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Early efficacy data observed with the novel c-Met–targeted antibody-drug conjugate (ADC) telisotuzumab adizutecan (formerly ABBV-400) in patients with colorectal cancer (CRC) have shown the potential to not only bring a c-Met–targeted agent into the CRC treatment landscape, but also an ADC to join fam-trastuzumab deruxtecan-nxki (Enhertu).

Several small-molecule agents targeting c-Met are already approved in non–small cell lung cancer (NSCLC), including capmatinib (Tabrecta),

 and cabozantinib (Cabometyx) holds an indication in renal cell carcinoma.

 However, when it comes to ADCs, telisotuzumab adizutecan represents one of the agents furthest along in development targeting c-Met. As of April 2024, 9 c-Met–targeting ADCs were under development in various phases of clinical studies, with additional preclinical studies ongoing.

“We’ve seen ADCs now enter the clinic for multiple tumor types, but we’ve not yet seen an ADC with an approval specific to colon cancer,” John Strickler, MD, said in an interview with 

. “Right now, the only ADC we have approved for colon cancer is from the pantumor approval of trastuzumab deruxtecan for patients with HER2-positive cancers. But [with] this therapeutic strategy, this class [of ADCs], we are likely to see more therapies enter the clinic.”

Telisotuzumab adizutecan showed meaningful improvements in overall response rate (ORR) for patients who received the drug at a dose of 2.4 mg/kg or greater every 3 weeks in a first-in-human phase 1 study (NCT05029882).

 Recent data presented at the 2024 European Society for Medical Oncology (ESMO) Congress also showed the agent has activity in patients with advanced gastric/gastroesophageal junction adenocarcinoma.

“We have a lot of experience with tyrosine kinase inhibitors [TKIs] and what we call the naked [monoclonal] antibodies in CRC, and unfortunately, nearly all that experience is unfavorable in that when we give patients these anti-MET therapies, the benefit, if it occurs at all, is fairly transient,” Strickler said. “One of the reasons for this is that c-Met expression or amplification can be heterogeneous. When you give these selective antibodies and TKIs, you’ll see brief, transient effects, but then the c-Met–negative clones will grow out and drive rapid resistance.”

Telisotuzumab Adizutecan Yields Promising Responses in CRC

Many advanced solid tumors have overexpression of c-Met, which can promote tumor progression and metastasis, and there are no approved therapies for patients with CRC and c-Met–overexpressing tumors.

 gene amplification and also overexpression of the protein after exposure to targeted therapies, particularly anti-EGFR therapies,” Strickler noted. “But interestingly, in the past couple of years, we’ve also seen signs that 

 is important as a driver of resistance to other targeted therapies that have emerged in the CRC space, specifically anti-HER2 therapies and KRAS G12C inhibitors, which are now FDA-approved for the treatment of patients with metastatic CRC. We see this broadly as a driver of acquired resistance in addition to primary resistance to those therapies.”

In the first-in-human study, patients with 

 wild-type, microsatellite stable (MSS) or mismatch repair–proficient (pMMR) CRC who experienced progression on prior therapies experienced an ORR of 18% when treated with the 2.4-mg/kg dose (n = 40) of telisotuzumab adizutecan. Patients treated at this dose level also experienced a median progression-free survival (PFS) of 5.3 months (95% CI, 3.8-5.9). Among those treated at the 3.0-mg/kg dose level (n = 41), the ORR was 24%, and the median PFS was 4.1 months (95% CI, 2.6-6.7). The ORR was lower in patients treated with the 1.6-mg/kg dose (n = 32) at 6%, with a median PFS of 5.1 months (95% CI, 2.8-6.8) observed (

Further, the clinical benefit rates (CBRs) among patients who received the 1.6-mg/kg, 2.4-mg/kg, and 3.0-mg/kg doses were 75%, 78%, and 68%, respectively. The ORR was 16% among all patients (n = 122) treated in the trial, and the median duration of response (DOR) was 5.5 months (95% CI, 4.1-not evaluable [NE]).

“Focusing on gastrointestinal [GI] cancers, we’ve seen very promising initial results in patients with CRC. Interestingly, patients who have higher levels of c-Met expression appear to [derive an] even greater benefit,” Strickler said.

Patients with a c-Met expression level of at least 10% with 3+ staining intensity in the trial’s biomarker-positive population achieved an ORR of 37.5% when treated with 2.4 mg/kg or more of telisotuzumab adizutecan; the median PFS in this population was 5.4 months (95% CI, 2.7-6.9). For patients who received at least 2.4 mg/kg of telisotuzumab adizutecan but were biomarker negative, the ORR was 14%, and they experienced a median PFS of 4.5 months (95% CI, 3.8-5.9). Regardless of c-Met expression, all patients treated at this dose level experienced an ORR of 20%, with a median PFS of 4.6 months (95% CI, 3.9-5.4).

c-Met Targeting Proves Efficacious in Gastroesophageal Cancer

“So far, we feel like the safety, tolerability, and activity of this therapy are favorable and could have broad applications not just in CRC but in other GI cancers, in particular gastroesophageal adenocarcinoma. [Telisotuzumab adizutecan will] probably [have applications] beyond GI cancers as well,” Strickler said.

Promising antitumor activity was observed when telisotuzumab adizutecan monotherapy (n = 42) was administered in the dose-expansion portion of the phase 1 study to patients with advanced gastric and gastroesophageal junction adenocarcinoma. Patients achieved an ORR of 28.6% (95% CI, 15.7%-44.6%); 1 patient achieved a complete response. Additionally, the median DOR was 4.24 months (95% CI, 2.96-NE) and the agent elicited a CBR of 71.4% (95% CI, 55.4%-84.3%) in patients.

Investigators also noted that the safety profile of telisotuzumab adizutecan in patients with gastric and gastroesophageal junction adenocarcinoma was generally consistent with what has been observed thus far in all patients treated with the agent. No grade 3/4 pneumonitis or interstitial lung disease events occurred.

“Although we’ve made a lot of progress with GI cancer [treatment], there’s still a lot of work to be done,” Strickler said. “One of the challenges is that once patients go through first- and second-line therapies, response rates drop off, and PFS for the approved agents is rather short. There are some promising signals, particularly among patients with higher levels of c-Met expression, [showing] that [telisotuzumab adizutecan] can generate higher response rates than the current standard of care [SOC]. It can potentially drive longer PFS, though we’ll need to see that validated in prospective studies, but it also raises the question of whether this is a therapy that’s so active it [may] need to be brought into earlier lines of therapy in combination with other cytotoxic chemotherapy.”

Delving Into Safety With the ADC in CRC and Gastric Cancers

Regarding safety with telisotuzumab adizutecan, hematologic treatment-emergent adverse effects (TEAEs) were dose dependent, as investigators noted the frequency and severity increased with higher doses. In the CRC population, patients in the 1.6-mg/kg, 2.4-mg/kg, and 3.0-mg/kg dose groups experienced grade 3 or higher TEAEs (38% vs 73% vs 88%); the most common grade 3 or greater hematological TEAEs were anemia (13% vs 33% vs 54%), neutropenia (6% vs 20% vs 32%), and thrombocytopenia (0% vs 8% vs 17%).

