In the April issue, researchers from the University of Alberta in Edmonton, Canada, reported that administering sirolimus (Rapamune) after liver transplantation in patients with nonresectable hepatocellular carcinoma (HCC) significantly increased survival rates. An anti-CD25 antibody induction regimen improved survival in liver transplant patients regardless of whether they had HCC.

Investigators, led by Christian Toso, MD, examined data for patients with HCC (n = 2491) and for those without HCC (n = 12167) who had a liver transplant between 2002 and 2009 and were listed in the US Scientific Registry of Transplant Recipients. All the patients received ≥6 months of maintenance therapy with an immunosuppressant, such as tacrolimus (Prograf ), steroids, mycophenolate mofetil, cyclosporine, or a sirolimus-based regimen. Some patients also received induction therapy with an anti-CD25 monoclonal antibody and some received thymoglobulin. Less than 10% of patients received maintenance therapy with cyclosporine or sirolimus. In the HCC subgroup, 12% of patients received induction therapy with an anti-CD25 antibody compared with 10.8% in the group without HCC. The study’s primary endpoint was patient survival at 5 years, and mortality from all causes was factored into survival outcomes data.

Investigators reported that of all the agents used, only anti-CD25 induction therapy with the drugs daclizumab (Zenapax) or basiliximab (Simulect) were associated with better 5-year survival rates. Of all the maintenance regimens, only sirolimusbased therapy improved 5-year survival after transplant, and this was only for patients with HCC. A multivariate analysis (Table) of HCC patients that adjusted for age, disease severity, year of transplant, neoadjuvant therapy, tumor volume, and the level of serum alpha fetoprotein found that those who received anti-CD25 therapy before transplant for HCC had a survival advantage of 6% compared with those who did not (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.45-0.9; P ≤.01); and sirolimus offered a 14.4% 5-year survival advantage compared with nonsirolimus regimens (HR, 0.53; 95% CI, 0.31-0.92; P ≤.05). Both results were statistically significant. The multivariate analysis showed that use of cyclosporine was associated with a 30% increase in mortality. Toso said sirolimus-based maintenance therapy was associated with worse survival in patients without HCC compared to other immunosuppressive regimens, but the trend was not significant.

Hepatology

In a presentation at the recent annual International Liver Conference in Europe, Toso said the activity of sirolimus in patients with HCC relates more to a cytostatic effect than a cytotoxic effect. “I would expect the rate of growth of an HCC recurrence will be slower in a patient treated with sirolimus,” he said. “I’m not sure that sirolimus will prevent recurrence or kill a preexisting tumor,” he added. Toso urged physicians to use sirolimus as maintenance therapy in patients with HCC but suggested waiting a few weeks after transplant before initiating therapy because sirolimus increases the risk of delayed wound healing and incisional hernia. He was less concerned with its association with an increase in hepatic artery thrombosis, which he said is uncommon. The article in is available at http://bit.ly/csjL8x.

Hepatology

Toso C, Merani S, Bigam DL, Shapiro J, Kneteman J. Sirolimus-based immunosuppression is associated with increased survival after liver transplantation for hepatocellular carcinoma. . 2009. [Epub ahead of print]

Hadeel Assad, MD

Breast cancer remains the most prevalent cancer among women in the US. In 2024, approximately 310,720 new cases of invasive breast cancer and 56,500 cases of ductal carcinoma in situ were diagnosed among women across the country. Additionally, approximately 42,250 women died from this disease.1

Figure. US Breast Cancer Statistics1,2

Metastatic breast cancer poses significant treatment challenges. Approximately 15% to 20% of cases of metastatic disease are HER2 positive, which promotes cancer cell growth.2

The treatment paradigm for metastatic HER2-positive breast cancer typically involves targeted therapies such as trastuzumab (Herceptin) and pertuzumab (Perjeta), often in combination with chemotherapy, to inhibit the HER2 protein and slow disease progression.3 The antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) displayed a high response rate of 79.7% (95% CI, 74.3%-84.4%) and a median investigator-assessed progression-free survival of 25.1 months (95% CI, 22.1-not estimable) in patients with HER2-positive metastatic breast cancer in the second-line setting (n = 261), according to data from the phase 3 DESTINY-Breast03 trial (NCT03529110).4

Small-molecule HER2 inhibitors, such as tucatinib (Tukysa), neratinib (Nerlynx), and lapatinib (Tykerb), have also shown positive results and intracranial responses when combined with chemotherapy (with/without trastuzumab) or endocrine therapy.5,6 Despite these advances, the response to treatment tends to be limited, and disease progression is inevitable. In addition, both the response rates and duration of response decrease as patients cycle through the lines of therapy. There remains a significant unmet need for better treatments that not only prolong life but also preserve the quality of life in women with metastatic disease.

Developing a Potential New Treatment Option for Patients With Breast Cancer

At the Barbara Ann Karmanos Cancer Institute, a National Cancer Institute–Designated Comprehensive Cancer Center in Detroit, Michigan, the Bone Marrow and Stem Cell Transplant, Hematologic Oncology, and Multiple Myeloma and Amyloidosis Multidisciplinary Teams (MDTs) have helped drive many treatment advancements in cellular immune therapies for cancers. This includes chimeric antigen receptor (CAR) T-cell therapy, which has revolutionized the treatment of certain hematologic malignancies, including specific types of leukemia and lymphoma, and has significantly improved response rates for these diseases.7-10 This personalized immunotherapy involves modifying a patient’s T cells, which are an integral part of the immune system, to recognize and attack cancer cells.

Karmanos Cancer Institute offers all approved CAR T-cell therapies for non-Hodgkin lymphoma, acute lymphoblastic leukemia, and multiple myeloma. The institute also supports research into new treatment indications for which CAR T-cell therapy could be used. I, along with other principal investigators at Karmanos, am now exploring the application of CAR T-cell therapy for solid tumors, including breast cancer, which presents a set of new challenges due to tumor microenvironment and antigen heterogeneity.

