11506 Background: Desmoid tumors (DT) are rare, locally aggressive tumors with few effective treatments. Varegacestat (VAR) is an investigational, once daily, oral gamma secretase inhibitor that previously showed antitumor activity in pts with DT in the RINGSIDE Phase 2 study. Methods: RINGSIDE Phase 3 was a double-blind, placebo (PBO)-controlled study in adults with progressing DT per RECIST v1.1 (NCT04871282). 156 pts were randomized 1:1 to once daily oral VAR 1.2 mg (n=79) or PBO (n=77). Imaging-based tumor response was assessed per RECIST v1.1 by blinded independent central review. The primary endpoint was progression-free survival (PFS). Alpha-controlled secondary endpoints were confirmed objective response rate (ORR), change in tumor volume (TV) at Week 24, and change in patient-reported worst pain intensity (WPI) at Week 12. Results: Demographics and disease characteristics were balanced between treatment arms. As of Oct 7, 2025, median duration of exposure was 20.3 months (range 0.8 – 34.6) for VAR and 11.1 months (range 0.2 – 34.6) for PBO. VAR demonstrated significantly better PFS compared with PBO (hazard ratio [HR]: 0.16 [95% CI: 0.07, 0.38; P <0.0001]). PFS consistently favored VAR in all subgroups analyzed. ORR was significantly better with VAR vs PBO (55.7% vs 9.1%; P <0.0001), with 3 CRs in the VAR arm and 1 CR in the PBO arm. Median duration of response was not reached in either arm. All alpha-controlled secondary endpoints demonstrated statistically and clinically significant superiority for VAR compared with PBO (Table). Overall, 95% of adverse events (AEs) were Grade 1-2 and there were no Grade 5 AEs. Grade 3/4 AEs were reported in 57% of VAR pts and 17% of PBO pts. AEs led to dose reduction in 63 (80%) VAR pts and 7 (9%) PBO pts; 16 (20%) VAR pts and 5 (7%) PBO pts discontinued due to AEs. In the VAR arm, the most frequently reported AEs were diarrhea (82%), fatigue (44%), and rash (43%). Ovarian toxicity occurred in 20/36 (56%) premenopausal women on VAR, resolved in 11/20 (55%), and did not lead to dose interruption or drug withdrawal. Conclusions: VAR demonstrated statistically significant and clinically meaningful antitumor activity and pain relief, achieving the highest ORR reported in a Phase 3 trial of systemic DT therapy, with no new safety signals. Clinical trial information: NCT04871282 . RINGSIDE phase 3 trial outcomes. VAR (n=79) PBO (n=77) HR (95% CI) or Difference; P value Median PFS (95% CI) - radiographic, months NE (NE, NE) 24.9 (13.8, NE) 0.16 (0.07, 0.38); P<0.0001 Confirmed ORR, n (%) 44 (55.7) 7 (9.1) P<0.0001 TV change (cm 3 ) at Week 24, LS mean (SE) -109.6 (40.64) 122.8 (42.72) -232.4 (57.39); P<0.0001 WPI (pain) change at Week 12, LS mean (SE) -2.24 (0.27) 0.18 (0.27) -2.42 (0.37); P<0.0001 Median best % change in TV* -83.4 11.3 * 1-year PFS, % (95% CI)* 94.2 (85.3, 97.8) 65.6 (52.3, 76.0) * 2-year PFS, % (95% CI)* 88.9 (77.9, 94.6) 56.7 (42.6, 68.6) * LS, least square; SE, standard error. *Not alpha-controlled endpoint.

