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FAK is a nonreceptor tyrosine kinase with a critical role in the interaction between the cell and the extracellular matrix, regulating cellular adhesion, motility, proliferation, and survival; overexpression of the kinase is associated with poor prognosis in patients with cancer. Efforts are underway to develop FAK-targeted therapies; although FAK inhibition alone has displayed modest activity to date, the approach has shown promise as a combinatorial agent.

FAK is a part of multiple signaling pathways that contribute to the survival and proliferation of cancer cells, including PI3K/AKT, P53, and RAS/RAF/MEK. Additionally, the FAK pathway has been shown to mediate resistance to anticancer therapies. Targeting the FAK pathway has been shown to have a sensitizing effect on radiotherapy and chemotherapy. Moreover, heightened expression of FAK and the activation of the downstream Wnt/β-catenin signaling pathway can contribute to adaptive or acquired resistance mechanisms to BRAF or MEK inhibitors, which has stirred interest in FAK inhibition in combination therapy.

Defactinib Shows Promise As a Combination Component in Ovarian Cancer 

The FAK-targeted agent that has shown the most promise to date and progressed the furthest in clinical development is the second-generation inhibitor defactinib (VS-6063). In the phase 1/2 FRAME trial (NCT03875820), investigators evaluated the safety and efficacy of defactinib in combination with the RAF/MEK inhibitor avutometinib in patients with advanced solid tumors, including low-grade serous ovarian cancer (LGSOC).

LGSOC is a RAS/MAPK-driven cancer in more than 70% of patients and currently has an unmet need for effective treatment options with no FDA-approved therapies. In preclinical study, avutometinib plus FAK inhibition displayed clinical synergy and antitumor activity in KRAS-mutated and wild-type LGSOC models. Additionally, FAK inhibition in combination with avutometinib and chemotherapy induced tumor regression and extended survival in a pancreatic cancer mouse model. 

"Avutometinib is a RAF/MEK inhibitor that is unique compared with other MEK inhibitors,” Bradley J. Monk, MD, FACS, FACOG, medical director of latephase clinical research at Florida Cancer Specialists & Research Institute in West Palm Beach, said in an interview with OncologyLive. “It is potentially the best-in-class [agent] based on its activity as well as its tolerability. The preclinical antiproliferative activity [with this agent] across multiple MAPK pathway alterations, [including] RAS, BRAF, and MEK, is transformational. Defactinib is a FAK inhibitor, and the idea is that together they could be synergistic.” 

"A classic escape mechanism [of RAF/MEK] inhibition is through the FAK pathway,” David M. O’Malley, MD, a professor in the Department of Obstetrics and Gynecology at The Ohio State University College of Medicine and director of the Division of Gynecologic Oncology at The Ohio State University Comprehensive Cancer Center– James in Columbus, added in an OncLive News Network Program. “Defactinib is an inhibitor to that escape pathway. So, we have dual inhibition at the RAF/MEK pathway and inhibition at the escape or resistance pathway with the FAK inhibitor. These mechanisms of action in this triple blockade have been shown to be efficacious.” 

Avutometinib plus defactinib received a breakthrough therapy designation from the FDA in May 2021 for the treatment of patients with recurrent LGSOC, regardless of KRAS status, following at least 1 prior line of treatment including platinum-based chemotherapy.

At a data cutoff of July 2023, findings from FRAME presented during the 5th Annual RAS-Targeted Drug Development Summit, which took place in September 2023 in Boston, Massachusetts, demonstrated that patients with LGSOC who received the combination of avutometinib and defactinib (n = 26) achieved an overall response rate (ORR) of 42%. Additionally, the median duration of response (DOR) and the median progression-free survival (PFS) were 26.9 months (95% CI, 8.5-47.3) and 20.0 months (95% CI, 11.1-31.2), respectively. Patients were heavily pretreated, with a median of 3.5 prior lines of therapy.

During the 2023 American Society of Clinical Oncology Annual Meeting, which took place in Chicago, Illinois, in June, study authors presented initial efficacy and safety findings from the phase 2 ENGOT-ov60/GOG-3052/RAMP 201 trial (NCT04625270). RAMP 201 enrolled patients with recurrent LGSOC who underwent prior chemotherapy; previous treatment with a MEK inhibitor was permitted. The study evaluated the combination of avutometinib plus defactinib as well as avutometinib monotherapy; the primary end point was ORR by blinded independent central review.

At the April 6, 2023, data cutoff, findings from an interim analysis of RAMP 201 demonstrated that patients who received the combination (n = 29) achieved a confirmed ORR of 45% (95% CI, 26%-64%), with 86% of patients experiencing tumor shrinkage. The median time to response was 5.5 months (range, 1.6-14.7), and the median DOR and PFS had not been reached. Comparatively, the ORR in the monotherapy arm (n = 30) was only 10% (95% CI, 2%-24%), underscoring the impact of the addition of FAK inhibition to RAF/MEK inhibition. Additionally, responses with the combination were observed in patients with KRAS-mutated (n = 15) as well as KRAS wild-type disease (n = 14), with respective ORRs of 60% and 29%. 

"[This is] great news for patients that now we have a combination that is tolerable and has an ORR of 45%,” Monk explained. “What does that 45% ORR mean? The Gynecologic Oncology Group [led the phase 2/3] Study 281 [NCT02101788] with another MEK inhibitor, trametinib [Mekinist], and [the ORR] was 26% vs 6% with chemotherapy. Then, I reported [data from] the [phase 3] MILO trial [NCT01849874] with another MEK inhibitor, binimetinib [Mektovi], which elicited an ORR of 16% vs 13% with standard-of-care chemotherapy.”

In March 2024, investigators presented findings from a subgroup analysis of RAMP 201 during the Society of Gynecologic Oncology Annual Meeting on Women’s Cancer (SGO 2024). Findings from the analysis showed that the response with avutometinib plus defactinib was consistent regardless of the number of prior lines of therapy a patient received; patients who received 1 to 3 prior lines (n = 11) and those who received 4 or more (n = 18) achieved ORRs of 45.5% (95% CI, 17%-77%) and 44.4% (95% CI, 22%-69%), respectively. Moreover, among patients with efficacy data available for their last line of treatment (n = 23), the combination elicited an ORR of 43.5% compared with 8.7% with the last prior line of therapy.

In December 2023, Verastem Oncology announced that it had initiated the confirmatory phase 3 RAMP 301 trial (NCT06072781), which will compare avutometinib plus defactinib with investigator’s choice of chemotherapy in patients with LGSOC. In the news release, the company also noted that it intends to submit a new drug application to the FDA seeking the accelerated approval of avutometinib plus defactinib in LGSOC supported by findings from RAMP 201 and FRAME.

