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Background Although treatment options and survival of HER2+ metastatic breast cancer (MBC) patients have greatly improved, the majority of MBC-patients still die of this disease. The relatively high levels of TILs observed in this BC subtype provide a rationale for immunomodulatory strategies, however, PD1-blockade has only shown modest response rates in this setting. While PD-1 blockade mainly acts on T cells, monalizumab targets the inhibitory immune checkpoint NKG2A which interacts with HLA-E on tumor cells, thereby unleashing NK- as well as CD8 T cells. We hypothesize that monalizumab can promote antibody-dependent cell-mediated cytotoxicity (ADCC) which is critical for trastuzumab efficacy. Clinical activity was shown in patients with head and neck cancer when monalizumab was combined with cetuximab (anti-EGFR). Here, we present the first results of the MIMOSA-trial investigating the efficacy of the novel combination monalizumab and trastuzumab in patients with HER2+ MBC. Methods In the phase II MIMOSA-trial (NTC04307329), HER2+ MBC patients were treated biweekly with 4mg/kg trastuzumab and 750mg monalizumab. Key eligibility criteria were progressive disease despite anti-HER2 therapy, had received a minimum of one and a maximum of three lines of palliative chemotherapy, had measurable disease according to RECIST1.1, and a serum LDH-level below 500U/L. Primary endpoint was objective response rate according to RECIST1.1. Secondary endpoints included clinical benefit rate (complete response CR, partial response PR or stable disease SD for at least 6 months) according to RECIST1.1, progression-free survival, overall survival and safety. Dose-limiting toxicities were continuously monitored throughout the trial and evaluated using a pre-defined Pocock-type boundary rule. Following a Simon’s two-stage design, 11 patients were included in stage I of the trial. If two or more responders were observed, further exploration is warranted in stage II. Results Between January 2021 and April 2022, eleven women of which ten are currently evaluable were enrolled in the trial. Patients received a median of two lines of prior treatment for MBC, of which 6 out of 11 patients were treated with trastuzumab emtansine (T-DM1). The majority of patients had hormone receptor positive BC (72% of the patients) and had low levels of tumor-infiltrating lymphocytes (TILs) with a median of 1% (ranging from 1% to 20%). Patients received a median of four cycles of trastuzumab and monalizumab. Treatment was well tolerated with no dose-limiting toxicities. No objective responses were observed in the first ten out of eleven evaluable patients. Therefore, MIMOSA stage I did not meet its primary endpoint, leading to discontinuation of the trial. Conclusions The novel combination of trastuzumab and monalizumab did not induce objective responses in heavily pre-treated HER2+ MBC patients. Citation Format: Veerle Geurts, Leonie Voorwerk, Karolina Sikorska, Roberto Salgado, Koen van de Vijver, Marloes van Dongen, Inge Kemper, Ingrid A. Mandjes, Martine Heuver-mes, John Haanen, Gabe S. Sonke, Hugo Horlings, Marleen Kok. Unleashing NK- and CD8 T cells by combining monalizumab (anti-NKG2A) and trastuzumab for metastatic HER2+ breast cancer: first results MIMOSA trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-06-01.

Given the success of immunotherapy in treating patients with metastatic disease in a variety of tumor types, there is tremendous enthusiasm for expanding the use of immunotherapy to those with early-stage cancer. Administering immunotherapy in the neoadjuvant, preoperative setting is a biologically sound approach because preclinical studies have shown that stronger and broader immune responses can be generated if immunotherapy is administered while the tumor and/or draining lymph nodes are intact. It is therefore likely that administering immunotherapy preoperatively will generate optimal immune responses, leading to high rates of pathologic response as well as improved long-term survival. Although neoadjuvant immunotherapy is currently only approved for use in combination with chemotherapy in triple-negative breast cancer and non–small cell lung cancer, it is anticipated that ongoing and future clinical trials will further define the role of neoadjuvant immunotherapy in many cancer types. These trials should be designed with appropriate survival endpoints and rigorous correlative studies to include imaging and biospecimen-based analyses to address currently unanswered questions that must be resolved to optimize the use of immunotherapy in early-stage disease.