BACKGROUND:Retroperitoneal sarcoma (RPS) encompasses a heterogenous group of rare malignancies that develop in the back of the abdomen. For localized primary disease, the mainstay of treatment is surgery. Beyond the primary site, patterns of disease manifestation vary by histologic type and include visceral organ metastasis, as well as intraabdominal multifocal disease. Although cure is extremely rare, some patients may still derive significant benefit from treatment. METHODS:A comprehensive literature search was performed and international, key opinion leaders for RPS met together to discuss principles of practice for multifocal and metastatic disease, summarized in 45 statements, each given a level of evidence and grade of recommendation. RESULTS:Patients should be evaluated in a multidisciplinary sarcoma center with experience in RPS and recognition of histologic type is critical to guide management. After pretreatment assessment that includes imaging and pathology review, the goals of treatment should be clarified upfront and aligned with the anticipated ability for the patient to tolerate treatment. Disease biology (e.g., disease-free interval) should be thoroughly understood. Treatment modalities can include a combination of surgery, non-surgical local therapy (radiation therapy, percutaneous tumor ablation and embolization) and systemic therapy. CONCLUSIONS:This updated consensus document gives comprehensive and practical clinical guidance to providers for the management of multifocal and metastatic RPS. The current document also serves as the foundation for future clinical and translational investigation, as we continue to optimize patient care in these complex and challenging cases.

Background:With negligible risk of distant metastasis, the primary treatment focus in patients with primary retroperitoneal well-differentiated liposarcoma (pRP-WDLPS) is local control. The recently completed phase 3 STRASS trial suggested a potential benefit to neoadjuvant radiotherapy (RT) in optimizing local control in these patients. This study investigates outcomes associated with neoadjuvant RT in a larger cohort of patients undergoing surgery for pRP-WDLPS. Methods:In this study from 24 participating sites, we retrospectively identified all patients with pRP-WDLPS who underwent curative-intent resection between January 1, 2002 and December 31, 2017. The primary endpoint was the cumulative incidence function (CIF) of local recurrence (LR), and the secondary endpoint was overall survival (OS). The impact of neoadjuvant RT on the CIF of LR was analyzed using a 1:2 propensity score matching (PSM). Findings:Of 582 patients included in the entire cohort, 72 patients (12%) received neoadjuvant RT. The 1:2 PSM group included 208 patients of which 138 patients (66%) underwent surgery alone and 70 patients (34%) underwent neoadjuvant RT and surgery. With a median follow up of 73 months, the 5- and 8-year CIF of LR for neoadjuvant RT and surgery group was 6% and 10%, respectively, and 26% and 33%, respectively, for the surgery alone group (odds ratio (OR) 0·85, 95% confidence interval (CI) 0·76-0·97, P < 0·001). The 5- and 10-year OS for the neoadjuvant RT and surgery group was 92% and 80%, respectively, and 84% and 71%, respectively, for the surgery alone group (HR 0·50, 95% CI 0·27-1·21, P = 0·07). Interpretation:To the best of our knowledge, this is the largest study to report outcomes of neoadjuvant RT for pRP-WDLPS. Neoadjuvant RT was associated with a significant decrease in LR compared to surgery alone. These data further validate the use of neoadjuvant RT for pRP-WDLPS. Funding:Funding was received from the Susan and Habib Gorgi Family Fund for Sarcoma Research.

Background Therapeutic options for BRAFV600-mutant melanoma in patients who progress on BRAF/MEK-inhibitors (BRAF/MEKi) and immune-checkpoint-inhibitor (ICI) therapy, are limited. We conducted a retrospective registry study to investigate post-ICI rechallenge with BRAF/MEKi, stratified by type of initial BRAF/MEKi therapy. Methods This retrospective study analysed patients from the EUMelaReg registry, who received adjuvant or first-line (1L) BRAF/MEKi in the advanced setting, followed by ICI therapy and were later retreated with BRAF/MEKi. Overall response rate (ORR) for rechallenge served as primary endpoint, disease-control rate (DCR), progression-free survival (PFS), and overall survival (OS) were further endpoints. A covariate-matched control group of patients who received BRAF/MEKi only after 1L ICI failure was selected for comparison. Results Among patients previously treated with adjuvant (n=42) or non-adjuvant (n=142) BRAF/MEKi, rechallenge after one interim ICI line resulted in ORRs of 26.2% and 30.3% and DCRs of 42.9% and 61.8%, respectively. Median PFS was 8.4 and 5.1 months, median OS 13.8 and 8.6 months, respectively. Overall, the rechallenge group had a 1-year OS of 43.2%, lower than the matched control (58.9%). The adjuvant subgroup was similar to control (55.4%), while the advanced subgroup showed notably poorer survival (39.9%). Subgroup analyses showed that both the pre-ICI response to BRAF/MEKi treatment and progressive disease prior to ICI were associated with outcome of the BRAF/MEKi rechallenge. Conclusion Rechallenge with BRAF/MEKi therapy under real-world conditions for advanced melanoma provides a valid treatment option. For patients who received their initial BRAF/MEKi therapy as adjuvant therapy there seems to be only limited impairment of outcomes.