“LGSOC has a unique molecular, histologic, and clinical profile that differs dramatically from the most common type of ovarian cancer. Response rates to standard of care treatments are disappointing, and there are still no FDA-approved treatments specifically for LGSOC,” Rachel N. Grisham, MD, section head of ovarian cancer and director of gynecologic medical oncology at Memorial Sloan Kettering Cancer Center in Westchester, New York, as well as the global lead investigator of RAMP 301, said in the news release. “The combination of avutometinib and defactinib continues to show promise in recurrent LGSOC, and I am looking forward to leading this confirmatory trial with the goal of establishing a new standard of care for people with this rare form of ovarian cancer.”

During SGO 2024, investigators presented the trial schema of RAMP 301. The open-label study is enrolling approximately 270 patients with recurrent LGSOC who have progressed on or after platinum-based therapy across North America, Europe, and Asia Pacific. Patients will be randomly assigned 1:1 to receive either avutometinib 3.2 mg twice weekly for 21 of 28 days plus defactinib 200 mg twice daily for 21 of 28 days or investigator’s choice of chemotherapy. The primary end point is PFS per RECIST 1.1 by blinded independent central review; secondary end points include investigator- assessed PFS, OS, ORR, DOR, disease control rate, and safety.

“If we can get this [combination] FDA approved, this will change the standard of care,” Monk said. “This will be the standard of care in patients [with LGSOC who underwent] prior therapy. [This combination generated] tumor shrinkage in most patients and an ORR, at least preliminarily, of 45%. Once we get accelerated approval [from the FDA], we’ll probably have to stop the confirmatory trial enrollment here, but that will take time. For now, look for the confirmatory trial [and] let’s get it enrolled so we can get this [regimen] approved.” 

Clinical Study of Additional FAK Inhibitors in Underway in Other Cancer Types 

Beyond LGSOC, early-phase clinical trials of FAK inhibitor monotherapy and combination regimens are underway in a variety of other cancers, including lung cancer, pancreatic cancer, hematologic malignancies, and advanced solid tumors. Another agent that has shown promise in multiple cancer types is the selective, ATP-competitive FAK inhibitor ifebemtinib (IN10018).

In a phase 1 study (NCT01335269) of patients with advanced or metastatic nonhematologic malignancies, ifebemtinib monotherapy displayed a manageable safety profile with preliminary activity at a maximum tolerated dose (MTD) of 200 mg once daily. During the dose escalation phase, among efficacy-evaluable patients (n = 49), 27% achieved a best response of stable disease and 51% of patients experienced progressive disease. The median duration of disease control was 99 days (95% CI, 87-141) and included 4 patients who had stable disease for at least 150 days. Notably, the population was heavily pretreated and included patients with metastatic pancreatic adenocarcinoma, platinum-resistant ovarian cancer, metastatic esophageal cancer, and metastatic soft tissue sarcoma.

Similarly, in a Japanese phase 1 study (NCT01905111) of patients with advanced or metastatic solid tumors, ifebemtinib monotherapy demonstrated a manageable safety profile with potential antitumor activity. No dose-limiting toxicities were reported, and the MTD was also 200 mg once daily. In a heavily pretreated population (n = 21) in which 67% of patients received at least 3 prior chemotherapy regimens, 1 patient experienced an objective response and 5 achieved stable disease.

Articles

FAK, a nonreceptor tyrosine kinase, plays a crucial role in cancer cell survival and proliferation, with its overexpression linked to poor prognosis. FAK-targeted therapies, particularly in combination with other agents, show promise in overcoming resistance mechanisms. Defactinib, a second-generation FAK inhibitor, combined with the RAF/MEK inhibitor avutometinib, has demonstrated significant efficacy in treating low-grade serous ovarian cancer (LGSOC), achieving notable response rates. Ongoing trials aim to establish this combination as a new standard of care for LGSOC, with potential applications in other cancer types.

Pathways

Although FAK inhibition alone has displayed modest activity to date, there is interest in developing FAK-targeted therapies for combination regimens. 

FAK Inhibition Emerges as a Potential Complementary Treatment Pathway

Legal requirements, an increasingly competitive labor market, and the rising costs of health care have driven many employers to self-funding models to offer affordable health care coverage to employees.

Self-funded health care offers the potential of not only cost savings, but also increased flexibility in the care provided, which benefits employers, employees, and providers alike.

 These assets can be further enhanced by pairing them with the enriched quality of care and cost savings provided by a concierge medicine benefits manager.

Cancer treatment has been a top driver of employer health care costs, and the need for treatment is expected to continue to increase.

 Cancer diagnoses are associated with substantial emotional burden along with loss in productivity, which contributes to additional indirect costs for both employees and employers.

 Hence, ensuring the best possible care for a person with cancer is in everyone’s interest. This kind of dedication and care also strengthens employer-employee relationships, building the foundations for a long-term and sustainable workforce.

A happy and healthy employee is productive and loyal and is likely to continue in their role for many years. Unfortunately, patient care is often impeded by cumbersome administrative practices related to insurance approvals.

 The last thing a patient with newly diagnosed cancer needs is to spend weeks waiting for appointments and testing—they need immediate treatment and care to help them along their cancer journey.

Concierge medicine benefits managers are professional liaisons between providers and patients who help employers tailor their health care benefits to maximize quality of care and cost savings.

 Whereas fee-for-service models emphasize high throughput, concierge medicine pushes for reduced wait times, longer and more comprehensive appointments to fully address patients’ needs and concerns, and more immediate access to necessary services.

 Instead of the patient trying to determine who can provide the best in-network care for their specific cancer type and waiting for an available appointment, a concierge medicine benefits manager conducts this research and directs them to the appropriate recommended place.

Concierge medicine also has the benefit of potentially reducing delays associated with determining whether specific diagnostics or treatments are covered by an insurance carrier and securing the required authorizations. For example, genetic testing is a recommended standard for many types of cancer to direct patients to optimized and targeted therapies that have the best efficacy and the lowest potential for adverse effects (AEs), but coverage of this testing varies among insurance companies.

 By gaining quick access to targeted therapies, with potentially less severe AEs, patients may remain in the workforce throughout their treatment. They can also avoid treatments that are less likely to be effective, reducing costs and improving outcomes.

In addition to having full knowledge of the best care facilities, concierge medicine benefits managers maintain a keen awareness for cost savings that benefit the employer. Indeed, cancer treatments can vary from one cancer center to another.11 Community-based care can offer a unique solution for the individual, including quality cost-effective care that is in proximity to the patient’s home. This allows for simpler scheduling and travel, ensuring quick access to needed services.

 Thus the concierge medicine benefits manager can help direct individuals to the most accessible facilities that may also offer overall cost-effectiveness. Moreover, the costs are known ahead of time, as they are not dependent on approvals and negotiations with insurance companies.

Providing health care through concierge medicine benefits employers by reducing costs and decreasing absenteeism, and investing in overall wellness helps maintain a healthy and productive workforce.

 In turn, employees get the benefit of rapid and consistent access to excellent care. This attentiveness to the whole patient throughout their illness supports overall wellness.

