Aaron S. Mansfield MD

Malignant pleural mesothelioma (MPM) is an inexorably progressive and almost universally fatal malignancy.¹ The vast majority of cases are associated with exposure to fibrous minerals, specifically asbestos or erionite fibers. In addition, prior thoracic radiation therapy² and germline loss of function BAP1 mutations³ have also been linked to the development of MPM. With the continued use of asbestos products in many countries, the incidence of MPM continues to rise worldwide, causing an estimated 43,000 deaths annually.⁴

Effective treatment options are largely lacking. The role of surgery and standard multimodality therapy remains controversial and may only benefit highly selected patients.^5,6 Folate antimetabolite-based chemotherapy, the current standard of care, has modest benefits and has been shown to improve overall survival by approximately 3 months.⁷ Chemotherapy provides even less of a benefit for patients with sarcomatoid subtypes of MPM.⁸

Recently, immunotherapies have been shown to be effective for the treatment of metastatic melanoma and prostate cancer and are now approved by the Food and Drug Administration (FDA) for these diseases. In MPM, a number of isolated cases demonstrate that immune-mediated mechanisms can effectively target this tumor. Consequently, immunotherapeutic strategies are felt to represent an attractive alternative for the treatment of MPM. The complexity of the immune system allows for many ways to therapeutically modulate anti-tumor immunity. A comprehensive review of the immunologic therapies tested in MPM is beyond the scope this focused review, but can be found elsewhere.⁹

This review specifically focuses on the therapeutic modulation of immune checkpoints for the treatment of MPM. Despite the ability of the immune system to recognize tumors, effective anti-tumor immune responses are blunted by many immunosuppressive mechanisms.¹⁰ In addition to successful T-cell receptor and major histocompatibility complex binding (signal 1), effective T-cell activation against self, tumor, and foreign antigens also depends on activating costimulatory signals (signal 2), and the presence of effector cytokines (signal 3). Immune activation is controlled by negative costimulatory signals, immune checkpoints. Immune checkpoints are critical to maintain the delicate balance between effective antimicrobial responses, self-tolerance, and prevention of autoimmunity. The two most characterized immune checkpoints are the cytotoxic T-lymphocyte antigen-4 (CTLA-4) - CD80/CD86 (B7-1/B7-2) checkpoint, and programmed cell death 1 (PD-1) - programmed cell death ligand 1 (PD-L1, B7-H1) - programmed cell death ligand 2 (PD-L2, B7-DC). Both of these pathways have been implicated in tumor-mediated suppression of anti-tumor immunity.

CTLA-4 Inhibition

CTLA-4 is a surface receptor expressed on T lymphocytes. CTLA-4 inhibits the costimulatory interaction between CD28 on T cells and CD80/CD86 on antigen-presenting cells by sequestering CD80/CD86 because of its higher binding affinity. Two human monoclonal antibodies targeting CTLA-4, ipilimumab (Yervoy, IgG1) and tremelimumab (IgG2), have been developed to disrupt CTLA-4 - CD80/CD86 binding and have been or are being studied for the treatment of solid tumors. The FDA approved ipilimumab for metastatic melanoma after an objective response rate of 10.9% and a median overall survival of 10.1 months were demonstrated in a subsequent clinical trial.¹¹ Tremelimumab, by comparison, in the first-line setting for metastatic melanoma, demonstrated an objective response rate of 10.7% and a median overall survival of 12.6 months.¹² Tremelimumab has demonstrated promising activity in MPM.¹³ In a phase II trial, including 29 pretreated patients with pleural and peritoneal mesothelioma, treatment with tremelimumab resulted in 3 objective responses, 2 up front and 1 after initial progression. In addition, disease stabilization occurred in 9 patients. Overall survival was very encouraging in this population, 48.3% and 36.7% at 1 and 2 years, respectively. Consequently, tremelimumab is being studied in ongoing clinical trials (NCT01655888, NCT01843374). Unfortunately, there are no predictive biomarkers to identify responders to CTLA-4 blockade. In some studies, patients with low levels of vascular endothelial growth factor were more likely to benefit from ipilimumab for the treatment of metastatic melanoma,¹⁴ but this relationship remains to be explored in MPM. Similar to the retrospective analysis of patients with metastatic melanoma who were treated with ipilimumab,¹⁵ an increase in the number of CD4⁺ICOS⁺ T lymphocytes after the initiation of therapy was associated with improved survival in MPM patients treated with tremelimumab. However, baseline levels of CD4⁺ICOS⁺ T lymphocytes were not predictive of treatment benefit.¹³ Further clinical trials, including correlative studies to develop predictive biomarkers, are needed to define the role of CTLA-4 blockade in the treatment of MPM.