Background T-cell receptor (TCR-T) therapies are based on the expression of an introduced TCR targeting a tumor associated antigen (TAA) which has been studied in several trials in cutaneous melanoma. We conducted a systematic review and meta-analysis aiming to assess the primary efficacy of TCR-based adoptive cell therapy in cutaneous melanoma. Methods We searched through PubMed electronic database from its inception until May 21, 2022. Primary endpoints were pooled objective response rate (ORR) and disease control rate (DCR). We conducted logistic regression analyses to identify potential predictive factors for tumor response. Results From 187 patients, 50 showed an objective response (pooled ORR 28%; 95% CI, 20%-37%) and a pooled DCR of 38% (95% CI, 27%-50%). Median PFS was 2, 9 months (95% CI, 1.4-3.1). A trend toward higher PFS was demonstrated for patients treated with cancer/testis antigens targeting TCR-T cells (HR 0.91 95% CI, 0.64-1.3, P = .61) among whom, patients treated with NYESO-1 targeting TCR-T showed a significantly higher PFS (HR 0.63 95% CI, 0.64-0.98, P = .03). In addition, the number of infused cells was associated with a significantly higher likelihood of tumor response (OR 6.61; 95% CI, 1.68-21.6; P = .007). Conclusion TCR-T therapy shows promising results in terms of antitumor activity and survival similar to those reported for TILs with a significantly higher benefit for cancer/testis antigens targeting cells. Since TCR-based therapy shows advantages of great potential over classic ACT strategies, further research in solid cancers is warranted (PROSPERO ID CRD42022328011).

PURPOSE Both immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor (VEGFR) inhibitors are approved for advanced renal cell carcinoma treatment and can cause cardiovascular events (CVs); thus, combination therapy could lead to major adverse CV events (MACE). Cardiac serum biomarker assessment and imaging, including left ventricular ejection fraction (LVEF) monitoring, can be used to evaluate MACE. METHODS To our knowledge, the JAVELIN Renal 101 trial, assessing avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma, is the first randomized study of ICI plus VEGFR inhibitor treatment to include prospective serial cardiac monitoring of LVEF and serum cardiac biomarkers. RESULTS MACE (defined as grade ≥ 3 CV AEs) occurred in 31 patients (7.1%) in the combination arm and 17 patients (3.9%) in the sunitinib arm. Patients in the combination arm who had high baseline troponin T values were at higher risk of MACE versus patients with low values (MACE in 6/35 v 7/135, respectively; relative risk, 3.31; 95% CI, 1.19 to 9.22). This association was not observed in patients treated with sunitinib. Other CV baseline risk factors and serum cardiac biomarkers were not significantly predictive for MACE, although a trend toward an association with dyslipidemia was seen in the combination arm. No clinical value of on-treatment routine monitoring of LVEF in relation to MACE was observed. Although LVEF decline was significantly more frequent in the combination arm, most patients recovered, and decline was not associated with other significant cardiac events or symptoms. CONCLUSION Patients with high baseline troponin T levels receiving ICI and VEGFR combinations may need to be monitored more closely for MACE. Routine monitoring of LVEF in asymptomatic patients is not recommended.

In the past 20 years we have seen the rise of a new era of cancer research that moved its focus away from the cancer cell itself and revealed a complexity of interactions, both within the tumor and with the host, that ultimately dictate the evolution and progression of the disease. We have witnessed the development of immunotherapies that changed the fate of many patients and new diagnostic strategies with the potential of changing clinical practice. In this article, several experts discuss what lies ahead.

Cytomegalovirus (CMV) infection/disease has been repeatedly reported in patients treated with immune-checkpoint inhibitors (ICIs) and most commonly involves patients with relapsed/refractory (R/R) immune-related adverse events (irAEs). In the current study, we present a patient with melanoma who developed CMV gastritis during treatment with pembrolizumab in the absence of irAEs and without previous or current immunosuppression. Moreover, we review the literature regarding CMV infection/disease in patients treated with ICIs for solid malignancies. We present the currently available data on the pathogenesis, clinical characteristics, endoscopic findings, and histologic features and highlight the potential differences among cases complicating R/R irAEs versus those occurring in patients who are immunosuppression naive. Finally, we discuss the currently available data regarding potential useful diagnostic tools as well as the management of these patients.

Purpose Patients with advanced melanoma refractory to first-line treatment have a need for effective second-line treatment options. A recent phase 3 trial showed promising results for adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) as second-line therapy in patients with advanced melanoma. However, it remains unknown how patients and their partners experience TIL therapy, which is key to evaluate and improve the quality of care. Methods Semi-structured interviews about the experience of TIL therapy were conducted with patients with advanced melanoma and their partners 2-4 weeks post-treatment (short-term) and >6 months after treatment (long-term). Results In total, 25 interviews were conducted with advanced melanoma patients treated with TIL (n=13) and their partners (n=12), with the majority being short-term interviews (n=17). Overall, patients and partners experienced TIL therapy as intense (uncertainty of successful TIL culture, multiple treatment-related toxicities, and extensive hospitalization). Patients and partners with young children or other caregiving responsibilities encountered the most challenges during TIL therapy. All patients, however, reported a recovery of all treatment-related toxicities within 2-4 weeks (except fatigue). Conclusion Clinical data justify the role of TIL therapy in the treatment of advanced melanoma. With the distinct nature of TIL therapy compared to the current standard of care, we have provided patient-centered recommendations that will further enhance the quality of TIL therapy. Implications for Cancer Survivors As more patients with advanced melanoma are expected to receive TIL therapy in the future, our findings could be incorporated into survivorship care plans for this novel group of advanced melanoma survivors treated with TIL. Implications for Cancer Survivors As more patients with advanced melanoma are expected to receive TIL therapy in the future, our findings could be incorporated into survivorship care plans for this novel group of advanced melanoma survivors treated with TIL.