Finally, another factor that cannot be ignored is the benefit of concierge medicine to providers. There has been increasing burnout among providers, even prior to the COVID-19 pandemic, and now more than ever it is time to reexamine the one-size-fits-all approach of prior health care models and adjust them toward better outcomes for patients and providers alike. Some of the biggest contributors to health care provider burnout include too many patients and too little time, an inability to provide full and comprehensive care to help patients during treatments, and administrative burden.

 Concierge medicine addresses all of these by supporting team-based care to allow for more time with individual patients to fully address their needs; it also eliminates the need for paperwork and phone calls to cover insurance negotiations, billing, approvals, and reimbursements.

 Concierge medicine allows providers to spend more time focusing on helping their patients and fulfilling the primary goal of medicine.

Ultimately, concierge medicine helps employers provide the most beneficial and comprehensive health care coverage more affordably. These models are tailored to provide optimized and individualized care for each employee and ensure the best outcomes to help them through their treatment. Concierge medicine benefits managers are expert guides who navigate the subtleties of quality and cost-effective care to maximize the treatment goals for employers, employees and providers alike, reducing the burden on all parties and allowing them to
focus on what matters most: wellness for the patient.

Robertson K, Lowther C. Benefit concierge services: legal issues to know. BenefitsPRO. November 12, 2018. Accessed February 15, 2024. bit.ly/4av4S7N

What is self funding? Health Care Administrators Association. Accessed February 20, 2024. bit.ly/3ITgaqS

Warshaw J. Why concierge medicine is the perfect fit for self-funded employers. LinkedIn. August 12, 2015. Accessed February 21, 2024. bit.ly/4as2SNF

Miller S. Cancer now top driver of employer health care costs, survey shows. SHRM. August 31, 2022. Accessed February 21, 2024. bit.ly/3VthgBf

Cong Z, Tran O, Nelson J, Silver M, Chung K. Pro- ductivity loss and indirect costs for patients newly diagnosed with early- versus late-stage cancer in the USA: a large-scale observational research study. 

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Moole H. Why employers should consider concierge medicine for employees? FindMyDirectDoctor. Updated February 27, 2021. Accessed February 15, 2024. bit.ly/3vuby7t

Hopkins C. Oncologists, patients still face unpredictable payor coverage for broad tissue NGS panels. Precision Medicine Online. May 17, 2021. Accessed February 22, 2024. bit.ly/3x9goaN

Phillips C. Financial navigation can reduce the financial toxicity of cancer care. National Cancer Institute. April 21, 2023. Accessed February 21, 2024. bit.ly/49bO9FR

Soman N. Understand the distinction: direct primary care vs concierge medicine. Decent. October 25, 2023. Accessed February 21, 2024. bit.ly/3vq2Tmu

Demyan D. How healthcare concierge services complement self-funded insurance. Roundstone. February 21, 2023. Accessed February 20, 2024. bit.ly/4a7j6fz

Cancer care and the self-insured business: doing right by employees while controlling costs and improving the bottom line. Regional Cancer Care Associates. October 1, 2018. Accessed February 21, 2024. bit.ly/3TQJBA3

Verrilli D. Community-based cancer care: a better all-around value. The US Oncology Network. November 2017. Accessed February 21, 2024. bit.ly/3vpcaLI

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Employers are increasingly adopting self-funded health care models to manage rising costs and enhance flexibility. Concierge medicine benefits managers play a crucial role in optimizing care quality and cost savings, particularly in cancer treatment, which is a significant cost driver. These managers streamline patient care by reducing administrative burdens and ensuring timely access to necessary services. This approach benefits employers by reducing costs and absenteeism, employees by providing rapid access to care, and providers by alleviating burnout. Overall, concierge medicine supports comprehensive, individualized care and improved patient outcomes.

Partner Perspective

The current health care economy has driven many employers to self-funding models to offer affordable health care coverage to employees.

Quality Over Quantity: What Concierge Medicine Can Offer to Patients With Cancer and Employers

Bladder cancer is the sixth most frequently occurring cancer in the United States, with a global mortality rate of 2.9%. The treatment paradigm in most subtypes of the disease was defined by chemotherapy for many years; however, recent updates from clinical studies have spurred hope that more modern agents, such as immunotherapeutics and antibody-drug conjugates (ADCs), can be added to the treatment armamentarium and spare patients from the toxicity that is often associated with traditional cytotoxic agents while maintaining, or even improving, efficacy.

, a panel of expert clinicians in the field of genitourinary oncology discussed updated findings from key clinical trials presented during the 2024 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU 2024), which was held in January in San Francisco, California. They highlighted key clinical trial updates in muscle-invasive bladder cancer, frontline treatment options in metastatic urothelial carcinoma, and the development of new approaches for patients in the second line and beyond.

Neoadjuvant and Adjuvant Therapy in Muscle-Invasive Bladder Cancer

The panelists began their conversation by discussing updates in muscle-invasive bladder cancer in the neoadjuvant setting, a setting in which chemotherapy, despite its limited activity, is the established treatment modality.

 “[In the neoadjuvant space] the data are certainly exciting,” Matthew Milowsky, MD, FASCO, said. “There’s a lot of integration of immune checkpoint blockade into the neoadjuvant setting, as well as other novel agents. A number of studies have looked at immune checkpoint blockade alone or in combination with chemotherapy.”

One such study of neoadjuvant immunotherapy that was presented during ASCO GU 2024 was the phase 2 GDFATHER-NEO trial (NCT06059547). GDFATHER-NEO is a multicenter, single-blinded study evaluating the GDF-15 neutralizing IgG4 monoclonal antibody visugromab (CTL-002) in combination with nivolumab (Opdivo) in patients with muscle-invasive bladder cancer who are ineligible for or refuse neoadjuvant cisplatin-based chemotherapy. The primary end points were pathologic complete response (pCR) and radiologic response rate; secondary end points include safety, event-free survival (EFS), and overall survival (OS).

Preclinical findings showed that GDF-15 neutralization showed promise in overcoming tumor immune escapes and immunosuppression mechanisms. Additionally, in the phase 1 study, the combination proved to be safe and effective with deep and durable responses in PD-1/PD-L1 relapsed/refractory metastatic solid tumors. The present study is recruiting patients and phase 2 data have not been published.

Another immunotherapy-based approach is being evaluated in patients with muscle-invasive bladder cancer in the phase 2 NURE-Combo trial (NCT04876313), which is examining nivolumab in combination with nab-paclitaxel (Abraxane) followed by radical cystectomy and adjuvant nivolumab. The primary end point is pCR; secondary end points include EFS, safety, and major pathological response.

Patients who received the study treatment (n = 31) achieved a ypT0N0 response rate of 38.7% (95% CI, 22%-56%) and 73.3% (95% CI, 55%-87%) achieved a yp≤1N0 response. Notably, no disease progression occurred during neoadjuvant treatment; at a median follow-up of 12 months (IQR, 9-17.5) the 12-month EFS rate was 89.1% (95% CI, 78.3%-100%). Study authors concluded that nivolumab plus nab-paclitaxel represents a safe and effective perioperative strategy in muscle-invasive bladder cancer and that their findings could expand opportunities for chemotherapy combinations in cisplatin-ineligible patients.