TEAEs also led to treatment discontinuation in 25 patients (20.5%), resulting from anemia (n = 4), pneumonitis (n = 3), and febrile neutropenia (n = 2). Events leading to discontinuation were considered related to telisotuzumab adizutecan in 13 patients.

Up Next: Telisotuzumab Adizutecan vs SOC in CRC

“The main next step for telisotuzumab adizutecan [includes] prospective validation against SOC therapies [with] larger randomized trials that can validate that patients have improved survival, PFS, response rates, and tolerability as compared with the current SOC. We are now in the development [stage of] these randomized trials,” Strickler said.

A phase 2 randomized trial (NCT06107413) was initiated in November 2023 and has 19 patients with metastatic 

 V600 wild-type, MSS or pMMR CRC enrolled as of April 23, 2024, who will receive telisotuzumab adizutecan in a combination-therapy approach. The safety lead-in portion of the study will enroll 30 patients to receive telisotuzumab adizutecan in combination with 5-fluorouracil and folinic acid plus bevacizumab (Avastin) at various doses. Stage 2 of the study, the dose optimization part, will enroll 176 patients in 4 investigational cohorts examining the investigational regimen at the low dose administered every 4 weeks, high dose administered every 4 weeks, low dose administered every 2 weeks, and high dose administered every 2 weeks. Additionally, there will be a fifth SOC cohort with leucovorin, fluorouracil, and irinotecan plus bevacizumab administered every 2 weeks.

“CRC in particular is notorious for having molecular heterogeneity, where 

 amplification [will] go together with other variants; for example, 

 alterations,” Strickler said. “Even when you give a targeted therapy, you may see that those other variants can drive rapid resistance as well. The advantage of an ADC is it only needs expression to enter the cell; if the patient has tumor cells that will drive resistance to the targeted therapy, it won’t matter because the drug will still get in and release its toxic payload to that tumor.”

In addition to the promise demonstrated with ADCs targeting c-Met in CRC, NSCLC data have also shown the efficacy of this approach. Findings from the same phase 1 study evaluating telisotuzumab adizutecan monotherapy in various patient populations were presented at the 2024 ESMO Congress and revealed that patients with 

 wild-type nonsquamous NSCLC treated with telisotuzumab adizutecan (n = 48) experienced an ORR of 47.9%. Patients experienced a median PFS of 6.9 months (95% CI, 5.4-7.3). As in the CRC population, responses were enriched in patients with higher c-Met protein expression. In patients with immunohistochemical staining of 3+ on at least 50% of tumor cells, the ORR was 77.8%.

Additionally, AbbVie, the drug manufacturer of another c-Met–directed ADC, telisotuzumab vedotin (Teliso-V), noted that they plan to submit Teliso-V to the FDA for accelerated approval as a monotherapy for the treatment of patients with previously treated c-Met-overexpressing, 

 wild-type nonsquamous NSCLC; the company anticipates a decision in 2025 for the c-Met targeted agent.

 In this patient population, the ORR was 34.6% (95% CI, 24.2%-46.2%) among patients with c-Met–high disease (n = 78) treated with Teliso-V, and 22.9% (95% CI, 14.1%-33.4%) among patients with c-Met–intermediate expression (n = 83).

“[Telisotuzumab adizutecan] is an active therapy that looks very promising for our patients with GI cancers and also for patients with 

-amplified tumors,” Strickler said. “It’s a therapeutic strategy that is currently under development [and] needs validation but so far looks very promising.”

Tabrecta. Prescribing information. Novartis Pharmaceuticals Corporation; 2023. Accessed September 10, 2024. bit.ly/47m6K2w

Tepmetko. Prescribing information. Merck KGaA; 2024. Accessed September 10, 2024. bit.ly/3XGc7GM

Xalkori. Prescribing information. Pfizer; 2023. Accessed September 10, 2024. bit.ly/3ATXc2u

Cabometyx. Prescribing information. Exelixis, Inc; 2023. Accessed September 10, 2024. bit.ly/43DW0cN

Mer AH, Mirzaei Y, Misamogooe F, et al. Progress of antibody-drug conjugates (ADCs) targeting c-Met in cancer therapy; insights from clinical and preclinical studies. 

. Published online April 10, 2024. doi:10.1007/s13346-024-01564-3

Sharma MR, Strickler JH, Sommerhalder D, et al. First-in-human study of ABBV-400, a novel c-Met–targeting antibody-drug conjugate, in advanced solid tumors: results in colorectal cancer. 

. 2024;42(suppl 16):3515. doi:10.1200/JCO.2024.42.16_suppl.3515

Strickler JH, Raimbourg J, Ghiringhelli F, et al. ABBV-400, a c-Met protein–targeting antibody-drug conjugate (ADC), in patients (pts) with advanced gastric/gastroesophageal junction adenocarcinoma (GEA): results from a phase I study. Poster presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract 1439P.

Raghav KPS, Hubert A, Fakih M, et al. Phase 2 randomized study evaluating safety, efficacy, and optimal dose of ABBV-400 in combination with fluorouracil, folinic acid, and bevacizumab in previously treated patients with metastatic colorectal cancer. 

. 2024;42(suppl 16):TPS3636. doi:10.1200/JCO.2024.42.16_suppl.TPS3636

De Miguel M, Yamamoto N, Raimbourg J, et al. ABBV-400, a c-Met protein-targeting antibody-drug conjugate (ADC), in patients (Pts) with advanced EGFR wildtype (WT) non-squamous (NSQ) non-small cell lung cancer (NSCLC): results from a phase I study. 

AbbVie showcases advancement of solid tumor pipeline at ESMO 2024, with new data in tumor types with high unmet needs. News release. AbbVie. September 9, 2024. Accessed September 10, 2024. bit.ly/4dV4j9L

Camidge DR, Bar J, Horinouchi H, et al. Telisotuzumab vedotin monotherapy in patients with previously treated c-Met–overexpressing non-squamous 

 wildtype advanced NSCLC: primary analysis of the LUMINOSITY trial. 

. 2024;42(suppl 16):103. doi:10.1200/JCO.2024.42.16_suppl.103

Articles

Telisotuzumab adizutecan, a c-Met–targeted antibody-drug conjugate (ADC), shows promise in colorectal cancer (CRC) treatment, with potential applications in other gastrointestinal cancers. Early trials indicate improved overall response rates and progression-free survival, particularly in patients with higher c-Met expression. The drug's safety profile is dose-dependent, with hematologic adverse effects increasing at higher doses. Ongoing studies aim to validate its efficacy against standard-of-care therapies. Additionally, telisotuzumab adizutecan demonstrates efficacy in non-small cell lung cancer, with plans for further regulatory submissions.

John Strickler, MD, details the latest data on the novel c-Met–targeted ADC telisotuzumab adizutecan and how the agent could affect the treatment of CRC.

Effectively Targeting c-Met in Colorectal Cancer Is Becoming a Reality With Novel Approaches

Although circulating tumor DNA (ctDNA) is in earlier stages of investigation for resected colon cancer, it has the potential to aid in accurately predicting the risk of recurrence, which is a challenge as there are no prospectively validated biomarkers from randomized studies available in this setting to determine whether adjuvant chemotherapy is necessary.

 The overtreatment of patients who may have been cured from surgery can also result in the adjuvant setting, according to John L. Marshall, MD.