CAR T-Cell Therapy in Clinical Trials

One such clinical study open at Karmanos is investigating the safety and efficacy of cellular immunotherapy in combination with targeted therapy for the treatment of solid tumors. In a phase 1 trial (NCT06241456), we are evaluating FT825/ONO-8250, an induced pluripotent stem cell–derived off-the-shelf CAR T-cell product targeting HER2-positive and other advanced solid tumors in combination with trastuzumab or cetuximab (Erbitux). Early data from this trial indicate no dose-limiting toxicities and no significant adverse effects, such as cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, or graft-vs-host disease. These findings suggest a promising avenue for developing effective cellular therapies for solid tumors, including HER2-positive breast cancer. The ongoing study enrolls participants with advanced HER2- and EGFR-expressing solid tumors such as breast, gastrointestinal, gynecologic, and head and neck cancers.11

Karmanos specialists have experience in providing commercially approved and investigational cellular therapies. We work closely with investigators, developing novel strategies to make this therapy safer, developing pathways toward new indications, and ensuring more accessibility to CAR T-cell therapy. With our robust clinical trials program and experienced team, we are committed to further improving outcomes for patients who are candidates for these therapies and overcoming associated challenges. We look forward to witnessing how this therapy can transform the standard of care for many of our patients in the future.

Hadeel Assad, MD, is a medical oncologist specializing in breast cancer. She is the co-leader of the Breast Cancer Multidisciplinary Team (MDT), a member of the Phase I Clinical Trials MDT, and a scientific member of the Population Studies and Disparities and the Molecular Therapeutics Research Programs at Karmanos Cancer Institute in Detroit, Michigan.

References

1. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74(1):12-49. doi:10.3322/caac.21820
2. Giaquinto AN, Sung H, Newman LA, et al. Breast cancer statistics 2024. CA Cancer J Clin. 2024;74(6):477-495. doi:10.3322/caac.21863
3. Swain SM, Miles D, Kim SB, et al; CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(4):519-530. doi:10.1016/S1470- 2045(19)30863-0
4. Cortés J, Kim SB, Chung WP, et al; DESTINY-Breast03 Trial Investigators. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022;386(12):1143- 1154. doi:10.1056/NEJMoa2115022
5. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609
6. Saura C, Oliveira M, Feng YH, et al; NALA Investigators. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2- positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: phase III NALA Trial. J Clin Oncol. 2020;38(27):3138-3149. doi:10.1200/JCO.20.00147
7. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439-448. doi:10.1056/NEJMoa1709866
8. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42. doi:10.1016/s1470- 2045(18)30864-7
9. Schuster SJ, Bishop MR, Tam CS, et al; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56. doi:10.1056/NEJMoa1804980
10. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852. doi:10.1016/ s01406736(20)31366-0
11. Fate Therapeutics highlights cancer-selective, HER2-targeting profile of FT825 / ONO-8250 CAR T-cell product candidate for treatment of advanced solid tumors at 2024 SITC Annual Meeting. News release. Fate Therapeutics. November 9, 2024. Accessed March 28, 2025. https://ir.fatetherapeutics.com/news-releases/news-release-details/fate-therapeutics-highlights-cancer-selective-her2-targeting

Pamela T. Soliman, MD, MPH

The mTOR inhibitors everolimus (Afinitor) and temsirolimus (Torisel) were both evaluated as part of combination regimens for patients with recurrent endometrial cancer with the goal of targeting the PI3K/ AKT/mTOR and RAS/RAF/MEK/ERK pathways, which are integral in endometrial tumorigenesis.1 However, although many doublet or triplet therapies have been examined in this setting, including regimens encompassing the aforementioned drugs, they have shown limited efficacy.1,2

“At least 50% of patients with endometrial cancer have some abnormality in the PTEN/AKT pathway, [and] one of the ways we’ve tried to treat endometrial cancer is by targeting some of the steps along the [pathway],” Pamela T. Soliman, MD, MPH, said in an interview with OncologyLive. “The future [will revolve around a couple of questions]. How do we identify patients who would benefit from this strategy of targeted therapy? And what is the right combination to give them the maximum benefit but also make it with manageable toxicity?”

The PI3K/AKT and RAS/RAF/MEK/ERK pathways involve mTOR as an important downstream player, making mTOR inhibitors a rational component of regimens for this patient population. Additionally, metformin induces metabolic changes and activates AMPK, which in turn inhibits the mTOR pathway, providing the baseline for Soliman and coinvestigators to examine the antidiabetic agent in combination with temsirolimus.1 Soliman added that because patients with endometrial cancer often have insulin resistance, addressing that and increasing the uptake of insulin in the peripheral circulation may inhibit the cancer.

Building on Findings with mTOR Inhibition Plus an Antidiabetic Agent

In a phase 1 study (NCT01529593), treatment with the combination of temsirolimus and metformin yielded an objective response rate (ORR) of 6% of patients with endometrial cancer (n = 2 of 33). Stable disease (SD) occurred in 39% of patients (n = 13 of 33), and 11 patients experienced SD for at least 4 months; these data translated to a clinical benefit rate (CBR) of 39%.

“When we’re looking at a population with recurrent disease [after] a number of different prior therapies, what I often tell patients is even if we can get the cancer control—even if it doesn’t shrink, but the cancer is able to be stabilized over time and they’re able to tolerate therapy—that still benefits them in the long run,” Soliman said. “If you combine the few responses and the higher percentage of SD, there were some patients who got benefit from this combination.”

Additionally, no grade 4 or 5 treatment-related adverse effects (TRAEs) occurred in patients treated with temsirolimus plus metformin. Grade 3 TRAEs included anemia and thrombocytopenia, which each occurred twice, and mucositis, fatigue, hypokalemia, weight loss, hypophosphatemia, increased aspartate aminotransferase levels, and increased alanine aminotransferase levels, which all occurred once. The most common any-grade TRAEs among the 32 patients who experienced toxicities in the phase 1 study were hypertriglyceridemia (44%), mucositis (41%), diarrhea (41%), anorexia (38%), anemia (31%), and nausea (25%).

“Although we were hoping for better responses…patients didn’t experience much toxicity,” Soliman said. “It was a tolerable [regimen], and some patients experienced benefit. With future studies, we’re trying to get more cancer control or higher response rates, but it’s important to also look at toxicity and tolerability because helping people live longer [and] making sure that they have a good quality of life is equally as important.”