“Right now, we’re still leaning on cytotoxic chemotherapy per NCCN [National Comprehensive Cancer Network] guidelines,” Elizabeth Plimack, MD, MS, FASCO, commented. “There’s a preference [for] dosedense accelerated MVAC [methotrexate, vinblastine, doxorubicin, and cisplatin] based on [data from the phase 3] VESPER trial [NCT01812369] and pT0 rates. [Additionally], the need for long-term time-to-event end points is critical in these studies. We’re trying to cure people and we need to prove that we’re doing that. There’s [also] a lot of enthusiasm for novel agents, including immunotherapy in this space.”

In the adjuvant setting of muscle-invasive bladder cancer, updated findings from 2 phase 3 studies were reported during ASCO GU 2024. In the phase 3 AMBASSADOR trial (NCT03244384), investigators compared adjuvant pembrolizumab (Keytruda) with observation in patients with muscle-invasive urothelial carcinoma who underwent radical surgery 4 to 16 weeks prior to receiving study treatment. The coprimary end points were OS and disease-free survival (DFS).

The median DFS in the pembrolizumab arm (n = 354) was 29.0 months (95% CI, 21.8-not reached [NR]) compared with 14.0 months (95% CI, 9.7-20.2) in the observation arm (n = 348; HR, 0.69; 95% CI, 0.54-0.87; 

 = .001). However, the OS end point was not met at the interim analysis; the median OS was 50.9 months (95% CI, 43.8-NR) vs 55.8 months (95% CI, 53.3-NR), respectively (HR, 0.98; 95% CI, 0.76-1.26; 

 = .884). The study authors concluded that their findings support adjuvant pembrolizumab as a new therapeutic option in this patient population and additional follow-up is ongoing for the final DFS and OS analyses.

Investigators also presented findings from DFS analyses of the phase 3 CheckMate 274 trial (NCT02632409), which compared adjuvant nivolumab with surveillance in patients with muscle-invasive bladder cancer at high risk after radical cystectomy. Only patients who underwent surgery within the past 120-day window were eligible for enrollment. The primary end point was DFS in the intent-to-treat (ITT) population and DFS in patients with a PD-L1 level of at least 1%.

 The median DFS in the ITT population was 22.0 months (95% CI, 18.8-36.9) with nivolumab (n = 353) compared with 10.9 months (95% CI, 8.3-15.2) in the surveillance arm (n = 356; HR, 0.71; 95% CI, 0.58-0.86). Additionally, adjuvant nivolumab provided a significant benefit over surveillance among patients in the PD-L1–positive subgroup (HR, 0.52; 95% CI, 0.37-0.72). Due to a lack of mature OS data, investigators utilized mixture cure models to estimate the impact of nivolumab on long-term survivorship; data from the models demonstrated that adjuvant nivolumab led to an estimated 6% to 9% absolute increase in the cure rate in the ITT population and a 23% to 25% absolute increase in the cure rate in the PD-L1–positive population compared with radical cystectomy alone.

Frontline and Maintenance Therapy for Metastatic Urothelial Carcinoma

The panelists transitioned their discussion to updates in metastatic urothelial carcinoma presented during ASCO GU 2024, starting with the phase 3 EV-302/KEYNOTE KN-A39 trial (NCT04223856), which compared enfortumab vedotin-ejfv (Padcev) plus pembrolizumab with the long-time standard-of-care platinum-based chemotherapy in patients with untreated locally advanced metastatic urothelial carcinoma. Primary findings from the study, which were presented during the European Society for Medical Oncology (ESMO) Congress in October 2023, demonstrated that the combination significantly improved progression-free survival (PFS) over chemotherapy (HR, 0.45; 95% CI, 0.38-0.54; 

 < .00001) and OS (HR, 0.47; 95% CI, 0.38-0.58; 

“EV-302 stole the limelight; it was an international randomized trial of 900 patients with locally advanced or metastatic urothelial carcinoma and this time they could have been eligible or not eligible for cisplatin,” Neeraj Agarwal, MD, FASCO, said. “The coprimary end points were PFS and OS. The most striking result was the doubling of OS at 31.5 months vs 16.1 months, with a 53% reduction in the risk of progression or death with enfortumab vedotin [plus] pembrolizumab. I don’t think we have seen these kinds of exciting results ever in our field. So this is obviously fantastic news for our patients.”

Findings from subgroup analyses presented during ASCO GU 2024 showed that the OS benefit displayed by enfortumab vedotin plus pembrolizumab over standard-of-care chemotherapy was consistently observed across prespecified subgroups. The most pronounced benefit was observed among patients with an ECOG performance status of 0 (HR, 0.36; 95% CI, 0.25-0.53) and those from Europe (HR, 0.40; 95% CI, 0.28-0.56). Study authors concluded that the results of the analyses supported the findings of the primary analysis, indicating the combination of enfortumab vedotin plus pembrolizumab is a new standard of care in frontline locally advanced or metastatic urothelial carcinoma (

Shortly after the presentation at ESMO 2023, in December 2023, the FDA approved the combination of enfortumab vedotin and pembrolizumab for the treatment of patients with locally advanced or metastatic urothelial cancer.

The panelists also highlighted updated findings from the phase 3 JAVELIN Bladder 100 trial (NCT02603432), which compared maintenance treatment with the PD-L1–directed monoclonal antibody avelumab (Bavencio) plus best supportive care with best supportive care alone in patients with advanced urothelial carcinoma who did not experience disease progression after completing frontline treatment with platinum-containing chemotherapy. Previously reported topline findings from the study showed that, after a minimum follow-up of 2 years, the addition of avelumab significantly prolonged OS vs best supportive care alone, at 23.8 months vs 15.0 months, respectively (HR, 0.76; 95% CI, 0.63-0.91; P = .0036).

In a patient-reported outcomes analysis presented at ASCO GU 2024, investigators noted that the addition of avelumab to best supportive care did not negatively affect patient quality of life. Patient-reported outcome scores remained stable throughout treatment, with a least-squares mean change from baseline of –0.05 (95% CI, –0.63 to 0.52), 0.68 (95% CI, 0.46-0.91), and –0.02 (95% CI, –0.04 to 0.0) in physical disease–related symptoms, emotional disease-related symptoms, and EQ-5D-5L index scores, respectively, among those who received at least 1 year of avelumab.

Also during ASCO GU 2024, investigators presented findings from the observational, retrospective PATRIOT-II study. PATRIOT-II collected data from 160 patients with metastatic urothelial carcinoma across 37 sites in the United States who received first-line avelumab maintenance therapy in routine clinical practice. Findings from the study showed that the real-world results were in line with those of JAVELIN Bladder 100; the median real-world OS at a minimum of 24 weeks post frontline avelumab initiation was 24.4 months (SE, 2.0; 95% CI, 20.4-28.4) and 30.5 months (SE, 3.6; 95% CI, 23.4-37.6) from the start of platinum-based chemotherapy.