“ctDNA is the closest thing we have to something that will change [the way we treat patients],” Marshall said in an interview with 

. “It’s all about the precision medicine piece of things, being able to identify appropriate genetic markers and use those markers to identify who should be treated, what therapies to use, [and] predictors of risk—this ranges now from screening through metastatic disease.” Marshall is chief of the Division of Hematology and Oncology, a professor of medicine and oncology, and director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers at Georgetown Lombardi Comprehensive Cancer Center in Washington, DC.

Given that more than 30% of patients with resectable colorectal cancer (CRC) will experience disease recurrence following surgery and adjuvant chemotherapy, there is great interest in using the presence of ctDNA in plasma after treatment to predict recurrence, as it has been shown to be a strong prognostic factor.

Findings from a large post hoc analysis of the phase 3 IDEA-France (NCT00958737) and IDEA-Greece (NCT01308086) trials revealed that at a median follow-up of more than 80 months, ctDNA was the most significant prognosticator for disease recurrence (adjusted HR, 5.21; 

 < .001) and death (adjusted HR, 4.81; 

 < .001) in patients with stage III colon cancer; the multivariable analyses adjusted for major prognostic factors in this patient population.

Data also showed that ctDNA was prognostic in patients with stage III high- and low-risk disease and in those treated with 3 and 6 months of adjuvant chemotherapy. The prognostic value of the Immunoscore assay was also evaluated and showed discriminant outcomes in patients who were ctDNA negative. In patients with both ctDNA-negative and Immunoscore-high results, the 5-year time to recurrence rate was greater than 90%.

“We have studies, and others are starting to have studies, looking at patients who are ctDNA positive after adjuvant therapy and what to do,” Marshall said. “The National Comprehensive Cancer Network guidelines still have not formally recommended doing ctDNA testing, and yet lots of us are [testing ctDNA]. The question is, how do you use this information to help the patient? The criticism from the guidelines is that you don’t know what to do with it if you have a positive test, and we’re trying to figure out, as quickly as we can, how to incorporate that [into treatment].”

The observational BESPOKE CRC study (NCT04264702), which was presented at the 2024 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, was the first large, prospective, US-based trial that reported data examining the utility of tumor-informed ctDNA in the adjuvant setting for patients with CRC. Findings from the interim analysis of the prospective, multicenter study revealed that ctDNA positivity during surveillance was prognostic of outcomes irrespective of whether patients with stage II to III CRC received adjuvant chemotherapy.

Additionally, ctDNA­ positivity at the minimal residual disease (MRD) time point was predictive of inferior disease-free survival (DFS) outcomes. Patients who were MRD positive (n = 93) experienced a 2-year adjuvant DFS rate of 29.86% (95% CI, 13.26%-48.54%) compared with 91.59% (95% CI, 88.38%-93.94%) among patients who were MRD negative (n = 530). The median DFS post surgery was 15.98 months (95% CI, 13.77-20.22) vs not reached (NR), respectively (HR, 12.1; 95% CI, 8.0-18.3; 

Furthermore, the benefit from adjuvant chemotherapy was only observed in patients who were MRD positive. Patients who had MRD-positive disease and received adjuvant treatment (n = 85) experienced a median DFS post surgery of 17.78 months (95% CI, 14.37-NR) vs 7.52 months (95% CI, 3.52-15.88) among those who underwent observation as adjuvant treatment (n = 100; HR, 3.06; 95% CI, 1.43-6.56; 

“We have ctDNA [and] MRD testing to decide about adjuvant therapy, and studies are ongoing there,” Marshall noted. “Sorting colon cancer into its different genetic subtypes is critical. We’re looking at the role of MRD [with] ctDNA testing in treatment, optimizing immunotherapy in those who have microsatellite-unstable disease, [and] trying to develop immunotherapy for those who aren’t, so that’s in both directions.”

Avoiding Overtreatment in the Adjuvant Setting

“Tissue-based testing and pure blood-based testing are of different quality, sensitivity, [and] specificity, but the reason to do [them] is that we dramatically overtreat [patients] with adjuvant therapy,” Marshall said. “Most of the patients we give adjuvant therapy to are already cured. Could we figure out who those patients are and not worry about exposing them to chemotherapy that they don’t need in the first place?”

The prospective phase 2/3 CIRCULATE-NORTH AMERICA study (NRG-GI008; NCT05174169) is active and currently enrolling patients with colon cancer to evaluate the role of ctDNA presence in risk stratification for either escalation or de-escalation of adjuvant therapy. Additionally, investigators plan to combine aggregate data with that from CIRCULATE-JAPAN.

“One [consideration] is selection of patients who need therapy, and the world is doing studies to try and figure that out,” Marshall noted. “But the second piece is, what if patients are still positive after you’ve done whatever [treatment] you were going to do? This is an emerging field that we and others are leading to try and identify therapies that potentially could intervene then, instead of waiting until the patient has obvious metastatic disease.”

Data from CIRCULATE-JAPAN, which is part of the larger GALAXY trial (UMIN000039205), showed that ctDNA-based MRD is both a prognostic and predictive tool across different actionable biomarkers in CRC, suggesting that there is potential for integration of MRD-driven targeted treatments in this patient population. DFS by ctDNA positivity and actionable biomarkers, including the 

 amplification, were examined in the trial. Patients with a 

 V600E mutation experienced a 24-month DFS rate of 87.9% (95% CI, 81.0%-95.4%) if they were ctDNA negative (n = 165) compared with not available for patients who were ctDNA positive (n = 10; HR, 201.40; 95% CI, 38.33-2080.89; 

 amplification, the 24-month DFS rates were 83.0% (95% CI, 70.4%-97.9%) for those who were ctDNA negative (n = 33) vs 16.3% (95% CI, 4.7%-57.3%) for those who were ctDNA positive (n = 14; HR, 9.18; 95% CI, 3.18-29.90; 

When asked about ongoing studies demonstrating promise in the adjuvant setting, Marshall noted, “It’s all early, so to say particularly promising is too strong. The bigger studies are just trying to prove the principle of the thing. To me, the exciting stuff is then, what do you do [treatment-wise]? How do you intervene on it? That’s still fairly early.”

The clinical validation study CORRECT-MRD I (NCT06398743) is recruiting patients with the primary objective of validating the association of postdefinitive therapy and prerecurrence follow-up cDNA positivity with recurrence-free interval. The trial had enrolled 233 of the anticipated 400 patients as of July 10, 2024, and will examine recurrence-free interval as the primary end point in patients with stage II to III CRC.

Beyond Biomarkers and ctDNA: New Adjuvant Therapies Are Critical

“Our discoveries in metastatic disease have not necessarily translated over to the adjuvant setting. We are pushing hard to try and identify new therapies we could bring to the table instead of just using the old ones a bit better. We need new therapies,” Marshall said. “We have failed to make significant advances compared with other cancers [as] we are still giving the same adjuvant therapy that we have been giving for 20 years, and there is no other cancer where that’s true. The reason to come to the 

 [SOGO] conference is that it falls on us to accelerate our understanding and the research. We’ll be talking about where we are today and how to move [the field] forward at the meeting.”