Background: The pivotal study aimed to determine the degree of perceived social functioning and body image of patients with basal cell carcinoma (BCC) located in the face/head region. The prospective multicenter surveywas filled by 61 BCC patients from 5 hospitals in Poland treated between January 1st, 2021, and November 31st, 2021, with vismodegib in a national drug program in a first-line palliative setting. Methods: All patients had deformations/scars after earlier surgical treatment or visible, unresectable BCC lesions on the skin of the face, which could impact their social functioning. The research instrument was an own-created survey questionnaire about perceived social functioning and the Body Self-Esteem Scale (BES). Descriptive statistics and Spearman's Rho test were performed. Results: No correlation was found between perceived social functioning limitations and the number of treatments received. Older patients tend to rate their family support higher, and additionally, another positive correlation with age and the feeling of being accepted by friends was described. Age and social support play a significant role in the functioning of patients after resection of BCC. Although most patients reported that surgery did not limit their social functioning, they still had limited contact with others. The body image survey's lowest-rated body parts were the face and body hair. Conclusions: Some of the patients in the present study showed a feeling of loneliness and a desire to limit social contact. To reduce BCC risk, patients should be educated about the ultraviolet carcinogenic effect on skin. There is also an emerging need to involve psycho-oncologists and the prehabilitation team in the qualification for resection of locally advanced BCC. Palliat Med Pract 2026; 20: e01326024

LBA9517 Background: PIVOTAL (NCT02938299) is an open-label, randomized, multicenter, phase 3 trial evaluating daromun as a neoadjuvant intralesional (IT) therapy for resectable, locally advanced stage III melanoma. The trial enrolled 256 efficacy-evaluable patients (pts) in the EU and met its primary endpoint, demonstrating a statistically significant improvement in recurrence-free survival (RFS; HR = 0.59; p = 0.005) for daromun versus upfront surgery, at a median follow-up (FU) of 21 months from randomization (Kähler et al, Ann Onc 2025, 36, 1166). Methods: Pts with skin and/or lymph node metastatic melanoma amenable to complete surgical resection were randomized (1:1) to receive 4 weekly IT injections of daromun (13 Mio IU of L19IL2 and 400 μg of L19TNF) followed by surgery or upfront surgery alone. Prior surgery, radiotherapy (RT) and/or systemic therapies (ST) were permitted, as well as any approved adjuvant treatment post-surgery.The primary endpoint was RFS, the secondary endpoints included DMFS, OS and safety. An event-free survival (EFS) sensitivity analysis was conducted, considering progression to unresectable melanoma before surgery, recurrence of the disease, or death due to melanoma or treatment as events. Results: An updated primary outcome analysis at a median FU of over 36 months from randomization (database cut-off Nov. 29, 2025) confirmed a clinically relevant improvement in RFS (HR = 0.60; p = 0.003) for daromun versus upfront surgery. The EFS sensitivity analysis carried out in the overall population was consistent with the RFS results (HR = 0.66; 95% CI = 0.47-0.92).The PIVOTAL trial included two clinically distinct subgroups: pts with newly diagnosed disease (n = 32; 12%) and pts with recurrence(s) after surgery and/or systemic (neo)adjuvant treatment (n = 224; 88%). Among the recurrent cohort, 86 pts (38.3%) had received and failed previous ST, while 138 pts (61.6%) had only received surgery/RT. Sensitivity EFS analyses were also performed in i) the recurrent cohort (HR = 0.59; 95% CI = 0.41-0.85), ii) the subgroup of pts in the recurrent cohort who had only received previous surgeries and/or RT (HR = 0.55; 95% CI = 0.34-0.89), and iii) the pts subgroup in the recurrent cohort who received prior ST (HR = 0.63; 95% CI = 0.36-1.08 ). The rate and type of treatment-related adverse events at a longer FU were consistent with previous reports, and no new safety risks were identified. Conclusions: With longer FU the highly significant reduction in the risk of recurrence or death with neoadjuvant daromun in pts with locally advanced stage III melanoma is confirmed. The sensitivity EFS analyses provide consistent, confirmatory evidence of daromun’s efficacy across the entire trial population and, more importantly, in the subgroup of pts with recurrent disease, regardless of any prior ST. No new safety signals were reported. Clinical trial information: NCT02938299 .