“We used to talk about [patients being] cisplatin fit [vs] cisplatin unfit. [Now] I think more about [them being] combination therapy eligible vs combination ineligible, Evan Y. Yu, MD, said. “I look at ECOG performance status, and if it’s 0 to 2, they have a GFR [glomerular filtration rate] greater than 30, and adequate organ function, in general they are a combination patient. Under those circumstances, most patients can receive enfortumab vedotin in combination with pembrolizumab based on EV-302 [data]. If they are not eligible for enfortumab vedotin, usually that is a patient with significant neuropathy or a patient with very poorly controlled diabetes. Neuropathy would represent an issue as well with the [phase 3 CheckMate]901 [NCT03036098] regimen based on the use of cisplatin, so I would lean more on the JAVELIN Bladder 100 regimen [after treatment with] gemcitabine, carboplatin, and maintenance nivolumab.”

Later-Line Therapies for Metastatic Urothelial Carcinoma

The panelists concluded their conversation with a brief discussion of ongoing and upcoming early-phase studies in patients with pretreated metastatic urothelial carcinoma. “Most of us were using platinum in the first line for metastatic disease, then probably using immune-oncology agents like pembrolizumab in the second line, and enfortumab vedotin in the third line. Now that you take your second- and third-line [agents], enfortumab vedotin and pembrolizumab, combine them up front, [and] move them to the first line like we’ve been talking about, that leaves a real question mark as to what we should be doing [in the] second line,” Yu commented.

The experts highlighted an ongoing phase 1/2 trial (NCT04863885) of ipilimumab (Yervoy) plus nivolumab and sacituzumab govitecan-hziy (Trodelvy) in patients with metastatic urothelial carcinoma who are ineligible for cisplatin therapy. The study is enrolling treatment-naive patients with an ECOG performance status of 1 or less who did not receive prior chemotherapy. The primary end points are safety and determining the maximum tolerated and recommended phase 2 doses; secondary end points include objective response rate (ORR), PFS, OS, and duration of response.

Finally, the panelists discussed preliminary findings from the phase 1 TROPION-PanTumor01 study (NCT03401385), which is examining the ADC datopotamab deruxtecan in patients with unresectable advanced or metastatic urothelial cancer following at least 1 prior line of therapy. The primary end point was safety; secondary end points included ORR and disease control rate (DCR).

At a median follow-up of 9.1 months (range, 5-17), preliminary findings from the study showed that response-evaluable patients (n = 26) achieved a confirmed ORR of 19.2% (95% CI, 6.6%- 39.4%), including a 3.8% complete response rate. The DCR was 80.8% (95% CI, 60.6%-93.4%). In terms of safety, datopotamab deruxtecan was tolerable, with a grade 3 treatment-emergent adverse effect rate of 33%; the agent is being further evaluated in patients with urothelial cancer in the phase 1/2 TROPION-PanTumor02 (NCT05460273) and the phase 2 TROPIONPanTumor03 (NCT05489211) clinical trials.

“We’re not curing patients, and we do have an opportunity to cure patients potentially as we move these therapies earlier, whether it be targeting HER2 earlier, using enfortumab vedotin plus pembrolizumab earlier, or different combinations of immunotherapy and ADCs in the adjuvant setting or targeted therapeutics,” Milowsky said in conclusion. “This is really the way and has been borne out in other diseases as well: RNA vaccine-based approaches in the adjuvant setting in combination with immune checkpoint blockade. These things are happening, but the faster we can make them happen…is going to ultimately translate to a higher cure rate for our patients overall.”

Shafique MA, Haseeb A, Siddiq MA, Mussarat A, Rangwala HS, Mustafa MS. Current and emerging treatments for urothelial carcinoma: a focus on enfortumab vedotin. 

. 2023;15:699-706. doi:10.2147/CMAR.S418009

Necchi A, Iacovelli R, Di Maio M, et al. Neutralizing GDF-15 in muscle-invasive bladder cancer (MIBC): a neoadjuvant immunotherapy trial of visugromab (CTL-002) in combination with the anti-PD1 antibody nivolumab (GDFather-Neo). 

. 2024;42(suppl 4):TPS712. doi:10.1200/JCO.2024.42.4_suppl. TPS712

Mercinelli C, Basile G, Raggi D, et al. First results of NURECombo: a phase 2 study of neoadjuvant nivolumab (NIVO) and nab-paclitaxel (ABX) followed by postsurgical adjuvant NIVO in patients (pts) with muscle-invasive bladder cancer (MIBC). 

. 2024;42(suppl 4):610. doi:10.1200/ JCO.2024.42.4_suppl.610

Apolo AB, Ballman KV, Sonpavde GP, et al. AMBASSADOR Alliance A031501: phase III randomized adjuvant study of pembrolizumab in muscle-invasive and locally advanced urothelial carcinoma (MIUC) vs observation. 

. 2024;42(suppl 4):LBA531. doi:10.1200/JCO.2024.42.4_suppl. LBA531

Geynisman DM, Yates G, Chepynoga K, et al. Estimating the impact of adjuvant treatment with nivolumab on long-term survivorship rates compared with surveillance: analyses of disease-free survival (DFS) from the phase 3 CheckMate-274 trial. 

. 2024;42(suppl 4):528. doi:10.1200/ JCO.2024.42.4_suppl.528

Powles TB, Valderrama BP, Gupta S, et al. EV-302/KEYNOTE- A39: open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). 

. 2023;34(suppl 2):S1340. doi:10.1016/j.annonc.2023.10.106

Van Der Heijden MS, Powles TB, Gupta S, et al. Enfortumab vedotin (EV) in combination with pembrolizumab (P) versus chemotherapy in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC): subgroup analyses results from EV-302, a phase 3 global study. 

. 2024;42(suppl 4):LBA530. doi:10.1200/JCO.2024.42.4_suppl. LBA530

FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed March 22, 2024. https://www.fda.gov/ drugs/resources-information-approved-drugs/fda-approvesenfortumab- vedotin-ejfv-pembrolizumab-locally-advancedor- metastatic-urothelial-cancer

Grivas P, Aragon-Ching JB, Bellmunt J, et al. Avelumab first-line maintenance (1LM) for advanced urothelial carcinoma (aUC): long-term patient-reported outcomes (PROs) in the phase 3 JAVELIN Bladder 100 trial. 

. 2024;42(suppl 4):581. doi:10.1200/JCO.2024.42.4_suppl.581

Grivas P, Barata PC, Moon HH, et al. Avelumab first-line maintenance therapy for locally advanced/metastatic urothelial carcinoma: results from the real-world US PATRIOT-II study. 