Joining Marshall as cochair of SOGO is E. Gabriela Chiorean, MD, of Fred Hutch Cancer Center in Seattle, Washington. SOGO, slated for February 15, 2025, in Pasadena, California, will also detail precision medicine and the latest advancements regarding ctDNA and more.

“We need to start over again is the answer. You’re asking me to bet on a horse—I’m not going to bet on a horse,” Marshall said on whether a therapy has the potential to best chemotherapy in the adjuvant setting. “We don’t know some of the basics [on] even how to start the horse race over again, and I believe that’s part of the reason we have languished.”

Dasari A, Yu G, Kopetz S, et al. Colon adjuvant chemotherapy based on evaluation of residual disease (CIRCULATE-NORTH AMERICA): NRG-GI008. 

. 2024;42(suppl 16):TPS3641. doi:10.1200/JCO.2024.42.16_suppl.TPS3641

Tsukada Y, Sagawa T, Srinivasan G, et al. CORRECT-MRD I: a clinical validation study to predict recurrence in stage II-III colorectal cancer (CRC) using a bespoke circulating tumor DNA (ctDNA) assay to detect molecular residual disease (MRD). 

. 2024;42(suppl 23):TPS98. doi:10.1200/JCO.2024.42.23_suppl.TPS98

Taieb J, Souglakos I, Boukovinas I, et al. Combined analyses of ctDNA and Immunoscore in stage III colon cancer patients: a post hoc analysis of the IDEA-France and -Greece trials. 

. 2024;35(suppl 1):S5. doi:10.1016/j.annonc.2024.05.018

Kasi PM, Aushev VN, Ensor J, et al. Circulating tumor DNA (ctDNA) for informing adjuvant chemotherapy (ACT) in stage II/III colorectal cancer (CRC): interim analysis of BESPOKE CRC study. 

. 2024;42(suppl 3):9. doi:10.1200/JCO.2024.42.3_suppl.9

Nakamura Y, Watanabe J, Hirata K, et al. Prognostic and predictive value of ctDNA-based MRD and actionable biomarkers in patients with resectable colorectal cancer: CIRCULATE-Japan GALAXY. 

. 2024;42(suppl 16):3609. doi:10.1200/JCO.2024.42.16_suppl.3609

10th Annual School of Gastrointestinal Oncology (SOGO). Physicians’ Education Resource, LLC. Accessed September 19, 2024. bit.ly/3TzHMag

Circulating tumor DNA (ctDNA) is emerging as a promising tool for predicting recurrence risk in resected colon cancer, potentially guiding adjuvant chemotherapy decisions. Current studies, including the BESPOKE CRC and CIRCULATE trials, highlight ctDNA's prognostic value, especially in minimal residual disease (MRD) contexts. Despite its potential, ctDNA testing is not yet formally recommended in guidelines, and its integration into treatment strategies remains under investigation. The need for novel adjuvant therapies is emphasized, as existing treatments have seen little advancement over the past two decades.

John L. Marshall, MD, details updates with ctDNA in colorectal cancer, and how precision medicine with ctDNA could change the way patients are treated. 

ctDNA Generates Momentum in Adjuvant Stage II/III Colon Cancer Setting

Investigators are examining and implementing several innovations that they hope will combat the persistent issue of limited access to cancer care for patients living in rural areas, including programs aimed at increasing clinical trial enrollment for these patients and improving patient catchment area data sharing among institutions.

“[Patients] in rural areas [lack] access to highly specialized or subspecialist oncologists, and they don’t have access to ancillary resources, [such as] survivorship opportunities, supportive care, or fertility and genetic counseling,” Ramya Thota, MD, medical oncologist in the Department of Hematology/ Oncology at Intermountain Health in Murray, Utah, said in an interview with 

. “Patients in rural communities sometimes lack the necessary infrastructure [for adequate care], and trying to incorporate a clinical trial into that is a huge burden. [Patients in] a clinical trial often need to come in for regular visits, and the travel and childcare costs all add up [for patients in rural areas].”

During the 2024 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois, Thota gave a presentation that examined the current state of access to cancer clinical trials for patients living in rural communities. In her presentation, she noted that approximately 70% of US counties have no active clinical trials and identified trial access and awareness, study infrastructure, socioeconomic factors, technology, and trust/perception as the major barriers to clinical trial access for patients in rural areas.

To combat these barriers to clinical trial access for these patients, Thota and others have argued for the increased implementation of decentralized clinical trials. Decentralized studies use online consent forms, the home delivery of investigational products, and mobile technology such as wearables for patient monitoring to lower the barrier to entry for patients in rural communities. These studies also allow for local laboratory work and imaging as well as standard-of-care (SOC) infusions at local centers to ease the need for visits to a larger center.

“There is strong enthusiasm [about decentralized clinical trials] given how successful we have been in providing regular cancer care via telehealth. We want to bring that to clinical trials,” Thota said. “The goal and emphasis are on bringing clinical trials closer to patients’ homes, whether it’s trying to deliver drugs directly to their home or to their local health care provider in the community.”

During the COVID-19 pandemic, the use of the decentralized clinical trial approach increased nationwide to accommodate restrictions placed on in-person care to curb the spread of the virus. The FDA and National Cancer Institute (NCI) adapted their procedures to include remote electronic patient consent, electronic patient monitoring, telehealth visits, direct-to-patient drug shipments, and laboratory testing and SOC therapy administration outside a patient’s enrolling center to continue clinical trials with limited in-person contact.

Findings from a special article from the Rural Health Working Group of the Alliance Clinical Trials Network published in the Journal of Clinical Oncology demonstrated that during the COVID-19 pandemic years of 2020 through 2022, the percentage of patients from rural communities enrolled in clinical studies increased. The increase was especially striking at NCI Community Oncology Research Program sites, which surpassed the trial enrollment seen at leading academic participating sites in each of the years from 2020 to 2022, after trailing behind the academic sites in 2019.

Moreover, a survey of the Rural Health Sub-Committee (RHSC) of the Alliance Clinical Trials Network Community Oncology Committee was conducted in 2021 to delineate member perceptions of how COVID-19–related regulatory changes influenced clinical trial enrollment in their centers and clinics. The results revealed that RHSC members who responded (n = 33) reported an increase in patients from rural areas enrolled in trials from pre–COVID-19 levels at a rate of 73%. Additionally, respondents identified remote consent (44%) and visit requirement adaptations (37%) as the process changes that had the greatest effect on enrollment. However, they also cited a lack of broadband connectivity from patients, challenges with staff in conducting remote visits, and reimbursement rates for remote engagements as barriers to implementation.

“We have come a long way in the past 4 years, but having proper broadband remains a challenge,” Thota said. “We are moving into a digital world, but how many of these patients [from rural areas] understand how to [properly] use those electronic devices that are being implemented? Some patients with poor digital literacy struggle with that.”

To continue the gains observed with the regulatory updates that were made during the COVID-19 era, the RHSC offered clinical trial design considerations designed to ease the burden on patients from rural areas. These suggestions included classifying the rurality of participants, minimizing repeat imaging within a trial, allowing remote consent for all participants, using telehealth and mobile technology, offering financial support, and emphasizing local care delivery and recruitment strategies.