Gastrointestinal stromal tumors are the most common sarcomas of the gastrointestinal tract. They are characterized by a distinct molecular profile, most frequently involving activating mutations in the KIT or PDGFRA genes, the identification of which has enabled the development of effective targeted therapies and has significantly improved patient outcomes. Despite significant therapeutic advances, treatment with tyrosine kinase inhibitors remains associated with the risk of primary or secondary resistance in a subset of patients. This phenomenon has highlighted the considerable biological heterogeneity of gastrointestinal stromal tumor, encompassing not only canonical mutational variants but also rare molecular alterations with distinct pathogenic mechanisms and clinical implications. Growing evidence suggests that detailed molecular characterization of gastrointestinal stromal tumors is of critical clinical importance, enabling improved risk stratification, optimization of treatment selection, and identification of patients requiring alternative therapeutic strategies. Therefore, comprehensive molecular diagnostics should be an integral part of the diagnostic and therapeutic approach to this heterogeneous group of tumors. The aim of this study is to provide an overview of current knowledge on rare molecular variants of gastrointestinal stromal tumors, as well as the available data on their clinical course and sensitivity to tyrosine kinase inhibitors and other therapeutic strategies.

MONETTE study design, Baseline tumor sample and blood samples, DoR, best percentage change from baseline in target lesion size, OS in PD-L1 and CD8/Ki67 biomarker evaluable populations, micrographs of PD-L1 expression and CD8+/Ki67 cells, baseline area of CD8+ T cells, Ki67+ cells, and proliferating CD8+ Ki67 + T cells in the central tumor region, OS in the baseline circulating immune cell biomarker population, longitudinal pharmacodynamic effects on T cells, OS in GDF-15 biomarker population and baseline GDF-15 as a prognostic marker for OS in monotherapy and combination therapy.