. 2024;42(suppl 4):697. doi:10.1200/ JCO.2024.42.4_suppl.697

Jain RK, Yang Y, Chadha J, et al. Phase I/II study of ipilimumab plus nivolumab (IPI-NIVO) combined with sacituzumab govitecan in patients with metastatic cisplatin-ineligible urothelial carcinoma. 

. 2024;42(suppl 4):TPS713. doi:10.1200/ JCO.2024.42.4_suppl.TPS713

Lisberg A, Drakaki A, Meric-Bernstam F, et al. Datopotamab deruxtecan in locally advanced/metastatic urothelial cancer: preliminary results from the phase 1 TROPION PanTumor01 study. 

. 2024;42(suppl 4):603. doi:10.1200/ JCO.2024.42.4_suppl.603

Bladder cancer treatment is evolving with the integration of immunotherapeutics and antibody-drug conjugates, offering potential alternatives to traditional chemotherapy. Recent clinical trials, such as GDFATHER-NEO and NURE-Combo, explore neoadjuvant immunotherapy in muscle-invasive bladder cancer. Adjuvant studies like AMBASSADOR and CheckMate 274 highlight pembrolizumab and nivolumab's efficacy. In metastatic urothelial carcinoma, the EV-302/KEYNOTE KN-A39 trial shows enfortumab vedotin plus pembrolizumab's superiority over chemotherapy. Emerging therapies, including ipilimumab and datopotamab deruxtecan, are under investigation for later-line treatment, aiming to improve patient outcomes.

Peer Exchange

Experts highlight clinical trial updates in muscle-invasive bladder cancer, frontline treatment options in metastatic urothelial carcinoma, and more.

Immunotherapy-Based Approaches Make Waves in Bladder Cancer

With a heavily shifting treatment paradigm as of late, all eyes are on the endometrial cancer landscape, especially concerning the subset of patients with mismatch repair–proficient (pMMR) disease, as several advancements have ushered in immunotherapy for those with recurrent/advanced mismatch repair–deficient (dMMR) or microsatellite instability–high (MSI-H) disease.

“An interesting area of research is pMMR endometrial cancer—how do we stratify some of these patients [by] looking at subgroup analyses and figuring out the best strategies? We know even with immunotherapy, there still is a high rate of recurrent disease. Looking at new approaches in that setting is what I’m most keen on,” Ritu Salani, MD, the director
of gynecologic oncology and the Gynecologic Oncology Fellowship at UCLA Health in Los Angeles, California, said in an interview with 

The immunotherapies dostarlimab-gxly (Jemperli) and pembrolizumab (Keytruda) have demonstrated promise in endometrial cancer, with pembrolizumab plus lenvatinib (Lenvima) holding an indication for the treatment of patients with pMMR disease. For those with dMMR disease, a couple of agents are available: Single-agent dostarlimab is approved for adults with recurrent or advanced disease who progressed on or following a platinum-containing regimen, and pembrolizumab is indicated for patients who are not candidates for curative surgery or radiation with MSI-H or dMMR disease that has progressed on prior systemic therapy in any setting.

Additionally, dostarlimab gained 2 approvals in 2023 for patients with dMMR recurrent or advanced endometrial cancer, first providing an option as monotherapy for adults who are not candidates for curative surgery or radiation and experienced disease progression on or following a prior platinum-containing regimen in any setting.

 The agent was
also granted approval in combination with carboplatin and paclitaxel, followed by single-agent dostarlimab, for primary advanced or recurrent endometrial cancer that is dMMR or MSI-H.

Pembrolizumab also has the potential to be the first immunotherapy approved in the front-line setting for patients with endometrial cancer regardless of MMR status; a supplemental biologics license application seeking approval of the agent in combination with carboplatin and paclitaxel followed by single-agent pembrolizumab for the treatment of patients with primary advanced or recurrent endometrial carcinoma was accepted by the FDA for priority review. The Prescription Drug User Fee Act date is June 21, 2024.

Examining the Role of Dostarlimab and Pembrolizumab in pMMR Disease

Homing in on pMMR disease, a press release published in December 2023 revealed that data from part 2 of the phase 3 RUBY trial (NCT03981796) demonstrated that dostarlimab plus chemotherapy followed by dostarlimab plus niraparib (Zejula) significantly improved progression-free survival (PFS) vs chemotherapy alone in patients with pMMR endometrial cancer, meeting the primary end point of the study.

“I’m excited about understanding some of the nuances of the use of immunotherapy in endometrial cancer,” Salani said. “[For example,] how do we sequence immunotherapy and which patients is it best for up-front vs using it in recurrent lines.”

The FDA approval of pembrolizumab plus lenvatinib for those with pMMR advanced endometrial carcinoma who are not candidates for curative surgery or radiation and have experienced disease progression following prior systemic therapy in any setting was based on data from the phase 3 study KEYNOTE-775 (NCT03517449).

The final prespecified overall survival (OS) analysis revealed that improved efficacy was seen regarding OS (HR, 0.70; 95% CI, 0.58-0.83) in patients with pMMR advanced, recurrent, or metastatic endometrial cancer treated with the combination of pembrolizumab and lenvatinib (n = 346) vs investigator’s choice of either doxorubicin or paclitaxel (n = 351). The median PFS was 6.7 months (95% CI, 5.6-7.4) vs 3.8 months (95% CI, 3.6-5.0), respectively (HR, 0.60; 95% CI, 0.50- 0.72), and the respective overall response rates (ORRs) were 32.4% vs 15.1%.8 (

The addition of pembrolizumab to paclitaxel and carboplatin also improved PFS in the phase 3 NRG-GY018 study (NCT03914612) for this patient population. At a median follow-up of 7.9 months, the median PFS was 13.1 months (95% CI, 10.5-18.8) with the combination (n = 290) vs 8.7 months (95% CI, 8.4-10.7) with placebo plus chemotherapy (n = 292; stratified HR, 0.54; 95% CI, 0.41-0.71; 

However, Salani noted that although immunotherapy remains a promising area of investigation, recurrent disease remains an area of uncertainty. “If a patient recurs, what do we do next? What’s the next best therapy for these patients? This can be a very challenging disease to treat and finding those best therapies in the second-line and third-line settings continues to be a challenge,” she explained.

dMMR Disease: Questions May Have Been Answered for Now

The United Kingdom has followed suit in advising that patients with dMMR disease receive immunotherapy; a final draft guidance published by the National Institute for Health and Care Excellence recommended the use of dostarlimab in combination with platinum-containing chemotherapy as a treatment for patients with advanced or recurrent endometrial cancer that is MSI-H or dMMR.

“We changed the standard of care for endometrial cancer,” Salani said, noting that although unanswered questions remain for the pMMR population, the dMMR population appears to be settled regarding optimal treatment approaches. “We had [data from] 4 phase 3 clinical trials that showed the addition of immunotherapy with a checkpoint inhibitor to chemotherapy with maintenance immunotherapy or checkpoint inhibitor use in the dMMR population clearly improved survival outcomes.”