Marching into the second decade after the approval of ipilimumab, it is clear that immune checkpoint inhibitors (ICIs) have dramatically improved the prognosis of melanoma. Although the current edge is already high, with a 4-year OS% of 77.9% for adjuvant nivolumab and a 6.5-year OS% of 49% for nivolumab/ipilimumab combination in the metastatic setting, a high proportion of patients with advanced melanoma have no benefit from immunotherapy, or experience an early disease relapse/progression in the first few months of treatment, surviving much less. Reasonably, the primary and acquired resistance to ICIs has entered into the focus of clinical research with positive (e.g., nivolumab and relatlimab combination) and negative feedbacks (e.g., nivolumab with pegylated-IL2, pembrolizumab with T-VEC, nivolumab with epacadostat, and combinatorial triplets of BRAF/MEK inhibitors with immunotherapy). Many intrinsic (intracellular or intra-tumoral) but also extrinsic (systematic) events are considered to be involved in the development of this resistance to ICIs: i) melanoma cell immunogenicity (e.g., tumor mutational burden, antigen-processing machinery and immunogenic cell death, neoantigen affinity and heterogeneity, genomic instability, melanoma dedifferentiation and phenotypic plasticity), ii) immune cell trafficking, T-cell priming, and cell death evasion, iii) melanoma neovascularization, cellular TME components(e.g., T

Background: Significant advancements, including development of immune checkpoint inhibitors and targeted therapies, have transformed outcomes in patients (pts) with unresectable or metastatic melanoma. However, pts who do not respond or who progress while receiving these regimens have limited options. Spartalizumab (PDR001) is a high-affinity, humanized monoclonal antibody blocking the programmed cell death 1 (PD-1) receptor. This study is evaluating combinations of spartalizumab with novel compounds to restore antitumor T-cell activity in pts with melanoma progressing after prior PD-1 blockade therapy. Methods: This randomized, open-label, 2-part, multicenter, open-platform, Phase II study (NCT03484923; PLATforM) will evaluate the safety and efficacy of spartalizumab combination treatment in pts with unresectable or metastatic melanoma progressing after prior anti-PD-1/L1 therapy and, if the tumor harbors a BRAF V600 mutation, a BRAF inhibitor. The primary endpoint is objective response rate per RECIST v1.1, with duration of response and assessment of paired tumor biopsies for biomarkers of antitumor T-cell activity as part of the secondary endpoints. Part 1, “selection”, will begin with 3 combination arms: (1) spartalizumab + LAG525 (LAG-3 antibody), (2) spartalizumab + capmatinib (c-MET inhibitor), and (3) spartalizumab + canakinumab (IL-1β antagonist). The PLATforM study will use an adaptive design during the selection part that allows for dropping arms for futility, adding new arms, and selecting 1 or multiple arms for further expansion. Bayesian methodology will be used with specific probability criteria for futility and efficacy assessments at each interim analysis. Pts (≈ 60-85) will be stratified by baseline lactate dehydrogenase level and randomized equally to all open arms during the selection part. Part 2, “expansion”, will further investigate the efficacy and safety of treatment combination(s) selected during part 1. The sample size for part 2 will be adaptive and based on predictive power calculations considering the results from part 1. Previously presented at ESMO 2018, FPN 1304TiP, Weber et al. Reused with permission. Citation Format: Caroline Robert, Reinhard Dummer, Ana Arance, Antoni Ribas, Jeffrey Weber, Georgina V. Long, John Haanen, Paul Nathan, Paolo A. Ascierto, Eduard Gasal, Anthony D'Amelio, Severine Bettinger, Aislyn D. Boran, Dirk Schadendorf. A randomized, open-label, open-platform, Phase II study evaluating the efficacy and safety of novel spartalizumab (PDR001) combinations in previously treated unresectable or metastatic melanoma (PLATforM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT120.