9576 Background: Patients with resected stage III BRAF V600 mutated melanoma can be treated with combined dabrafenib and trametinib (D/T) with significant improvement of recurrence-free survival (RFS). The results of the pivotal Combi-AD study showed overall survival (OS) improvement only for patients with BRAF V600E mutations, while for V600K there was even an OS impairment as compared to placebo, although not statistically significant. Methods: We analysed EUMelaReg data for patients with adjuvant D/T therapy for resected stage III melanoma. Only patients with V600E and V600K mutations were selected, where n=93 from a total of 1,033 patients (9.0 %) harboured V600K. Results: Demographics of patients with V600K mutations differed significantly for age (67 vs. 58 years, p <0.001) and a higher proportion of males (67.0% vs. 54.6%, p=0.03) at baseline. Other baseline variables, including substage, were not significantly different. One year of treatment was completed in 51.6% for V600K, and 62.8% for V600E, respectively, while with V600K mutations 22.6% of the patients stopped for toxicity (vs. 18.8% with V600E), and 10.8% for disease recurrence (vs. 6.9%), which was not statistically significant. After a median follow-up of 41.7 (V600K) and 41.2 (V600E) months, Kaplan-Meier analysis estimated 4-year overall survival of 75.7% for V600K compared to 77.8% for V600E. The 4-y-RFS estimates were 48.3% for V600K and 47.0% for V600E. These differences were not statistically significant. Cox regression analysis revealed no different results when adjusted for demographic co-variates, including age and sex, for RFS and OS, respectively. Conclusions: It appears that V600E and V600K mutations are not associated with a different outcome from adjuvant treatment with combined D/T. The findings offer no explanation for differences found in the Combi-AD trial, although part of these differences also resulted from a different natural course of V600K mutated melanomas the placebo group. A longer follow-up will help to further confirm these results and also analyse the possible role of further treatments in the metastatic setting. Baseline characteristics and outcome. V600E(N=940) V600K(N=93) P-value SEX 0.035 Female 426 (45.3%) 31 (33.3%) Male 514 (54.7%) 62 (66.7%) AGE <0.001 Mean (SD) 57.4 (13.8) 65.6 (11.9) Median [Min, Max] 58.0 [17.0, 90.0] 67.0 [28.0, 87.0] ECOG 0.1 0 846 (90.0%) 82 (88.2%) 1 51 (5.4%) 8 (8.6%) 2 5 (0.5%) 2 (2.2%) Baseline Stage 0.34 III 8 (0.9%) 1 (1.1%) IIIA 126 (13.4%) 7 (7.5%) IIIB 293 (31.2%) 29 (31.2%) IIIC 470 (50.0%) 54 (58.1%) IIID 43 (4.6%) 2 (2.2%) STAGE III DIAGNOSIS TYPE 0.96 Primary Diagnosis 679 (72.2%) 68 (73.1%) Relapse 260 (27.7%) 25 (26.9%) SUBTYPE 0.06 SSM 358 (38.1%) 26 (28.0%) NMM 315 (33.5%) 44 (47.3%) NOS 207 (22.0%) 18 (19.4%) MUP 49 (5.2%) 4 (4.3%) OUTCOME 4-Year RFS (95%-CI) 0.47 (0.43; 0.51) 0.48 (0.38; 0.61) 0.94 4-Year OS (95%-CI) 0.78 (0.75; 0.81) 0.76 (0.65; 0.88) 0.94

Table S7. Clinical responses of advanced PDGFRA-mutant GIST patients treated with first-line imatinib.