The phase 3 DUO-E trial (NCT04269200) was 1 of the 4 trials whose findings demonstrated a survival advantage for patients treated with immunotherapy followed by maintenance therapy; those with dMMR disease who received durvalumab (Imfinzi) plus olaparib (Lynparza; n = 48) achieved an 18-month PFS rate of 62.7% (95% CI, 46.9%-75.0%), vs 67.9% (95% CI, 51.1%- 80.0%) for those who received durvalumab (n = 46) vs 31.7% (95% CI, 16.7%-47.9%) for the carboplatin/paclitaxel arm (n = 49).

Moreover, patients with pMMR disease achieved 18-month PFS rates of 42.0% (95% CI, 34.1%- 49.6%), 31.3% (95% CI, 24.2%-38.6%), and 20.0% (95% CI, 14.1%-26.7%) in the doublet (n = 191), durvalumab (n = 192), and chemotherapy (n = 192) arms, respectively.

Findings from part 1 of the RUBY trial, which supported the approval of dostarlimab plus carboplatin and paclitaxel followed by single-agent dostarlimab, showed that treatment with the combination reduced the risk of disease progression or death by 72% vs chemotherapy alone for patients with dMMR disease (HR, 0.28; 95% CI, 0.16-0.50).

 In the phase 1 GARNET trial (NCT02715284), data from which supported the approval of dostarlimab monotherapy in this population, patients with dMMR endometrial cancer who received the agent (n = 141) achieved an ORR of 45.4% (95% CI, 37.0%-54.0%) that comprised a 15.6% complete response rate; the median duration of response was not reached, and 54.7% of patients responded to treatment for at least 24 months.

Open for Debate: Additional Markers and Subgroups for pMMR

When examining pMMR disease, Salani noted that, “I don’t think we should clump it as just pMMR—it’s a very heterogeneous group. When we look at the pMMR group, the dMMR group may also overlap with this; if a patient has dMMR and then recurs, they would also fall into this bucket where maybe immunotherapy is not the ideal choice if they’ve already been treated with it before.”

She also added that “we have options for 

 wild-type [disease] with selinexor [Xpovio] maintenance. We have a very interesting trial looking at that where the preliminary data have been compelling.”

 wild-type advanced or recurrent endome- trial cancer experienced improvements in PFS when treated with selinexor maintenance therapy vs placebo in the phase 3 SIENDO/ENGOT-EN5 study (NCT03555422). At a median follow-up of 25.3 months, patients achieved a median PFS of 27.4 months (95% CI, 13.1-not reached) in the selinexor arm (n = 77) vs 5.2 months (95% CI, 2.0-13.1) in the placebo arm (n=36; HR, 0.42; 95% CI, 0.25-0.70; 1-sided nominal 

 mutation type and particularly HER2 and looking at the role of trastuzumab [Herceptin]—whether it’s trastuzumab or the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki [Enhertu]— is very interesting,” Salani noted. “There may [also] be other markers such as TROP2 [and] FRα. Understanding when [it’s appropriate] to use these agents, and also the timing of using the agents, [is key]. That is a landscape that’s still to be developed.”

Several trials are underway examining agents in these spaces with investigations focusing on the combination of mirvetuximab soravtan- sine-gynx (Elahere) and pembrolizumab in patients with FRα-positive relapsed serous endometrial cancer. Trastuzumab deruxtecan is also being explored in combination with olaparib in solid tumors.

Additionally, Salani noted the importance of examining surgical approaches. “We’re understanding that surgeries are a critical part of gynecologic cancer care but it’s not the place where we’re going to make the most progress—that’s with targeted therapies.” She cited research in cervical cancer where advancements have been seen regarding de-escalation of surgical intervention. “[In certain cases], doing a simple hysterectomy or conization may be more appropriate than doing a radical hysterectomy, which has increased surgical morbidity. Offering the best therapy to our patients, not compromising oncologic outcomes but minimizing morbidity, is important,” Salani said. “Studies that are looking at doing less radical surgery can be impactful for patients, and that’s an important change.”

Gynecologic Malignancy Meeting Homes in on Molecularly Targeted Treatments

Noting that pMMR endometrial cancer is an area she’s keen to discuss at the 

 International Symposium on Ovarian Cancer and Other Gynecologic Malignancies

 Meeting, Salani is also excited to discuss cervical cancer at the event, which she is cochairing.

Sessions including “Navigating Recurrence: Innovative Approaches to Cervical Cancer Management” will do a deep dive into new research in that sector, whereas sessions such as “Medical Crossfire

: Navigating the Management of pMMR in Endometrial Cancer – Debates and Insights” will examine unanswered questions in the field of endometrial cancer. HER2-targeted therapy will also be a focus, and clinicians will have the opportunity to discuss emerging targets following the "Biomarker Testing in Endometrial Cancer: Overview of Current Practices and Future Prospects" presentation.

“I’m looking forward to hearing where the landscape is going for cervical cancer,” Salani said. “We’ve made great strides with the addition of immunotherapy [in gynecologic oncology], but we need to continue to improve the care for patients if they have disease recurrence,” she added.

NCCN. Clinical Practice Guidelines in Oncology. Ovarian cancer including fallopian tube cancer and primary peritoneal cancer, version 1.2024. Accessed March 12, 2024. https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf

Oncology (cancer)/hematologic malignancies approval notifications. FDA. Updated March 7, 2024. Accessed March 12, 2024. bit.ly/4a9JHIt

FDA grants regular approval to dostarlimab-gxly for dMMR endometrial cancer. FDA. February 9, 2023. Accessed March 12, 2024. bit.ly/3Va1E5r

FDA approves dostarlimab-gxly with chemotherapy for endometrial cancer. FDA. July 31, 2023. Accessed March 12, 2024. bit.ly/3wYCxs2

FDA grants priority review to Merck’s application for Keytruda (pembrolizumab) plus chemotherapy as treatment for primary advanced or recurrent endometrial carcinoma. News release. Merck. February 20, 2024. Accessed March 12, 2024. bit.ly/4a9tFhF

Jemperli (dostarlimab) plus Zejula (niraparib) combination significantly improved progression-free survival in primary advanced or recurrent endometrial cancer in RUBY part 2 phase III trial. News release. GSK. December 18, 2023. Accessed March 12, 2024. bit.ly/3v6ZlFG

Lenvima. Prescribing information. Eisai Inc; 2023. Accessed March 12, 2024. bit.ly/3PnCMDt

Makker V, Colombo N, Casado Herráez A, et al. Lenvatinib plus pembrolizumab in previously treated advanced endometrial cancer: updated efficacy and safety from the randomized phase III Study 309/KEYNOTE-775. 

. 2023;41(16):2904-2910. doi:10.1200/JCO.22.02152

Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. 