A previous study also examined metformin in combination with the mTOR inhibitor everolimus and the hormone therapy letrozole (Femara).2 Data showed the triplet elicited a CBR of 50% in patients with recurrent endometrial cancer (n = 54) and a partial response (PR) rate of 28%, with 22% of patients experiencing SD. Additionally, the median progression-free survival was 5.7 months (95% CI, 3.0-8.1), and the median overall survival was 19.6 months (95% CI, 14.2-26.3).

No patients experienced grade 5 AEs, and hypertriglyceridemia occurred at grade 4 in 1 patient. “With a lot of mTOR inhibitors, one of the AEs is hyperglycemia,” Soliman said. “We’ve seen in different studies of metformin that you can add the drug to other [agents] and it doesn’t increase toxicity very much; it’s a well-tolerated and safe drug. These studies were ongoing [at the time we started the phase 1 trial], but we had already added metformin in a different trial that was published a couple of years ago to the combination of everolimus and letrozole…. There seems to be some role in adding metformin, [but] I don’t think we’ve figured out perfectly where we can get the biggest benefit, or which patients would benefit the most.”

Additional Combinations Under the Microscope

As investigators believe metformin inhibits the mTOR pathway through upstream activation of 5’-AMPK, they combined it with the potent, selective adenosine triphosphate–competitive mTORC1/2 inhibitor sapanisertib in a phase 1 dose-escalation study (NCT03017833).3 Among 30 evaluable patients with solid tumors, 4 patients experienced a PR, which included 1 patient with endometrial cancer; 1 other patient with endometrial cancer was enrolled in the trial and experienced progressive disease.

Furthermore, the AKT/mTOR inhibitor ibrilatazar (ABTL0812) was also examined in patients with advanced/recurrent endometrial cancer and stage III and IV squamous non–small cell lung cancer not amenable to radiation in the phase 1/2 ENDOLUNG trial (NCT03366480).4 The combined patient population (n = 38) achieved an ORR of 65.8% (95% CI, 52.0%-78.9%), which included a complete response rate of 13.2% and a PR rate of 52.6%. Notably, the SD rate was 34.2%, and no patients experienced progressive disease, translating to a 100% disease control rate. Investigators of the trial noted that the data warranted further confirmation in prospective, randomized trials.

Further Homing In on Rational Combinations

When asked where research should go next with mTOR inhibitors, Soliman noted, “We’re still trying to figure it out, and one [element] is patient identification. More and more with endometrial cancer, we’re using patients’ molecular subtypes or molecular classifications to guide cancer therapy. Which patients truly benefit from these medications? Since [conducting] this [phase 1] trial, newer-generation mTOR inhibitors, AKT inhibitors, [and] a lot of agents [have emerged] in ongoing trials. We’re also looking at [potential] combinations with other drugs.

In addition to antiestrogen therapy, is there a role for [cyclin-dependent kinase] 4/6 inhibitors that also potentiate the same pathway?” Regarding molecular classification, a subgroup of patients with PI3K/ PTEN and RAS alterations who received temsirolimus plus metformin in the phase 1 study experienced SD.1 Investigators highlighted this as significant because approximately 22% of those with endometrial cancer have PIKC3A hyperactivity, approximately 42% to 54% of patients have PTEN mutations or repression, and 10% to 30% of patients have KRAS mutations. “In this patient population where we’re trying to give patients [with endometrial cancer] the best option, offering patients a clinical trial allows us to get a better idea of response rates and tolerability for a lot of these newer drugs,” Soliman said. “Here, it’s a priority for us to put patients on trials. It’s important wherever you’re practicing to consider clinical trials for these patients because there is an unmet need for women with endometrial cancer [who experience] recurrence.”

Michael K. Wong, MD, PhD, FRCPC

Although Merkel cell carcinoma (MCC) remains an aggressive form of skin cancer associated with treatment challenges to treatment, the development of immunotherapy approaches and increased multidisciplinary collaboration have improved the management of this malignancy, according to Michael K. Wong, MD, PhD, FRCPC.

“MCC is an area that is ripe for research, and it’s one of opportunity for great outcomes for our patients,” Wong said in an interview with OncLive®. “When possible, it’s better to [consider] immunotherapy as a frontline therapy because in all the clinical trials of immunotherapy in MCC, the [overall] response rate [ORR] has been highest in the frontline. In the second- or third-line of therapy, it’s effective but the ORR is lessened. [However], there are a variety of [situations] where that may not be the case, and that’s why having a total assessment by [a multidisciplinary] team is important for our patients with MCC.”

Wong is a physician in chief and professor of oncology in the Department of Medicine at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

Retifanlimab-dlwr (Zynyz) became an approved immunotherapy option for patients with MCC when, in March 2023, the FDA granted accelerated approval to the agent for the treatment of adult patients with metastatic or recurrent locally advanced MCC. The regulatory decision was supported by data from the single-arm phase 2 PODIUM-201 study (NCT03599713), which demonstrated that patients with chemotherapy-naive metastatic or recurrent locally advanced MCC who received retifanlimab (n = 65) achieved an objective response rate of 52% (95% CI, 40%-65%), including a complete response rate of 18%. Notably, 76% of responders experienced a duration of response (DOR) of at least 6 months, and 62% had a DOR of at least 12 months.

In the interview, Wong discussed the historical challenges associated with treating patients with MCC, the importance of multidisciplinary management of the disease, and the impact of the emergence of immunotherapies such as retifanlimab in the space.

OncLive: What have been some of the treatment challenges for patients with MCC?

Wong: MCC is one of the most aggressive skin cancers we know of, and it has a very high mitotic rate. It has a reputation for extensive metastatic ability. In the past, this was a disease that was difficult to treat; it was treated with cytotoxic chemotherapy and radiation. [However], there have been tremendous changes in the management of MCC, to the point where we now have the routine expectation of response, and we see long-term survivors of this disease.