Importance:Patients with melanoma are at risk of developing subsequent cutaneous malignant neoplasms, and the effect of prior immunotherapy is unknown. Objective:To analyze new skin cancers in participants with high-risk stage II melanoma treated with adjuvant pembrolizumab or placebo. Design, Setting, and Participants:The multicenter double-blind, phase 3 KEYNOTE-716 randomized clinical trial enrolled 976 participants 12 years or older with completely resected stage IIB or IIC cutaneous melanoma between September 23, 2018, and November 4, 2020. Follow-up was completed on February 16, 2024. This analysis was not prespecified in the trial protocol. Interventions:Participants were randomly assigned to receive intravenous pembrolizumab, 200 mg (2 mg/kg for pediatric participants), or placebo, every 3 weeks for no more than 17 cycles. Main Outcomes and Measures:Secondary analyses of incidence and time to diagnosis of new melanoma or other cutaneous malignant neoplasm, sensitivity analysis of recurrence-free survival (RFS) with new primary melanoma counted as an event, and incidence of immune-mediated severe skin reactions. Results:A total of 976 participants were assigned to treatment (487 to pembrolizumab and 489 to placebo), of whom 589 (60.3%) were male (median age at diagnosis, 61 [IQR, 52-69] years). The median follow-up was 52.8 (range, 39.4-64.8) months. In the pembrolizumab group, 37 participants (7.6%) were diagnosed with new skin cancers (median time to diagnosis, 168.0 [range, 1.0-1182.0] days); 12 (2.5%) had new invasive primary melanoma, 6 (1.2%) had new primary melanoma in situ, 19 (3.9%) had basal cell carcinoma (BCC), and 9 (1.8%) had cutaneous squamous cell carcinoma (cSCC). In the placebo group, 56 participants (11.5%) were diagnosed with new skin cancers (median time to diagnosis, 177.0 [range, 1.0-1043.0] days); 9 (1.8%) had new invasive primary melanoma, 9 (1.8%) had new primary melanoma in situ, 26 (5.3%) had BCC, and 17 (3.5%) had cSCC. Median RFS with new primary melanoma counted as an event was not reached with pembrolizumab and was 59.2 months (95% CI, 53.9 months to not reached) with placebo (hazard ratio, 0.65; 95% CI, 0.52-0.80); 48-month RFS was 68.7% and 56.5%, respectively. Immune-mediated severe skin reactions occurred in 16 of 483 participants (3.3%) in the pembrolizumab group and 3 of 486 (0.6%) in the placebo group (grade 3 or 4: 14 [2.9%] vs 3 [0.6%]). Conclusions and Relevance:In this secondary analysis of a randomized clinical trial, the incidence of new primary melanoma was not different between groups, whereas nonmelanoma skin cancers were more common with placebo. The RFS benefit of pembrolizumab remained after accounting for new primary melanomas. Immune-mediated severe skin reactions occurred infrequently and were manageable. These findings support the use of adjuvant pembrolizumab in high-risk stage II melanoma. Trial Registration:ClinicalTrials.gov Identifier: NCT03553836.

Abstract Gastrointestinal stromal tumor (GIST) is the most common sarcoma, and 85% of cases harbor mutations in KIT or PDGFRA receptor tyrosine kinases. Imatinib (IM), a type II TKI, can treat many KIT-mutant GIST, but not GIST with the most common PDGFRA mutation, exon 18 D842V. D842V is resistant to all type II TKIs. Avapritinib (AVA), a type I TKI, was developed and is FDA-approved for all PDGFRA exon 18 mutant GIST but is costly and has severe cognitive side effects in some patients. AVA is also not widely available outside the United States, leaving many exon 18 mutant GIST patients without treatment options. However, limited clinical evidence reports the usage of IM to treat non-D842V exon 18 mutations. As IM is a more tolerable, cost-effective, and accessible drug than AVA, utilizing IM therapy in certain cases would provide treatment for those who cannot access or tolerate AVA. As it is not feasible to model every observed mutation, we utilized in vitro models to predict exon 18 mutations that could be treated with IM. Through collaboration and AACR GENIE, we curated a cohort of 1000+ PDGFRA-mutant GIST. 66% had D842V while the remaining had non-D842V point mutations and complex in/dels. Strikingly, 78% of mutations involved the D842 residue, which plays a key role in the autoinhibition of PDGFRA, and mutations like D842V disrupt this. As nearly every single amino acid substitution at the 842-residue was observed in our cohort, we hypothesized that the characteristics of the 842-position amino acid determine IM sensitivity and will predict treatment responses for any exon 18 mutation. To test our hypothesis, we used Ba/F3 and CHO cells to express every possible D842X and D842_D846delinsX mutation. This 4-residue deletion was the most common in/del in the cohort; therefore, we chose to profile this mutation backbone as well. IM sensitivity was determined by calculating an IC50 value using immunoblotting for phosphorylated and total PDGFRA. We observed similar trends in IM sensitivity depending on the class of amino acid at the 842-position, with little difference between D842X and D842_D846delinsX mutant kinases. Seven out of eight hydrophobic residues conferred IM resistance while amino acids from other classes (polar, +/- charged, special case) conferred IM sensitivity/intermediate sensitivity. Notably, alanine conferred IM sensitivity, different than the other hydrophobic substitutions and in silico modeling revealed how the side chain structure at the 842-position affects IM binding/activity. Lastly, we determined that our results are concordant with first-line IM response data, as patients with predicted IM-sensitive mutations experienced a longer median progression-free survival than those with predicted or known IM-resistant mutations (30 vs 4 months, p <0.0001). Our work highlights an approach to optimize clinical guidelines for the TKI treatment for PDGFRA-mutant GIST based on specific patient mutations. Citation Format: Homma M. Khosroyani, Alina Teuber, Ajia Town, Lillian Klug, Denisse Evans, Jerry Call, Sara Rothschild, Neeta Somaiah, Prapassorn Thirasastr, Ping Chi, Marion Liu, Peter Hohenberger, Piotr Rutkowski, Patrick Schoffski, Abbas Agaimy, Mehdi Brahmi, Carol Beadling, Sebastian Bauer, Johanna Falkenhorst, Michael C. Heinrich. Using in vitro models to predict imatinib responses in PDGFRA-mutant gastrointestinal stromal tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 8.