Programmed cell death 1 (PD-1) is another immune checkpoint receptor expressed on T-cell lymphocytes. Both of its ligands, PD-L1/(B7-H1) and PD-L2/(B7-DC), have homology with the B7 family of costimulatory molecules. Upon its discovery in peripheral blood monocytes, PD-L1 was shown to negatively regulate T cells through IL-10 production.¹⁶ Subsequently, it became clear that PD-L1 (B7-H1) inhibits T-cell proliferation by engagement of PD-1,¹⁷ and consequently it is now mostly referred to as PD-L1. PD-L1 is normally expressed by antigen-presenting cells where it controls immune activation. Tumor cells can aberrantly express PD-L1, and the engagement of PD-L1 with PD-1 within the tumor microenvironment induces apoptosis of tumor-specific T-cells.¹⁸ Another ligand for PD-1, PD-L2 (B7-DC), also inhibits T-cell receptor mediated proliferation.¹⁹ Expression of PD-L1 by tumor cells has been correlated with worse survival in many malignancies, including various forms of renal cell carcinoma,^20-23 and MPM.²⁴ In MPM, PD-L1 (as defined by 5% or greater expression by tumor cells) was detected in 40% of cases, including almost all sarcomatoid mesotheliomas except for 1 desmoplastic tumor. PD-L1 expression remained associated with poor survival following multivariate analysis adjusting for subtype, extent of disease, and age.

Future of PD-1 blockade in MPM

Some antibodies have been developed to inhibit the PD-1/PD-L1 axis and have been tested primarily in melanoma, renal cell carcinoma, and non-small cell lung cancer (NSCLC),^25,26 but some early-phase clinical trials have included patients with MPM (eg, NCT01772004 with the PD-L1 inhibitor MSB0010718C), and a phase II clinical trial is planned in MPM.²⁷ Ongoing clinical trials and other translational studies foreshadow the potential difficulties in targeting the PD-1/PD-L1 axis in MPM. The most mature data for the use of anti-PD-1 therapy are available for metastatic melanoma.^28,29 In fact, the FDA recently approved the fully humanized IgG4 anti-PD-1 antibody pembrolizumab for the treatment of melanoma in the US. A separate anti-PD-1 antibody, nivolumab, was approved in Japan also for the treatment of metastatic melanoma, and received clearance from the FDA in December 2014. One study suggests that response to therapy is enriched in patients whose tumors express PD-L1,²⁵ however, several issues obfuscate our understanding of these data.

First, while there are numerous antibodies marketed for the detection of PD-L1 by immunohistochemistry, their diagnostic performance has been highly inconsistent across laboratories. Available antibodies detect different epitopes of PD-L1. Recently, discordant patterns of PD-L1 expression in NSCLC were attributed to different affinities, cross reactivity, or variable expression of distinct target epitopes.³⁰

Second, tumor heterogeneity and sampling error may also affect detection of PD-L1. For example, although there are cases of diffuse PD-L1 expression, it can be very focal (ie, limited to the periphery of the tumor). Furthermore, the expression of PD-L1 is dynamic. While interferon-a is well known to upregulate PD-L1 expression,¹⁸ many other therapies may also affect PD-L1 expression. For example, doxorubicin was found to downregulate cell surface expression of PD-L1 in breast cancer cell lines and xenografts,³¹ whereas paclitaxel and etoposide increased PD-L1 cell surface expression in breast cancer cell lines.³² PD-L1 expression was upregulated by MAP-kinase activation in melanoma cells resistant to BRAF inhibition,³³ and in an epidermal growth factor receptor (EGFR) mutant model of NSCLC, where EGFR inhibition downregulated expression.³⁴ Accordingly, the choice of the antibody for PD-L1 detection, the timing of biopsy, sampling error, and prior and concurrent therapies may affect PD-L1 expression and its detection. While the FDA has not required a companion diagnostic test for the use of the PD-1 inhibitor pembrolizumab for the treatment of metastatic melanoma, reliable predictive biomarkers are needed. In addition, as we learn how other therapies affect PD-L1 expression we can begin to explore combinations of immune checkpoint inhibitors and other treatments.