An important [aspect] of MCC is that it’s a lesion that can creep up on individuals. It’s not pigmented, so it’s not like a mole where one can see a change. In fact, if you survey patients with a diagnosis of MCC as to what they were told in the beginning, you get [responses about the disease looking like] a cyst or a bug bite, so it’s difficult to detect. However, the key is, as an adult, if you notice any changes in your body in a significant way that are persistent and unrelenting, then it’s time to seek medical attention. We know that MCC is a lesion that grows because of how mitotic it is. It grows, begins to change, and becomes symptomatic. If you start having symptoms, that’s a red flag to seek medical attention.

There are certain situations in which MCC can be more prominent. We know that it occurs in a population that, on average, is [approximately] 10 years older than the average melanoma population. We know there’s a propensity for it to occur in individuals with an immunologic issue, either from pre-existing disease or long-term immunosuppression.

What is important to know about identifying MCC and differentiating it from other forms of skin cancer?

MCC is considered a rare tumor, [but] we are finding that the incidence is going up in [the United States, which] reflects the fact that we are better at recognizing it. [This is] because we are learning more about it, and patients and physicians are paying attention to this rare cancer. Importantly, on the side of diagnosis, there are new tools and ways of interrogating tissue to make a diagnosis.

The incidence [rate] used to be [approximately] 1 per 1 million [individuals], but MCC is becoming more prevalent as we are [better] understanding the disease. Whenever there’s [a lesion] and there’s doubt as to what it is, the next step is to do a biopsy. MCC is distinctive under the microscope; it looks very different than melanoma, squamous cell carcinoma, or basal cell carcinoma. Once you have a [sample] under the microscope, the diagnosis comes to the forefront quickly.

How can a multidisciplinary care be used for the management of MCC?

The key to successful treatment of MCC is a multidisciplinary approach, which means that you want to engage the surgeon, radiation oncologist, and medical oncologist. The reason for that is that is this disease is best handled in a way that involves all 3 specialties. I tell patients that one of the most important individuals involved in their care is the pathologist, who is someone they never see.

Upon the discovery of the disease, the patient undergoes a thorough physical examination to ensure that we understand exactly what’s going on. We want to make sure that we know the location [of the disease] and that there isn’t any obvious clinical spread. Depending on the what the physician sees, they may order further imaging, such as a CT scan.

If the disease is localized, the treatment requires a surgeon to remove the tumor. We know that a biopsy and [tumor resection] is not good enough; [the patient] needs to have a proper excision. That’s important because MCC tumors have a reputation for being more than you see. Whenever we see MCC on the skin, it’s a bit like an iceberg, and you worry about the part you don’t see.

The analysis under the microscope tells you whether you need a complete resection. Oftentimes, patients will say, ‘Did the doctor get it all?’ Knowing that requires the pathologist to declare the margins are free. We [also] know that there are certain features under the microscope associated with spread beyond the primary site, which includes depth of invasion and involvement of other critical structures deep in the skin.

If [a patient] checks those boxes, then a surgeon may sample the lymph nodes associated with that site. Sometimes surgeons will map out [the surrounding] lymph nodes and take samples to ensure the disease hasn’t spread. We determine [when to do that] by looking at the [sample] under the microscope and the physical examination.

All of this comes back to the importance of a multidisciplinary approach. What we see from the resection and whether the lymph nodes are positive [determine] whether we need radiation. [Radiation is sometimes needed] to sterilize the area around the tumor so that we get rid of [the disease] once and for all. Luckily, MCC is one of those tumors which are particularly sensitive to radiation, so it’s a good modality to use.

I’m a medical oncologist, and, in the past, we didn’t get too involved because there weren’t a lot of [treatment] options, but there’s been tremendous change in the field, and that has to do with the recognition that this tumor is sensitive to immunotherapy. That has been a real breakthrough in this area. It turns out that MCC is a cancer that can evoke an immune response in the body. By using immunotherapy, you can unleash the patient’s immune system to attack the cancer. That has been a revolutionary change in the treatment of MCC.

How has the FDA approval of retifanlimab and the development of other immunotherapies affected the treatment paradigm of MCC?

Retifanlimabi s an immunotherapy, and it [adds to the] line of known immunotherapies that can attack the cancer. The current way we treat MCC—whether it’s locally advanced locally or metastatic—is to use medicines that will trigger the immune system to fight the cancer. These medicines target PD-L1.

There are now several [agents] that are used in MCC. Useful [agents include] avelumab [Bavencio], pembrolizumab [Keyrtuda], nivolumab [Opdivo], and retifanlimab. These are very effective immunotherapies. The use of immunotherapies in MCC comes with some of the highest response rates in oncology, approaching 50% to 60%. These responses can occur quickly, and within 1 to 3 infusions you can know whether you’ve triggered [a response].

The use of immunotherapy is global in a sense that it will attack the cancer anywhere in your body. Patients with extensive disease can respond to immunotherapy dramatically, and that has been the real key in in the change of how we treat this cancer. The advantage of immunotherapy is that it’s a bit like the gift that keeps on giving. It is intrinsic to the patient, and you’re triggering something within that patient. At some point, we can allow the patient’s immune system to take over, and we don’t need to treat them forever. With these robust responses, the door opens for a cure, and we are able to have long-term results in the absence of having to give [continuous] therapy. This has truly revolutionized [the treatment of] this disease.

Is there any other ongoing research in the field that could help move the needle for treatment?

The recognition that immunotherapy works in MCC has been a [key] breakthrough. It means that all the research in immunotherapy and all of those concepts we have in other cancers become applicable to MCC. We’re interested in using other checkpoint inhibitors, [such as] the addition of an antibody to an anti–CTLA-4 [agent] or an anti-LAG3 [agent]. Those are strategies have found use in other cancers, in particular melanoma. Their use is now being pioneered in MCC.

We [also] have recognized that vaccine therapies may be important. We now have intratumor oncolytic vaccines, where you can inject a vaccine directly into the tumor to induce an immune response. Something which is unique to MCC and not found in any other cancer is a recognition that there may be a viral link-up. The Merkel cell polyomavirus is found ubiquitously and for reasons we don’t understand it can integrate into the skin and cause MCC.

This is all new [research], but something that’s come as an offshoot of the recognition that we could use molecules that attack specific pathways within the Merkel polyomavirus to affect a response in the tumor. [This is] an exciting area which is growing. We don’t know where it’s going to go, but there’s a hint of efficacy. It’s something unique to MCC that is not found in any other cancer.