Refining Catchment Area Data Sharing to Improve Care for Patients in Rural Areas

Another factor that could be limiting access to cancer care for patients who reside in rural areas is the self-determination of catchment areas of NCI-designated cancer centers. Many cancer centers have launched efforts using geospatial data to better understand disparities in care, including those faced by rural populations, and inform cancer prevention efforts. These approaches have been shown to expedite the tracking of cancer incidence and mortality trends related to catchment area geography, identify areas with cancer care disparities, and inform the implementation of interventions to address these issues.

However, centers often engage in these efforts independent of one another, limiting the effect of an effective intervention to 1 area. In response, investigators at multiple institutions partnered to form the Catchment Area Research and Data Science (CARDS) group in 2022. The aim of the CARDS group is to foster collaboration for investigators involved in cancer center catchment area data collection, analysis, and use to streamline efforts to provide care to underserved populations, such as those in rural areas.

“Over the past several years, cancer centers have been trying to [determine] how to best go about performing surveillance of the cancer burden in our catchment areas and multiple standards [were developed],” Todd Burus, MAS, said in a separate interview with 

. “We noticed that many institutions were doing the same things [and] accessing the same data sources. They were trying to build the same type of resources, and there were a lot of duplication efforts. The collective asked, ‘What if we were all [able to] think together about some best practices, try to develop some efficiency measures, and try to share resources in a way that we weren’t utilizing as much time and effort on the back end of trying to obtain, understand, and display these data?’”

Burus is one of the founders of the CARDS group and a data visualization specialist at the University of Kentucky (KU) Markey Cancer Center in Lexington. He was also the lead author of a commentary published in 

, which examined the effect of 2 initiatives developed by the CARDS group that were implemented to improve access to catchment area data for researchers and ultimately improve care for underserved populations, such as patients in rural areas.

In 2018, the KU Cancer Center created the Organize and Prioritize Trends to Inform KU Cancer Center (OPTIK) program, which consists of a database and multiple data visualization applications. Data from public websites, state health department partners, and internal sources are compiled annually and used in the visualization applications, allowing researchers to examine demographic, screening, risk factor, cancer incidence, and cancer mortality trends within their catchment area. Investigators present their findings from OPTIK annually to the institution’s catchment area leadership to inform outreach efforts and identify catchment area needs.

Building upon the OPTIK concept, researchers at the KU Markey Cancer Center developed the Cancer InFocus data gathering and visualization platform, which automates the collection of catchment area data. A series of Python programs are used to access publicly available data, including cancer rates, social determinants of health, and behavioral risk factors. These data can then be evaluated alone or visualized via mapping applications.

“We’ve accessed files to create points on a map [to] see who our gastroenterologists and our colon and rectal surgeons are [and where they are located],” Burus explained. “We map them, [and one] can look at a catchment area, add that layer, and see how they are distributed. [We can look and see that] here are rural areas, here are areas where maybe we don’t have as high colorectal cancer [CRC] screening rates or where we have higher rates of CRC. This allows [investigators] to generate hypotheses so that they can begin targeting areas that they might want to reach out to [that are] the areas of greatest need.”

Burus and his coinvestigators generalized the Cancer InFocus software for use on data from any set of US counties and offered it for use by other centers through a no-cost licensing agreement. The Cancer InFocus software was subsequently licensed by KU Cancer Center to enhance the OPTIK platform and aid in the collec- tion and visualization of catchment area data. As of May 2024, the Cancer InFocus software has been licensed by 26 cancer centers and 1 state cancer registry.

Thota R. Extending clinical trial access in rural settings. Presented at: 2024 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2024; Chicago, IL.

Stout NL, Nikcevich D, Henderson TO, et al; Alliance Rural Health Sub-Committee of the Community Oncology Committee Members. Improving rural clinical trial enrollment: recommendations from the Rural Health Working Group of the Alliance Clinical Trials Network. 

. 2024;42(14):1722-1725. doi:10.1200/JCO.23.01667

Burus T, Martinez J, DelNero P, et al. Interinstitutional approach to advancing geospatial technologies for US cancer centers. 

. 2024;8:e2400099. doi:10.1200/CCI.24.00099

Investigators are examining and implementing several innovations that they hope will combat the persistent issue of limited access to cancer care for patients living in rural areas.

A Multipronged Approach Can Address Disparities in Cancer Care for Patients in Rural Communities

Recently updated data from clinical studies evaluating immunotherapy-based combination regimens in renal cell carcinoma (RCC) have shown that upcoming regimens are poised to offer additional treatment options personalized to patients’ therapeutic needs and have confirmed the benefit of entrenched regimens.

“With more and more options available for kidney cancer, we’re starting to get to the point where patients are going to have [a] choice,” Wenxin “Vincent” Xu, MD, said. “Not every patient is going to need every treatment option. We not only have advances in biomarkers, which are important for choosing [therapy], but we have [made] advances where patients can choose which mechanisms, adverse effects [AEs], and effects on quality of life are most important to them. We now have 5 tyrosine kinase inhibitor [TKI] choices, TKI and immunotherapy [combinations], and HIF2α inhibitors. [For example], a patient who is struggling with AEs now has an opportunity to experience a TKI break and still [receive] active therapy.”

, a panel of RCC clinicians discussed recent updates in non–clear cell and clear cell RCC. They highlighted new data regarding front-line treatment approaches in advanced clear cell RCC, including that from the phase 3 CheckMate 214 (NCT02231749) and CheckMate 9ER (NCT03141177) trials, which investigated nivolumab (Opdivo) plus ipilimumab (Yervoy) and nivolumab plus cabozantinib (Cabometyx), respectively, and the phase 3 CLEAR study (NCT02811861) of lenvatinib (Lenvima) plus pembrolizumab (Keytruda). 

The panelists then transitioned to the second-line and later settings of clear cell RCC, discussing updated data from studies such as the phase 3 CONTACT-03 trial (NCT04338269) of atezolizumab (Tecentriq) plus cabozantinib and the phase 3 KEYNOTE-564 trial (NCT03142334) of pembrolizumab monotherapy. The investigators concluded their discussion by briefly taking stock of the evolving landscape of non–clear cell RCC, spotlighting results from the phase 2 PAPMET trial (NCT02761057), which compared sunitinib (Sutent) with cabozantinib, crizotinib (Xalkori), or savolitinib (Orpathys) in advanced papillary RCC and led to the initiation of the phase 2 PAPMET2 trial (NCT05411081) of cabozantinib with or without atezolizumab in this patient population.

Combination Regimens Remain at the Forefront of Advanced Clear Cell RCC

In recent years, the FDA has approved multiple combination regimens for the first-line treatment of patients with clear cell RCC. The long-term follow-up data that have matured since these regimens’ approvals have afforded a more comprehensive understanding of each combination’s benefits.

“We’ve seen huge advancements in terms of landscape changes and how new therapies for the frontline setting are now considered,” Pedro Barata, MD, MSc, said. “For the majority of patients, we often [consider] an immunotherapy-based combination regimen. We have immunotherapy combined with another immunotherapy agent—nivolumab plus ipilimumab—but we also have combinations of immune checkpoint inhibitors with targeted therapies.”

Data from CheckMate 214 supported the 2018 FDA approval of the combination of nivolumab and ipilimumab for patients with previously untreated or intermediate- or poor-risk RCC. The study compared nivolumab plus ipilimumab followed by nivolumab monotherapy with sunitinib in adult patients with previously untreated RCC with a clear cell component. The primary end points of the study were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in patients with International Metastatic RCC Database Consortium (IMDC) intermediate- or poor-risk disease.