Alternatives to the detection PD-L1 expression in biopsy specimens are also being explored. For example, circulating soluble PD-L1 may identify a subset of tumors expressing PD-L1. Circulating PD-L1 has been identified in the serum of patients with renal cell carcinoma, and is associated with more aggressive disease patterns.³⁵ Additionally, phenotypical changes of circulating T cells may indicate the presence of PD-L1 expression at the tumor site. One group of investigators suggested that the presence of circulating T cells co-expressing CD8, CD11a and PD-1 could be indicative of PD-L1 expression by the tumor. In their study, the level of Bim, a pro-apoptotic molecule, was significantly higher in these CD8⁺/CD11a⁺/PD-1⁺ cells compared to CD8⁺/CD11a⁺/PD-1^- cells in patients with metastatic melanoma and prostate cancer,³⁶ suggesting that Bim expression in these cells may be indicative of PD-1/PD-L1 interaction.

Measuring Responses

Immune checkpoint inhibitors also challenge the use of traditional response criteria. Shrinkage of tumors following checkpoint inhibition may be preceded by stable disease or transient pseudo-progression (tumor enlargement) from immune cell infiltration of tumor. This phenomenon is difficult for physicians to separate from progression of disease, and selected clinical trials now allow continuation of therapy as long as there is no symptomatic worsening (eg, NCT01905657). Ongoing research is focused on distinguishing tumor immune infiltration from tumor progression. For example, technetium-linked IL-2 single-photon emission computed tomography is being explored in patients with metastatic melanoma being treated with immunotherapy (NCT01789827). Detection of IL-2 receptor in this setting may help distinguish immune infiltration from tumor progression. Accordingly, this strategy may complement standard imaging modalities in the setting of progression on immune checkpoint inhibitors, providing a rationale to continue with immunotherapy when IL-2 receptor is detected at tumor sites.

Although we are just coming to understand the relevance of immune checkpoint blockade in many malignancies, we will see the exploration of these inhibitors in novel settings. While immune checkpoint blockade has primarily been tested in subsequent lines of therapy, trials for first-line therapy are being developed (NCT02041533) and may be worth exploring in MPM. Other clinical trials are exploring the possibilities of various combinations of immune checkpoint inhibitors. For example, combined anti-CTLA-4 and anti-PD-1 blockade was tested in metastatic melanoma and was associated with a higher response rate than seen with either agent alone.³⁷ In addition, clinical trials are testing PD-1 blockade with immune checkpoint inhibitors against lymphocyte activation gene 3 (LAG-3) (NCT01968109) and killer immunoglobulin receptor (KIR) (NCT01714739). Recent animal models have also shown that PD-1/PD-L1 axis blockade may enhance the effects of oncolytic virotherapy.³⁸ This strategy may be considered in future clinical trials in light of ongoing studies exploring the safety and efficacy of intrapleural viral therapy in MPM (NCT01503177 and NCT01721018).

Conclusion

Immune checkpoint inhibition represents a promising approach to the treatment of MPM. Larger studies to validate the degree of PD-L1 expression in MPM and to identify predictive biomarkers for anti-CTLA-4 and anti-PD1/PD-L1 therapy are needed. Overcoming difficulties with the detection of PD-L1, the modulation of PD-L1 expression, and improved assessment of treatment responses will enhance the utilization ofimmune checkpoint inhibition in MPM.

About the Authors:

Aaron S. Mansfield, MD, assistant professor of medicine and oncology, Department of Oncology, Division of Medical Oncology, Mayo Clinic, and Tobias Peikert, MD, assistant professor of medicine, Department of Internal Medicine and Department of Immunology, Division of Pulmonary and Critical Care Medicine, Mayo Clinic.

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18. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793-800.
19. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nature Immunol. 2001;2(3):261-268.
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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

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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
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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