Finally, there’s a recognition that we have barely begun to scratch the surface of this disease. We are finding more ways to attack it, and it’s an area of prolific interest and research. I’m certain that there’s more to come in a short time.

Reference

FDA grants accelerated approval to retifanlimab-dlwr for metastatic or recurrent locally advanced Merkel cell carcinoma. FDA. March 22, 2023. Accessed May 14, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-retifanlimab-dlwr-metastatic-or-recurrent-locally-advanced-merkel

Tanios S. Bekaii-Saab, MD

Guided approaches with circulating tumor DNA (ctDNA) have just begun to scratch the surface of showing prognostic and predictive abilities in colorectal cancer (CRC), and new data have further shed light on ctDNA’s role. Clinical trials demonstrated that ctDNA-guided approaches can reduce the use of chemotherapy without compromising outcomes in those with minimal residual disease (MRD)–positive disease, and that celecoxib (Celebrex) benefited these patients.1,2

“The results continue to be consistent across [the board] whether it’s the CIRCULATE-Japan GALAXY trial [UMIN000039205], [the observational] BESPOKE study [NCT04264702] from the US, or other smaller studies—they all suggest that patients who have MRD assessment may benefit at least from a discussion about whether to [move forward with] or forgo treatment,” Tanios S. Bekaii-Saab, MD, said in an interview with OncologyLive. “Assessment of MRD has made its way into CRC, specifically in the earlier stages of the disease, but also more into oligometastatic disease. Now, the role continues to be explored further. Most of the data we’ve had so far, except [for from] a couple of studies, were from large observational studies.”

The final analysis of the BESPOKE CRC study subcohort was published in 2025 as the largest multicenter ctDNA study reported in the US to date. It revealed that ctDNA testing following surgery led to a change in adjuvant treatment for 1 out of 6 patients with stage II/III CRC.3 Additionally, the adjuvant plan was validated for most patients, and a benefit with adjuvant chemotherapy was solely observed in those with MRD-positive disease.

Furthermore, the phase 2/3, prospective NRG-G1008 (CIRCULATE-North America) study (NCT05174169) is currently ongoing to evaluate the role of ctDNA in risk stratification for escalation or de-escalation of adjuvant therapy in patients with resected colon cancer.4 Aggregate data are planned to be combined with those from CIRCULATE-JAPAN.

Examining New Readouts of Data that Further Explore ctDNA's Role

According to an updated analysis of the phase 3 CALGB/SWOG 80702 study (NCT01150045), ctDNA was highly prognostic for disease-free survival (DFS) and overall survival (OS) in patients with stage III colon cancer, and ctDNA positivity appeared to be predictive of the benefit of adjuvant therapy with celecoxib for DFS and OS.5 Primary findings showed that patients in the study who received the anti-inflammatory drug plus FOLFOX (fluorouracil, leucovorin, and oxaliplatin) vs FOLFOX and placebo did not experience a statistically significant difference in DFS (HR, 0.89; 95% CI, 0.76-1.03; stratified log-rank P = .12).

“[Although] this study was negative for celecoxib’s effect vs placebo following adjuvant therapy, there were hints that there was a small subgroup of patients who may benefit,” Bekaii-Saab explained. “In the follow-up [data], approximately less than half of the patients had enough material that they could assess their MRD [with], and those who had MRD-positive disease appeared to benefit from the addition of celecoxib vs those who did not.”

Patients in the ctDNA-positive group experienced an estimated 5-year OS rate of 61.6% (95% CI, 52.4%-72.4%) when given celecoxib (n = 99) compared with 39.9% (95% CI, 29.6%-53.8%) when given placebo (n = 74; HR, 0.58; 95% CI, 0.38-0.90; P = .0135). Additionally, those who were ctDNA negative and received celecoxib (n = 375) achieved an estimated 5-year OS rate of 91.8% (95% CI, 88.9%-94.7%) vs 91.3% (95% CI, 88.4%-94.3%) in the placebo arm (n = 392; HR, 0.86; 95% CI, 0.55-1.35; P = .5098).

“The question is [whether that] would change our standard today,” Bekaii-Saab said. “Does it mean that patients who are MRD positive should be put on celecoxib? Celecoxib does come with its own toxicities. This study was a post hoc analysis, it was also a retrospective look, and less than half of the patients had materials [available to examine for MRD]. All these limitations have to be taken into account before making a decision, but I believe it’s worth discussing with patients. I’m finding myself at least having some level of discussion with patients about this [therapy], given the pros and the cons, and the fact that the data are still [developing] and further study [is needed].”

Another study that was reported as negative has posed important questions about the role of ctDNA in guiding decisions. The phase 3 ALTAIR study (NCT04457297) revealed that there was not a statistically significant DFS benefit when patients who were ctDNA positive following curative resection in the CIRCULATE-Japan study were given trifluridine/ tipiracil vs placebo.2 A numerical benefit was seen, as the median DFS was 9.30 months (95% CI, 7.92- 10.84) vs 5.55 months (95% CI, 4.17-7.33), respectively (HR, 0.79; 95% CI, 0.60-1.05; P = .107). Additionally, investigators found that the DFS benefit was clinically meaningful in patients who had resected stage IV disease.

“That [study] was a bit disappointing,” BekaiiSaab noted. “However, on the other side, one would ask the question: Is trifluridine/tipiracil the right agent? It is a fluoropyrimidine, and patients were already exposed to capecitabine. Does that make sense? Should we go more toward targeted approaches? [For example], if a patient has a BRAF V600E mutation, do we go to BRAF-targeted strategies, rather than just switch to another chemotherapy? That study, unfortunately, tells us that another chemotherapy may not cut it.”

Trying to Determine the Necessity of Adjuvant Chemotherapy

The phase 2 DYNAMIC study (ACTRN12615000381583) randomly assigned patients with resected stage II colon cancer to either standard management, which included adjuvant treatment decisions based on conventional clinicopathologic criteria, or ctDNA-guided management, which encompassed observation for those who were ctDNA negative and adjuvant chemotherapy for those who were ctDNA positive.1 The 5-year relapse-free survival rate was 88.3% in the ctDNA arm (n = 294) vs 87.2% in the standard of care (SOC) arm (n = 147), confirming initial findings from the study that these patients could benefit from a ctDNA-guided approach, as the use of chemotherapy was reduced and survival outcomes were maintained.