. 2023;388(23):2159-2170. doi:10.1056/NEJMoa2302312

Final draft guidance: dostarlimab with platinum-based chemotherapy for treating advanced or recurrent endometrial cancer with high microsatellite instability or mismatch repair deficiency. National Institute For Health And Care Excellence. February 2024. Accessed March 12, 2024. bit.ly/49Pbeiv

Westin SN, Moore K, Chon HS, et al; DUO-E Investigators. Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer: the phase III DUO-E trial. 

. 2024;42(3):283-299. doi:10.1200/JCO.23.02132

Phase III RUBY trial of Jemperli (dostarlimab) plus chemotherapy meets end point of overall survival in patients with primary advanced or recurrent endometrial cancer. News release. GSK. October 30, 2023. Accessed March 12, 2024. bit.ly/497P9uF

Jemperli. Prescribing information. GlaxoSmithKline; 2023. Accessed March 12, 2024. bit.ly/4ab1DT6

Slomovitz B, Pérez Fidalgo A, Hamilton E, et al. Long-term follow up of selinexor maintenance in patients with 

wt advanced or recurrent endometrial cancer: a prespecified subgroup analysis from the phase 3 ENGOT-EN5/GOG-3055/SIENDO study. 

. 2023;41(suppl 36):427956. doi:10.1200/JCO.2023.41.36_suppl.427956

Dougherty B. Antibody-drug conjugates — a kind of molecular "smart bomb" — are emerging as an important form of targeted treatment across a variety of cancers. Dana-Farber Cancer Institute. January 11, 2024. Accessed March 12, 2024. bit.ly/4cf1xLM

15th Annual International Symposium on Ovarian Cancer and Other Gynecologic Malignancies™ agenda. Physicians’ Education Resource®. Accessed March 12, 2024. bit.ly/3TyMq8Y

Recent advancements in immunotherapy have significantly impacted the treatment landscape for endometrial cancer, particularly for patients with mismatch repair–deficient (dMMR) or microsatellite instability–high (MSI-H) disease. Immunotherapies like dostarlimab and pembrolizumab have shown promise, with new approvals and ongoing trials exploring their efficacy. However, challenges remain in treating mismatch repair–proficient (pMMR) endometrial cancer, where recurrence rates are high. Research is ongoing to identify optimal treatment strategies, including the sequencing of therapies and the potential role of targeted treatments and surgical approaches in improving patient outcomes.

Cover Story

Exploration continues for the use of immunotherapy in patients with mismatch repair–proficient endometrial cancer.

Clinicians Turn Their Focus to pMMR Disease Following Immunotherapy’s Entrance Into dMMR Endometrial Cancer

Randomized trials are widely recognized to play a pivotal role in the approval process of new antineoplastic agents, the development of novel combination regimens, and the decision-making associated with the establishment of clinical guidelines. And few would challenge the past, current, and future utility of such studies in defining optimal cancer management. 

Despite this high-level consensus conclusion, it is relevant to note the publication of numerous solid, data-based critiques that have challenged individual standard elements of randomized trials in oncology. These include the common exclusion of individuals 65 years and older and patients with relevant comorbid medical conditions, prior therapies, or a history of other cancers; the limited accrual of individuals from certain ethnic groups and those with lower socioeconomic status; the validity of primary end points (overall survival vs other measures of clinical benefit); and the increasing cost of conducting these studies

This commentary highlights another aspect of the randomized trial process that may cloud subsequent interpretation and specifically relates to decisions made in the critical development of the studies themselves. The examples given during this discussion will be from the realm of gynecologic oncology due to the clinical background of this author, but it is certain the issues noted will be relevant to other areas of oncologic medicine.

To begin, consider past decisions by the Gynecologic Oncology Group (GOG) to employ a particular dose of a chemotherapy agent, such as cisplatin, as a single agent or as a component of a combination regimen in a clinical investigative effort. Justification for a recommendation to deliver the so-called maximally tolerated dose is understandable because, realistically, it would not be considered safe to subsequently administer a higher dose in routine clinical practice.

Thus, it was quite reasonably elected to administer cisplatin at a dose of 75 mg/m

 (every 3 weeks for 6 cycles) in combination with paclitaxel in the paradigm-changing trial that compared this novel approach with a standard-of-care regimen (cisplatin plus cyclophosphamide) as primary chemotherapy for advanced ovarian cancer.

It is interesting to note that a subsequent phase 3 trial conducted by the GOG that compared single-agent cisplatin delivered at 100 mg/m

 (every 3 weeks for 6 cycles) with the lower cisplatin dose (75 mg/m

) combined with paclitaxel resulted in the same objective response rate, progression-free survival, and overall survival for both regimens.

 Because crossover from single-agent cisplatin to a third study arm (single-agent paclitaxel) was common in this trial, one might reasonably inquire how certain investigators and clinicians are certain of the ideal systemically administered dose of cisplatin and the optimal use of the agent when employed as a component of initial therapy for ovarian cancer.

Realistically, any existing questions related to systemic cisplatin are unlikely to be explored in ovarian cancer management in the future.

However, the issue of the optimal dose of intraperitoneal cisplatin employed in primary therapy for ovarian cancer based on clinical trial experience is, in the opinion of this commentator, far more problematic. Several randomized, phase 3 trials on small-volume residual stage III ovarian cancer, all of which employed intraperitoneal cisplatin at a dose of 100 mg/m

 (vs an intravenous cisplatin-based regimen), revealed improvements in both progression-free survival and overall survival with the regional approach.

In a more recently conducted GOG study, intraperitoneal cisplatin-based chemotherapy was compared with an all-systemic carboplatin-plus-paclitaxel approach and failed to reveal a difference in survival outcomes between the regional and systemic strategies.

 Unfortunately, in this study, the intraperitoneal cisplatin dose was reduced to 75 mg/ m

Randomized trials are crucial in oncology for drug approval and treatment guidelines, yet they face criticism for excluding older patients, those with comorbidities, and certain ethnic groups. The trials often lack diversity and have high costs. In gynecologic oncology, the optimal dosing of cisplatin remains debated, with conflicting trial results on its efficacy in ovarian cancer. The inclusion of bevacizumab in trials complicates interpretations, and the absence of a consistent control arm raises questions about standard care. These issues highlight the complexity of trial design and interpretation in oncology.

Randomized trials are widely recognized to play a pivotal role in the decision-making associated with the establishment of clinical guidelines.

Vol. 25 No. 6 | Oncology Live®

FAK Inhibition Emerges as a Potential Complementary Treatment Pathway

Quality Over Quantity: What Concierge Medicine Can Offer to Patients With Cancer and Employers

Immunotherapy-Based Approaches Make Waves in Bladder Cancer

Clinicians Turn Their Focus to pMMR Disease Following Immunotherapy’s Entrance Into dMMR Endometrial Cancer

The Critical Nature of Decision-Making in the Development of Phase 3 Clinical Trials

The New Frontier With Integrative Oncology: Shooting for the Stars