tumors align with indications awarded to dostarlimab-gxly (Jemperli) for patients with dMMR recurrent or advanced solid tumors and pembrolizumab for patients with unresectable or metastatic TMB-H disease (TABLE 1 ^6,10,11).

Antibody-Drug Conjugates

Matulonis said a few other trends in the space include finding a place for antibody-drug conjugates (ADCs) and turning a focus on developing novel targeted therapies. “The development of targeted specific drugs to specific tumors may come from novel ADCs,” Matulonis said.

In September 2021, the FDA approved the tissue factor–directed antibody and microtubular inhibitor conjugate, tisotumab vedotin-tftv (Tivdak), for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.¹² The approval was based on data from 101 patients treated in the phase 2 innovaTV 204 trial (NCT03438396), in which the agent elicited an objective response rate of 24% (95% CI, 15.9%33.3%), with a median duration of response of 8.3 months (95% CI, 4.2–not reached).12

“Tisotumab vedotin doesn’t have a marker, it’s tissue factor,” Matulonis said, noting that the FDA approval does not indicate that tissue factor must be present. “However, there are other ADCs in development that require a biomarker, namely mirvetuximab soravtansine, which is being considered for accelerated approval.”

At the Society of Gynecologic Oncology 2022 Annual Meeting on Women’s Cancer, Matulonis presented data from the single-arm phase 3 SORAYA trial (NCT04296890), which assessed the efficacy of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer who had received 1 to 3 prior lines of therapy, experienced disease recurrence within 6 months of the last platinum-based regimen, and who have high folate receptor–alpha (FRα) expression.¹³ The ADC is designed with a FRα-binding antibody, a cleavable linker, and maytansinoid DM4 payload.

The overall response rate (ORR) among 105 treated patients was 32.4% (95% CI, 23.6%42.2%), consisting of 5 complete responses and 29 partial responses. The agent elicited the highest response among patients who had prior treatment with a PARP inhibitor (n = 50), with an ORR of 38.0% (95% CI, 24.7%-52.8%).¹³

“These results position mirvetuximab soravtansine to become a practice-changing, biomarker-driven, standard-of-care treatment option for patients with FRα-positive, platinum-resistant ovarian cancer,” Matulonis said at the meeting.

The Status of PARP in Ovarian Cancer

With 3 PARP approvals in the first-line maintenance setting, the use of these agents is deeply embedded in the treatment of patients with ovarian cancer (TABLE 2^14-16). However, there is a long road ahead for investigators, as resistance mechanisms present barriers to their continued efficacy.

Matulonis has been on that road since 2011, when early data demonstrated that a synergistic effect existed with the combination of PI3K and PARP inhibitors in breast cancer with or without BRCA mutations. In 2019, Matulonis and Dana-Farber colleague Panagiotis A. Konstantinopoulos, MD, PhD, published data from a phase 1 study (NCT01623349) of the combination of olaparib and alpelisib (Piqray), an α-specific PI3K inhibitor in patients with recurrent triple-negative breast cancer or high-grade serous ovarian cancer.¹⁷ Konstantinopoulos is the director of translational research in gynecologic oncology at Dana-Farber and an associate professor of medicine at Harvard Medical School.

Efficacy data from the trial showed that among the 28 patients with epithelial ovarian cancer 36% had a partial response, 50% had stable disease, and 11% had progressive disease. One patient (4%) was unevaluable for response using RECIST 1.1. Of note, 8 patients had stable disease for at least 6 months at the time of analysis.¹⁷

In early 2021, the phase 3 trial EPIK-O (NCT04729387) was initiated to evaluate alpelisib plus olaparib or single-agent cytotoxic chemotherapy in adult patients with platinum-resistant or refractory high-grade serous ovarian cancer with no germline BRCA mutation. Patients in the experimental arm received the maximum-tolerated dose determined in the previous study (alpelisib 200 mg orally once daily and olaparib 200 mg orally twice daily).¹⁸

“It took 10 years, but we finally got to the point where this could potentially serve as a study to support an FDA approval,” Matulonis said. “It’s early on, but it’s pretty exciting.”

Passion Reflected in Words

Looking back at how the trajectory of her career has led her to become a prominent leader of the next generation of investigators, Matulonis’ favorite quotes echo her sentiments of her current positions. “One of my favorite quotes is from Buzz Lightyear, ‘To infinity and beyond.’ That’s my go-to—think big. Another is from Billie Jean King, ‘Pressure is a privilege,’ which is etched into the National Tennis Center in Queens, [New York],” she said. “There’s a lot of pressure [in our work,] but what we do really is a privilege. All the faculty are hardworking, and I try to make sure they’re not completely overlapping in terms of what kind of research they’re doing.

“I know some are pursuing drug development [and] some are working solely on novel immunotherapies. [Elizabeth H. Stover, MD, PhD] is working on rare tumors….We are charging faculty with coming up with new ideas about how to tackle clinical problems, then giving them the resources to do that.”

Although Matulonis noted that at times her role is somewhat akin to being an air traffic controller, her passion for the work is evident in the way she speaks of inspiring the next wave of innovation in the field. “I see it as a mission of mine because of the need for new drug development and new treatment strategies for our patients,” she said.

“It is imperative that we train the next generation competently and well. To be a successful faculty member, to stay in academics, those individuals [must] feel that they are productive, that they are enjoying what they’re doing, [and] that they feel fulfilled. That’s important, I want to keep them engaged.”