Additional data from DYNAMIC showed the 5-year OS rates were 93.8% in the ctDNA arm vs 93.3% in the SOC arm (HR, 1.05; 95% CI, 0.47- 2.37; P = .887). Patients in the ctDNA arm who had ctDNA-negative disease (n = 246) experienced a 5-year OS rate of 95.3% compared with 85.6% in the ctDNA-positive group (n = 45; HR, 3.30; 95% CI, 1.20-9.05; P = .014). Investigators noted that most patients who are ctDNA positive following surgery can achieve ctDNA clearance with adjuvant chemotherapy and this is associated with positive outcomes. They added that although validation of these findings is needed, there could be potential to improve the precision of the ctDNA-informed approach by increasing variant number and incorporating ctDNA molecular burden.

Bekaii-Saab will discuss the use of ctDNA in the clinic and more at the 2025 International Symposium of Gastrointestinal Oncology conference, which he is cochairing.6 Slated for September 12 to 13, 2025, in Austin, Texas, the multidisciplinary meeting will comprehensively review the gastrointestinal cancer landscape and focus on examining the complex array of recent studies that are informing clinical practice. As the role of ctDNA continues to be examined, the conference will cover that aspect of care and more.

“Attendees [of] the conference will come out of it with what I hope is a clear understanding of the shifting landscape on a yearly basis. What they want to take home with them is one, what do I do for my patients after this conference? How can I change my practice in a way that’s positively affecting outcomes?” Bekaii-Saab noted. “The second is a clear understanding of what’s coming. What should I need? What should I continue to pay attention to and what may be a practice-changing element next year or the year after?”

References

1. Tie J, Wang Y, Lo SN, et al. Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer: overall survival and updated 5-year results from the randomized DYNAMIC trial. J Clin Oncol. 2024;42(suppl 16):108. doi:10.1200/ JCO.2024.42.16_suppl.108
2. Bando H, Watanabe J, Kotaka M, et al. A randomized, doubleblind, phase III study comparing trifluridine/tipiracil (FTD/ TPI) versus placebo in patients with molecular residual disease following curative resection of colorectal cancer (CRC): the ALTAIR study. J Clin Oncol. 2025;43(suppl 4):LBA22. doi:10.1200/JCO.2025.43.4_suppl.LBA22
3. Shah PK, Aushev VN, Ensor J, et al. Circulating tumor DNA for detection of molecular residual disease (MRD) in patients (pts) with stage II/III colorectal cancer (CRC): final analysis of the BESPOKE CRC sub-cohort. J Clin Oncol. 2025;43(suppl 4):15. doi:10.1200/JCO.2025.43.4_suppl.15
4. Lieu CH, Yu G, Kopetz S, et al. NRG-GI008: colon adjuvant chemotherapy based on evaluation of residual disease (CIRCULATE-North America). J Clin Oncol. 2025;43(suppl 4):TPS310. doi:10.1200/JCO.2025.43.4_suppl.TPS310
5. Nowak JA, Shi Q, Twombly T, et al. Prognostic and predictive role of circulating tumor DNA (ctDNA) in stage III colon cancer treated with celecoxib: findings from CALGB (Alliance)/SWOG 80702. J Clin Oncol. 2025;43(suppl 4):LBA14. doi:10.1200/ JCO.2025.43.4_suppl.LBA14

Katy E. Beckermann, MD

Clinical trial updates presented during the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), including from the phase 3 CheckMate 9ER (NCT03141177) and COSMIC-313 (NCT03937219) studies, have further validated combination regimens as the first-line treatment for patients with advanced renal cell carcinoma (RCC). Because of the numerous options, investigators must carefully consider factors such as sarcomatoid features, disease risk status, and patient fitness when selecting from the current regimens.

“We have several clear ‘right answers’ when it comes to first-line [treatment] for patients with advanced RCC,” Elizabeth M. Wulff-Burchfield, MD, said. “My perspective is that not every efficacy outcome matters for every patient. [For example], in the beginning, if [a patient] is in visceral crisis, then the only outcome that matters is objective response rate [ORR]. It’s OK to let that guide us, but if we have more indolent disease, among other [factors], the possibility of a treatment-free interval can rise in our prioritization. It is [acceptable] to, in addition to knowing the data, prioritize some of the outcomes differently for different patients.”

During an OncLive Peer Exchange filmed during ASCO GU, expert investigators discussed significant updates in the RCC space from the meeting and beyond. They highlighted data from final analyses of CheckMate 9ER and COSMIC-313, discussed treatment selection considerations for patients with treatment-naive disease, and looked forward to results from clinical trials of the investigational agents HC-7366 and CBM588 in the frontline, second line, and beyond.

Nivolumab Forms Basis of Frontline IO Combinations

In first-line RCC, the FDA has approved nivolumab (Opdivo) as a component in 2 combination regimens.1,2 The first was in April 2018, when frontline nivolumab plus ipilimumab (Yervoy) was approved for patients with intermediate- or poor-risk advanced RCC. In January 2021, nivolumab plus cabozantinib (Cabometyx) was approved in the first line. The approvals were supported by findings from the phase 3 CheckMate 214 (NCT02231749) and CheckMate 9ER trials, respectively.

“We have all of these immunotherapy [IO]–based combinations approved in frontline RCC, but the one that revolutionized the field was [investigated in] CheckMate 214 because [that study] led to the approval of the first IO-based combination and, to date, the only IO/IO regimen in treatment-naive metastatic RCC,” Moshe Ornstein, MD, MA, commented.

At a median follow-up of 99.1 months (range, 91.0-107.3), longterm follow-up data from CheckMate 214 showed that patients who received nivolumab plus ipilimumab (n = 550) achieved a median overall survival (OS) of 52.7 months (95% CI, 45.8-64.5) vs 37.8 months (95% CI, 31.9-43.8) among 546 patients who received sunitinib (Sutent; HR, 0.72; 95% CI, 0.62-0.83).3 The 90-month OS rates were 35.1% vs 24.9%, respectively. The median progression-free survival (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).