During the 2024 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), investigators presented long-term follow-up data from CheckMate 214. At a median follow-up of 99.1 months (range, 91.0-107.3), patients in the intent- to-treat population who received the combination (n = 550) achieved a median OS of 52.7 months (95% CI, 45.8-64.5) compared with 37.8 months (95% CI, 31.9- 43.8) among those treated with sunitinib (n = 546; HR, 0.72; 95% CI, 0.62-0.83). The median PFS was 12.4 months (95% CI, 9.9-16.8) vs 12.3 months (95% CI, 9.8-15.2), respectively (HR, 0.88; 95% CI, 0.75-1.03). The HR for OS and PFS remained stable in the intermediate- and poor-risk population (OS: HR, 0.69; 95% CI, 0.59-0.81; PFS: HR, 0.73; 95% CI, 0.61-0.87) and improved over time in the favorable-risk population (OS: HR, 0.82; 95% CI, 0.60-1.13; PFS: HR, 1.76; 95%CI, 1.25 2.48).

“The question through the years has always been, ‘How have the data matured, and what happens to patients, long term?’ This is the longest follow-up we had for any immunotherapy combination,” Martin H. Voss, MD, said. “In my mind, the most striking data are the duration of response [DOR] data. Fifty percent of patients who are still being tracked after achieving a response to ipilimumab/nivolumab remain in response. The median DOR for this regimen is [greater than] 80 months, which stands out across all the data and is something that I think of when I consider this for my patients.”

CheckMate 9ER also evaluated a nivolumab-containing combination regimen, but with cabozantinib as its partner, vs sunitinib in patients with previously untreated clear cell RCC belonging to any IMDC risk group. Prior findings from the study supported the January 2021 FDA approval of the combination as a frontline treatment for these patients. The study’s primary end point was PFS by blinded independent central review (BICR) and OS was the key secondary end point.

Updated findings from CheckMate 9ER presented during ASCO GU 2024 showed that patients who received the combination (n = 323) achieved a median PFS per BICR of 16.4 months (95% CI, 12.5- 19.3) compared with 8.4 months (95% CI, 7.0-9.7) among patients treated with sunitinib (n = 328; HR, 0.58; 95% CI, 0.49-0.70). At a median follow-up for OS of 55.6 months (range, 48.1-68.1), the median OS figures were 46.5 months (95% CI, 40.6-53.4) vs 36.0 months (95% CI, 29.2-42.8), respectively (HR, 0.77; 95% CI, 0.63-0.95). Notably, PFS and ORR data favored the combination arm regardless of patient IMDC risk group.

“In contrast to CheckMate 214, patients received a time-limited amount of nivolumab on this trial; however, cabozantinib was continued and was started at lower than the maximal dose [than what is] used as monotherapy, but we [still] see preservation of the clear improvement in meaningful cancer control outcomes as we see continued follow-up,” Elizabeth Wulff-Burchfield, MD, explained. “Treatment-free survival [TFS] is 1.5 times [that with] sunitinib in the nivolumab/cabozantinib arm. One of our patients’ main goals is to have the life that they envision for themselves, which is TFS, and we’re seeing that they can attain that at a greater rate [with nivolumab plus cabozantinib].”

Later in 2021, findings from CLEAR supported the approval of frontline pembrolizumab plus lenvatinib for patients with advanced RCC. The combination led to a significant PFS (HR, 0.39; 95% CI, 0.32-0.49; 

< .0001) and OS (HR, 0.66; 95% CI, 0.49-0.88; 

= .0049) benefit compared with sunitinib.

During the 2024 ASCO Annual Meeting, investigators presented findings from a biomarker analysis of CLEAR that demonstrated that the PFS benefit observed with pembrolizumab plus lenvatinib vs sunitinib was maintained in the analysis sets for PD-L1 expression per immunohistochemistry (HR, 0.47; 95% CI, 0.37-0.60), gene expression via RNA sequencing (HR, 0.52; 95% CI, 0.41-0.68), and gene alterations with whole-exome sequencing (HR, 0.49; 95% CI, 0.38-0.63). The HRs for PFS also favored the combination across RCC driver mutation (mutant or wild-type 

) and gene signature (high vs low) subgroups.

“In the biomarker analysis, we [examined] several different categories of biomarkers, including PD-L1 tumor mutations and transcriptomic signatures,” Xu said. “No matter which way you slice the data, lenvatinib/pembrolizumab [performs] significantly better than sunitinib. We can’t tell a patient that [they’re] the 1 patient who needs this regimen, but we can tell [them] that it seems, with the data that we have, these combination therapies are better and are the appropriate choice for most patients.”

Options in Clear Cell RCC Expand After Disease Progression, but Questions Linger

When selecting a regimen in the second line and beyond in clear cell RCC, several factors, such as safety profile, treatment goals, and patients’ disease characteristics, must be weighed. However, how to best select and, if necessary, sequence available regimens in this space remains an open question. “The way I [consider] the refractory setting is impacted by the frontline regimen that I chose. Another aspect that I now [consider is] the CONTACT-03 data,” Barata said.

CONTACT-03 enrolled patients with clear cell or non–clear cell RCC with or without a sarcomatoid component who experienced disease progression following treatment with an immune checkpoint inhibitor. Patients were randomly assigned 1:1 to receive atezolizumab plus cabozantinib or cabozantinib monotherapy. The co–primary end points were independent centrally assessed PFS and OS; secondary end points included ORR, DOR, and safety.

Findings presented during the 2023 ASCO Annual Meeting demonstrated that patients who received atezolizumab plus cabozantinib (n = 263) did not experience improved outcomes vs those treated with cabozantinib alone (n = 259); in the overall population, the median PFS was 10.6 months (95% CI, 9.8-12.3) vs 10.8 months (95% CI, 10.0-12.5), respectively (stratified HR, 1.03; 95% CI, 0.83-1.28; 

 = .784), and the median OS was 25.7 months (95% CI, 25.1-not estimable [NE]) vs NE (95% CI, 21.1-NE), respectively (stratified HR, 0.94; 95% CI, 0.70-1.27; 

“The question that CONTACT-03 raises is how far to take this result; atezolizumab is a PD-L1 inhibitor, which [as a class is] not commonly used in RCC,” Xu said. “[These results] tell us that stimulating the tumor more with PD-L1 inhibitors is not having a strong clinical effect on tumor response. The real unanswered question here is whether we can extrapolate that to the postadjuvant setting. We now have an approved adjuvant therapy in RCC—pembrolizumab—which improves DFS [disease-free survival] and OS. The first-line treatment landscape after progression on adjuvant pembrolizumab is a big question for the field. Based on CONTACT-03, many [of us] are worried that we shouldn’t be giving additional PD-L1 inhibitors right after adjuvant pembrolizumab. But what is the definition of ‘right after’—how many months, is it a year? Do we challenge some patients and not others? These are questions that need to be answered in the coming years.”