“Perhaps the most interesting of the updates with this 8-year follow-up is in the favorable-risk population,” Ornstein added. “Originally, the [FDA] approval was for [patients at] intermediate and poor risk, and in the National Comprehensive Cancer Network [NCCN] guidelines, it was a preferred regimen in intermediate- and poor-risk [disease]. But with additional follow-up, we noticed the curves split at approximately 48 months in favor of nivolumab plus ipilimumab, with a median OS in the favorable-risk population of approximately 78 months for the patients who received nivolumab plus ipilimumab vs [approximately] 67 months for [patients at favorable risk who received sunitinib]. The HR was 0.82, although the CI crossed 1. However, it is now one of the preferred regimens in the NCCN guidelines, even in favorable-risk [disease].”

During ASCO GU, investigators presented findings from a post hoc analysis of CheckMate 214, which evaluated kidney injury molecule-1 (KIM1) as a prognostic and predictive biomarker in advanced RCC.4 Patients in both the investigational and control arms with high baseline KIM-1 levels experienced worse OS outcomes than those with low (HR, 2.74; 95% CI, 2.14-3.52) or medium (HR, 2.05; 95% CI, 1.62-2.59) baseline levels. Additionally, patients with high baseline KIM-1 in both arms also had worse PFS than patients with KIM-1 low (HR, 1.53; 95% CI, 1.18-1.97) or KIM-1 medium (HR, 1.57; 95% CI, 1.21-2.03) levels.

The panelists then discussed the final follow-up results of CheckMate 9ER presented during ASCO GU.5 At a median follow-up of 67.6 months (range, 60.2-80.2) in the intention-to-treat population, the median PFS in the nivolumab plus cabozantinib (n = 323) and sunitinib (n = 328) arms was 16.4 months (95% CI, 12.5-19.3) and 8.3 months (95% CI, 7.0-9.7), respectively (HR, 0.58; 95% CI, 0.49-0.70). The 60-month PFS rates were 13.6% and 3.6%, respectively. The median OS was 46.5 months (95% CI, 40.6-53.8) and 35.5 months (95% CI, 29.2-42.8), respectively (HR, 0.79; 95% CI, 0.65-0.96); the 60-month OS rates were 40.9% and 35.4%, respectively.

“Cabozantinib is one of the preferred TKIs [tyrosine kinase inhibitors], and in the refractory setting, we see a lot of combinations using it as a backbone,” Pedro C. Barata, MD, MSc, FACP, noted.

Wulff-Burchfield added, “My overall impression [of the CheckMate 9ER update] was that it was very affirming to the data we have seen previously. This regimen is clearly superior to sunitinib [in terms of PFS]. One thing that stands out to me is how the hazard ratio is evolving in a different direction for patients with favorable-risk disease[compared with what we saw in] CheckMate 214. [These data] affirm that these are VEGF-driven tumors. Sunitinib is VEGF targeted, as is cabozantinib, even though cabozantinib has a broader mechanism of action. [These data] do not give us an obvious solution of a one-size-fits-all approach for our favorable-risk patients, but they certainly cement [this regimen] in the canon for first-line [therapy] in the overall population.”

In COSMIC-313, investigators added cabozantinib to ipilimumab and nivolumab in the frontline RCC setting.6 Patients were randomly assigned 1:1 to receive the triplet (n = 428) or placebo plus nivolumab and ipilimumab (n = 427). The primary end point was PFS per RECIST 1.1 and OS is the secondary end point.

Data from the final analysis presented during ASCO GU demonstrated that patients who received the triplet achieved a median PFS of 16.6 months (95% CI, 14.0-22.6) vs 11.2 months (95% CI, 9.3-14.0) for those in the placebo arm (HR, 0.82; 95% CI, 0.69-0.98). The 24-month PFS rates were 44% and 37%, respectively. The median OS was 41.9 months (95% CI, 34.8-47.9) with the triplet vs 42.0 months (95% CI, 34.9-53.1) with placebo (HR, 1.02; 95% CI, 0.85-1.23; P = .08366). The 36-month OS rate in both arms was 54%.

Following encouraging data from the phase 2 LITESPARK-003 (NCT03634540) and phase 1/2 LITESPARK-024 (NCT05468697) studies, which examined the HIF-2α inhibitor belzutifan (Welireg) in combination with cabozantinib or palbociclib (Ibrance), respectively, investigators have initiated the phase 3 LITESPARK-012 study (NCT04736706) to evaluate belzutifan as a triplet component.7 The trial is examining pembrolizumab (Keytruda) plus lenvatinib (Lenvima) with or without belzutifan or quavonlimab for the frontline treatment of patients with advanced clear cell RCC (ccRCC).

LITESPARK-012 is an open-label, multicenter study that will enroll approximately 1653 adults with advanced or metastatic ccRCC with measurable disease per RECIST 1.1 and a Karnofsky performance score of at least 70%. Eligible patients will be randomly assigned 1:1:1 to receive belzutifan plus pembrolizumab and lenvatinib (arm A); coformulated pembrolizumab and quavonlimab plus lenvatinib (arm B); or pembrolizumab plus lenvatinib (arm C). The coprimary end points are PFS and OS per RECIST 1.1 in arms A vs C and B vs C.

“We have learned a lot about how to manage adverse effects in a triplet arm,” Katy E. Beckermann, MD, said. “We might see better exposure to the TKI and get better benefits. I’m excited to see [LITESPARK-012] read out. All of us want to see more cures in the frontline. There are a couple of [other] ongoing frontline trials that are about to start [enrolling] looking at triplet combinations of various immunotherapy regimens. I am looking forward to seeing those open and start enrolling.”

When selecting a treatment regimen in the frontline, Ornstein noted that patients with a visceral crisis who need an immediate response should usually be treated with an IO/TKI combination. He added that PD-L1 testing is largely not appropriate when selecting a frontline regimen; he often chooses the CheckMate 214 regimen for patients with sarcomatoid features because of poor historical outcomes with TKI therapy in this population.