Defining Pembrolizumab’s Role in the Adjuvant Setting

Findings from KEYNOTE-564 supported the November 2021 FDA approval of adjuvant pembrolizumab in patients with RCC at intermediate-high or high risk of recurrence after nephrectomy alone or after resection of metastatic lesions. KEYNOTE-564 randomly assigned patients 1:1 to receive adjuvant pembrolizumab or placebo. The primary end point was investigator-assessed DFS and OS was the key secondary end point.

Updated findings from KEYNOTE-564 presented during ASCO GU 2024 showed that, at a median follow-up of 57.2 months (range, 47.9-74.5), patients in the pembrolizumab arm (n = 496) experienced a significant OS benefit compared with those in the placebo arm (HR, 0.62; 95% CI, 0.44-0.87; 

 = .002). Pembrolizumab also displayed a significant DFS benefit vs placebo (HR, 0.72; 95% CI, 0.59-0.87). The findings made KEYNOTE-564 the first study to demonstrate significant and clinically meaningful improvement with an adjuvant treatment in RCC.

“The KEYNOTE-564 [regimen], once it demonstrated an OS benefit, was clearly seen as a new standard in the postnephrectomy setting,” Voss said. “[These findings] created this new space that we must think through and that we must address with dedicated clinical trials. A lot of the trials that we’ve recently [performed], and some of the trials that we are seeing now, are allowing patients to [enroll] if they’ve had prior adjuvant therapy. I would argue we need dedicated trials that not only allow for it, but where the requirement must be that the progression occurred after adjuvant [therapy] to address this question.”

If Not a Checkpoint Inhibitor, Then What? Alternative Options in the Refractory Setting

The panelists ended their discussion of treatment options in the second and later lines of clear cell RCC therapy by offering their perspective on treatment sequencing following treatment with a checkpoint inhibitor.

The HIF2α inhibitor belzutifan (Welireg) is approved by the FDA for treating patients with advanced RCC following treatment with a PD-L(1) inhibitor and a VEGF TKI. The regulatory decision was supported by findings from the phase 3 LITESPARK-005 (NCT04195750) study, which compared the agent with everolimus (Afinitor) in this patient population.

Updated findings from LITESPARK-005 presented during ASCO GU 2024 demonstrated that belzutifan continued to offer a PFS (HR, 0.74; 95% CI, 0.63-0.88) and an OS (HR, 0.88; 95% CI, 0.73-1.07; 

 = .099) benefit vs everolimus. Additionally, findings from a patient-reported outcomes analysis showed prolonged time to confirmed deterioration by Functional Assessment of Cancer Therapy Kidney Cancer Symptom Index-Disease Related Symptoms (HR, 0.53; 95% CI, 0.41-0.69; 2-sided nominal 

 < .0001) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (HR, 0.75; 95% CI, 0.58-0.96; 2-sided nominal 

 = .0185) with belzutifan. The respective difference in scores from baseline to week 17 were 1.45 (95% CI, 0.70-2.19; 2-sided nominal 

 = .0002) and 6.83 (95% CI, 3.21-9.55; 2-sided nominal 

 < .0001) in favor of the belzutifan arm.

“We’re getting more follow-up data to help us understand patient experiences [with these agents],” Wulff-Burchfield said. “I personally prescribe belzutifan, and I [also] prescribe tivozanib [Fotivda, but] I use them differently. I consider belzutifan as a TKI break for my patients, but because it has a slower onset of action, I have to be thoughtful about the most appropriate patient for that [agent] depending on their disease [characteristics]. We learn something from [all these studies]; these are valid therapies, and [there are] more to come.”

Immunotherapy Looks to Carve Out Its Place in Non–Clear Cell RCC

Although non–clear cell RCC is less common than clear cell disease, research in this area has seen significant gains in recent years, with an emphasis on adding immunoncology agents to the treatment arsenal. “[We] are starting to realize that non–clear cell RCC is not just an afterthought to clear cell RCC but is its own set of biologically distinct diseases. Non–clear cell RCC is not just 1 entity but is over a dozen entities, with some more common than others. Approximately 30% of all RCCs are non–clear cell,” Wulff-Burchfield noted.

The phase 2 PAPMET trial (NCT02761057) compared the existing standard-of-care treatment, sunitinib, with cabozantinib, crizotinib, or savolitinib in adult patients with papillary RCC. Data from the study demonstrated that patients who received cabozantinib (n = 44) achieved a median PFS of 9.0 months (95% CI, 5.6-12.4) compared with 5.6 months (95% CI, 2.9-6.7) among patients who received sunitinib (n=46; HR, 0.60; 95% CI, 0.37- 0.97; 1-sided 

 = .019), 2.8 months (95% CI, 2.6-3.6) in the crizotinib arm (n = 28), and 3.0 months (95% CI, 2.8-7.2) in the savolitinib arm (n = 29). The respective median OS values were 20.0 months (95% CI, 11.3-not reached [NR]), 16.4 months (95% CI, 12.8-21.6), 19.9 months (95% CI, 11.2-NR), and 11.7 months (95% CI, 6.7-28.9); cabozantinib led to a 16% reduction in the risk of death vs sunitinib (HR, 0.84; 95% CI, 0.47-1.51).

Considering the positive findings with cabozantinib reported in PAPMET, investigators launched and subsequently presented the design of the phase 2 PAPMET2 study (NCT05411081) during ASCO GU 2024. PAPMET2 is the first randomized study of immunotherapy in papillary RCC; patients will be randomly assigned 1:1 to receive cabozantinib monotherapy or cabozantinib in combination with atezolizumab. The primary end point is a comparison of the median PFS between the 2 arms, and secondary end points include ORR, OS, and safety.

Another phase 2 study, KEYNOTE-B61 (NCT04704219), is examining the combination of pembrolizumab with lenvatinib for the frontline treatment of patients with advanced or metastatic non–clear cell RCC. The primary end point of the study is ORR by BICR per RECIST 1.1; secondary end points included DOR, PFS, OS, and safety.

At a median follow-up of 22.8 months (range, 16.6-27.6), updated findings from KEYNOTE-B61 presented during ASCO GU 2024 showed that pembrolizumab plus lenvatinib displayed durable efficacy; the ORR among patients who received the combination (n=158) was 50.6% (95% CI, 42.6%- 58.7%), including an 8.2% complete response rate, and the Kaplan-Meier estimated median DOR was 19.5 months (range, 1.5+to 23.5+). The Kaplan-Meier estimated median PFS and OS figures were 17.9 months (95% CI, 15.1-22.1) and NR (95% CI, NR-NR), respectively.

“[Patients with] translocation type [disease] did well with lenvatinib plus pembrolizumab and had the highest ORR,” Wulff-Burchfield said. “The disease control rate [DCR] was [approximately] 80%, which is wonderful because it’s such an aggressive biology in adult patients. Patients with papillary disease [also] did very well, with an ORR of [approximately] 50% and a DCR of approximately 80%. The chromophobe [subgroup] did not perform as well, with an ORR of approximately 35%, but we still saw disease control. I’m hopeful that we will have meaningful correlatives that will help us understand the mechanistic underpinnings of why this [regimen] is helping [patients], especially with chromophobe disease, because [we had thought] it doesn’t respond to anything until we saw [these data].

FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. FDA. April 16, 2018. Accessed September 16, 2024. https://www. fda.gov/drugs/resources-information-approved-drugs/fda- approves-nivolumab-plus-ipilimumab-combination-intermediate- or-poor-risk-advanced-renal-cell

Tannir NM, Escudier B, McDermott DF, et al. Nivolumab plus ipilimumab (NIVO + IPI) vs sunitinib (SUN) for first-line treatment of advanced renal cell carcinoma (aRCC): long-term follow-
up data from the phase 3 CheckMate 214 trial. J Clin Oncol. 2024;42(suppl 4):363. doi:10.1200/JCO.2024.42.4_suppl.363

FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. FDA. January 22, 2021. Accessed September 16, 2024. https://www.fda.gov/drugs/resources-information- approved-drugs/fda-approves-nivolumab-plus-cabozantinib- advanced-renal-cell-carcinoma

Bourlon MT, Escudier B, Burotto M, et al. Nivolumab plus cabozantinib (N + C) vs sunitinib (S) for previously untreated advanced renal cell carcinoma (aRCC): results from
55-month follow-up of the CheckMate 9ER trial. J Clin Oncol. 2024;42(suppl 4):362. doi:10.1200/JCO.2024.42.4_suppl.362

FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. FDA. August 10, 2021. Updated August 11, 2021. Accessed September 16, 2024. https://www.fda.gov/ drugs/resources-information-approved-drugs/fda-approves- lenvatinib-plus-pembrolizumab-advanced-renal-cell-carcinoma

Motzer RJ, Porta C, Eto M, et al. Biomarker analyses in patients with advanced renal cell carcinoma (aRCC) from the phase 3 CLEAR trial. J Clin Oncol. 2024;42(suppl 16):4504. doi:10.1200/ JCO.2024.42.16_suppl.4504

Choueiri TK, Albiges L, Tomczak P, et al. Efficacy and safety
of atezolizumab plus cabozantinib vs cabozantinib alone after progression with prior immune checkpoint inhibitor (ICI) treatment in metastatic renal cell carcinoma (RCC): primary PFS analysis from the phase 3, randomized, open-label CONTACT-03 study. J Clin Oncol. 2023;41(suppl 17):LBA4500. doi:10.1200/ JCO.2023.41.17_suppl.LBA4500

FDA approves pembrolizumab for adjuvant treatment of renal cell carcinoma. FDA. November 17, 2021. Accessed September 16, 2024. https://www.fda.gov/drugs/resources-information- approved-drugs/fda-approves-pembrolizumab-adjuvant- treatment-renal-cell-carcinoma

Choueiri TK, Tomczak P, Park SH, et al. Overall survival results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab versus placebo for the treatment of clear cell renal cell carcinoma (ccRCC). J Clin Oncol. 2024;42(suppl 4):LBA359. doi:10.1200/JCO.2024.42.4_suppl.LBA359

FDA approves belzutifan for advanced renal cell carcinoma. FDA. December 14, 2023. Accessed September 14, 2024. https:// www.fda.gov/drugs/resources-information-approved-drugs/fda- approves-belzutifan-advanced-renal-cell-carcinoma

Powles T, Albiges L, Jalkanen KJ, et al. Belzutifan versus everolimus in participants (pts) with previously treated advanced renal cell carcinoma (RCC): patient-reported outcomes (PROs) in the phase 3 LITESPARK-005 study. J Clin Oncol. 2024;42(suppl 4):361. doi:10.1200/JCO.2024.42.4_suppl.361

Pal SK, Tangen C, Thompson IM Jr, et al. A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial. Lancet. 2021;397(10275):695-703. doi:10.1016/ S0140-6736(21)00152-5

Maughan BL, Plets M, Pal SK, et al. SWOG S2200 (PAPMET2): a phase II randomized trial of cabozantinib with or without atezolizumab in patients with advanced papillary renal cell carcinoma (PRCC). J Clin Oncol. 2024;42(suppl 4):TPS493. doi:10.1200/JCO.2024.42.4_suppl.TPS493

Voss MH, Gurney H, Atduev V, et al. First-line pembrolizumab plus lenvatinib for non–clear cell renal carcinomas (nccRCC): extended follow-up of the phase 2 KEYNOTE-B61 study. J Clin Oncol. 2024;42(suppl 4):2. doi:10.1200/JCO.2024.42.4_suppl.2

Recent advancements in immunotherapy-based combination regimens for renal cell carcinoma (RCC) have expanded treatment options, offering personalized approaches based on patient needs. Key trials, such as CheckMate 214, CheckMate 9ER, and CLEAR, have demonstrated significant benefits in overall survival and progression-free survival for various combinations, including nivolumab with ipilimumab or cabozantinib, and pembrolizumab with lenvatinib. The evolving landscape also includes second-line treatments and non-clear cell RCC, with ongoing research into the efficacy of novel agents like belzutifan and the role of immunotherapy in diverse RCC subtypes.

A panel of experts detail updated data and developments in the advanced renal cell carcinoma space with immunotherapy-based combination regimens.

Immunotherapy Combinations Dominate Frontline Discussions in Advanced RCC

There is little doubt that the rate of chance in cancer management of most disease entities has rapidly accelerated. Who would have considered, for example, as recently as a decade ago that manipulation of an individual’s immune system would be an effective strategy in inducing long-term remissions in metastatic non–small cell lung cancer?

Although such developments surely represent meaningful improvements in the standard of care for a substantial population of patients presenting with or subsequently developing advanced cancers, the speed at which new drugs, combination regimens, and novel approaches are being introduced into routine practice surely presents a vexing challenge for treating oncologists as they attempt to provide the best possible care for their patients. Unfortunately, it is critical to note that regulatory approvals, publications in high-impact medical journals, or impressive abstract presentations at major national/international cancer meetings do not necessarily help a busy clinician decide the optimal approach for the next patient being seen in the office.

In the not so distant past, with a slower pace for the introduction of novel therapeutics, it was easier for the oncology community to examine in the conduct of randomized trials the questions of optimal regimen sequencing, defining the potential for persistence of drug sensitivity to a previously administered single agent or combination regimen following disease recurrence or the relative clinical use of several alternative options. Today, such objective comparative data that might be helpful in decision support are increasingly scarce.

The rapid evolution in cancer management, particularly in advanced epithelial ovarian cancer, presents challenges for oncologists. Traditional chemotherapy regimens have remained largely unchanged, but the introduction of molecular testing and new therapeutic options like PARP inhibitors and bevacizumab has complicated treatment decisions. Despite advancements, there is a lack of direct comparative data to guide optimal treatment strategies. Clinicians must navigate unresolved issues, such as the timing and choice of therapies, without clear evidence, relying instead on expert opinion and regulatory guidance to make informed decisions for patient care.

The speed at which new drugs, combinations, and novel approaches are being introduced into routine practice presents a challenge for treating oncologists

Vol. 25/No. 13 | Oncology Live®

Effectively Targeting c-Met in Colorectal Cancer Is Becoming a Reality With Novel Approaches

ctDNA Generates Momentum in Adjuvant Stage II/III Colon Cancer Setting

A Multipronged Approach Can Address Disparities in Cancer Care for Patients in Rural Communities

Immunotherapy Combinations Dominate Frontline Discussions in Advanced RCC

The Escalating Need for Robust Decision Support in Oncology: Ovarian Cancer as an Example