“[In patients without] clear sarcomatoid histology, I’m not convinced that any of these IO/TKI regimens are better for any specific site of disease,” Ornstein explained. “Lenvatinib plus pembrolizumab has good data in [metastases of the] liver and bone, [as does] cabozantinib. We’re trying to tease out these subgroup analyses to see if we can determine which specific regimen can target which specific disease [type]. In summary, in sarcomatoid disease, I’m leaning toward an IO/IO combination. If patients need an [immediate] response, I’m giving an IO/TKI, focusing on [which] TKI [is appropriate for] a specific patient and for the favorable-risk population, I’m comfortable using all of them. I appreciate that ipilimumab plus nivolumab is now in the NCCN guidelines [in the favorable-risk group] because it makes it more available from an insurance perspective.”

Novel Agents Attract Attention in Multiple Disease Settings

Following their discussion of the frontline treatment landscape, the panelists shifted their conversation to highlight ongoing clinical trials of the investigational agents HC-7366 and CBM588. HC-7366 is a first-in-class GCN2 serine/threonine kinase activator, which investigators hypothesize can be combined with belzutifan to treat patients with ccRCC who experience disease progression.8 CBM588 is a live bacterial agent containing a strain of Clostridium butyricum, which has shown the potential to boost clinical outcomes in combination with immune checkpoint inhibition.9

HC-7366 is being evaluated as monotherapy and in combination with belzutifan in patients with advanced or metastatic ccRCC in a phase 1b study (NCT06234605).8 To be eligible for the monotherapy arm, patients must have received 1 to 4 prior lines of therapy, including belzutifan or another HIF-2α inhibitor. In the combination arm, patients need to have received 1 to 3 prior lines of therapy for metastatic disease, including at least 1 anti–PD-1/anti– PD-L1 agent and a VEGF TKI. The primary end points are establishing the maximum tolerated and recommended phase 2 doses, and safety and tolerability. At the time of ASCO GU, enrollment was ongoing into 2 combination cohorts and a monotherapy cohort.

In another phase 1 trial (NCT06399419), CBM588 is being examined in combination with nivolumab and ipilimumab in adult patients with metastatic RCC with a clear cell or sarcomatoid component who have received no prior systemic therapy for RCC beyond 1 prior adjuvant/neoadjuvant therapy for resectable RCC.9 The primary objective is to determine the regimen’s safety and tolerability, and efficacy will be secondarily assessed.

CBM588 is also under evaluation in combination with cabozantinib and nivolumab in another phase 1 trial (NCT05122546); the study is enrolling patients with treatment-naive RCC with a clear cell, papillary, and/or sarcomatoid component.10 Patients were randomly assigned 2:1 to receive the triplet (n = 20) or cabozantinib plus nivolumab (n = 10).

Updated study data presented at ASCO GU showed that patients in the investigational arm achieved a median PFS of 19.7 months compared with 13.4 months in the control arm (HR, 0.74; 95% CI, 0.25-2.23; P = .59). Moreover, the ORRs were 84% and 20%, respectively. The study authors added that there were no additional toxicity signals and that the further development of CBM588 should be prioritized.

“We’ve seen data regarding antibiotic use for patients with RCC and how that impacts not only their gut microbiome but their efficacy outcomes as well,” Wulff-Burchfield said. “I’m looking forward to hearing more from [these studies of CBM588].”

References

1. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. FDA. April 16, 2018. Accessed March 13, 2025. https://www. fda.gov/drugs/resources-information-approved-drugs/fdaapproves-nivolumab-plus-ipilimumab-combination-intermediateor-poor-risk-advanced-renal-cell
2. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. FDA. January 22, 2021. Accessed March 13, 2025. https://www.fda.gov/drugs/resources-informationapproved-drugs/fda-approves-nivolumab-plus-cabozantinibadvanced-renal-cell-carcinoma
3. Tannir NM, Albigès L, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 8-year follow-up results of efficacy and safety from the phase III CheckMate 214 trial. Ann Oncol. 2024;35(11):1026-1038. doi:10.1016/j. annonc.2024.07.727
4. Xu W, Vemula SV, Motzer R, et al. Evaluation of circulating kidney injury marker-1 (KIM-1) as a prognostic and predictive biomarker in advanced renal cell carcinoma (aRCC): post-hoc analysis of CheckMate 214. J Clin Oncol. 2025;43(suppl 5):437. doi:10.1200/JCO.2025.43.5_suppl.437
5. Motzer R, Escudier B, Burotto M, et al. Nivolumab plus cabozantinib (N+C) vs sunitinib (S) for previously untreated advanced renal cell carcinoma (aRCC): final follow-up results from the CheckMate 9ER trial. J Clin Oncol. 2025;43(suppl 5):439. doi:10.1200/JCO.2025.43.5_suppl.439
6. Albiges L, Motzer R, Trevino S, et al. Cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC): final results of COSMIC-313. J Clin Oncol. 2025;43(suppl 5):438. doi:10.1200/ JCO.2025.43.5_suppl.438
7. Choueiri TK, Powles T, Voss MH, et al. LITESPARK-012: pembrolizumab plus lenvatinib with or without belzutifan or quavonlimab for advanced renal cell carcinoma. Future Oncol. 2023;19(40):2631-2640. doi:10.2217/fon-2023-0283
8. Shah N, Bupathi M, Garmezy B, et al. A phase 1b, open-label, safety, tolerability, and efficacy study of HC-7366 in combination with belzutifan in patients with advanced or metastatic renal cell carcinoma (NCT06234605). J Clin Oncol. 2025;43(suppl 5):TPS609. doi:10.1200/JCO.2025.43.5_suppl.TPS609
9. Agarwal R, Ebrahimi H, Zengin ZB, et al. Dose finding study of CBM588 in combination with nivolumab and ipilimumab in patients with metastatic renal cell carcinoma: a phase I study. J Clin Oncol. 2025;43(suppl 5):TPS611. doi:10.1200/ JCO.2025.43.5_suppl.TPS611
10. Ebrahimi H, Meza LA, Dizman N, et al. Cabozantinib (cabo) and nivolumab (nivo) with or without CBM588 in patients with metastatic renal cell carcinoma: updated clinical outcomes of a phase I study. J Clin Oncol. 2025;43(suppl 5):543. doi:10.1200/ JCO.2025.43.5_suppl.543