Mutation analysis of our PDGFRA-mutant GIST cohort reveals clustering around the exon 18, 842-codon position. A, The protein domains of PDGFRA (AL, activation loop; AP, ATP-binding domain; EC, extracellular domain) and the exon distribution of unique primary mutations seen in PDGFRA-mutant GIST (n = 1,379 cases). B, Breakdown of mutations seen in exon 18 PDGFRA-mutant GIST cases (n = 1,122/1,379). The gray-colored proportion in the chart indicates mutations with five or fewer reported cases (n = 90/1,122). C, Number of cases with exon 18 in/del mutations and the net number of deleted residues in the final protein sequence, along with the breakdown of the type of mutations observed with a 4-residue deletion. Red “X” denotes the number of amino acids inserted (X = 1, XX = 2). D, Proportion of cases with mutations that directly alter the 842 residue. E, Distribution of the amino acid occupying the 842-position in exon 18–mutant cases (n = 1,122). Colors in the legend correspond to the amino acid class of the 842-position residue (hydrophobic, polar uncharged, special case, positively charged, and negatively charged). [Portions of A were Created in BioRender. Khosroyani, H. (2026) https://BioRender.com/l88qy7p.]

PURPOSE:Stage IIB/IIC melanoma has a high risk of recurrence after resection. Combined BRAF/MEK inhibitor therapy showed benefit in resected high-risk stage III and advanced melanoma. The objective of this study was to investigate its role in stage IIB/IIC. METHODS:Adult patients with resected stage IIB/IIC cutaneous melanoma which had a BRAF V600E/K mutation were randomized 1:1 to receive encorafenib (enco) 450 mg QD + binimetinib (bini) 45 mg BID orally for one year or placebo. The study planned to randomize 815 patients and was designed to demonstrate superiority regarding recurrence-free survival (RFS). Following a premature termination of accrual, the study was amended with safety as the primary endpoint and RFS as secondary endpoint. RESULTS:Between June 9, 2022, and October 9, 2023, 339 patients were screened for a BRAF mutation and 110 randomized. Data cutoff was 19 Nov. 2024, after the last patient discontinued study participation. Among randomized patients, 87 (79%) had a BRAF V600E mutation, and 39 (35%) AJCC8 stage IIC. Median follow-up was 12 and 7 months for enco/bini and placebo arms, respectively. Among 54 patients who initiated enco + bini, grade ≥ 3 treatment-related adverse events (AE) occurred in 13 (24%) patients, and 18 (33%) patients had an AE leading to permanent treatment discontinuation. RFS at 12 months was 86% (95% CI: 65-95%) in the enco + bini and 70% (95% CI: 46-85%) in the placebo arm, distant metastasis-free survival at 12 months was 92% (95% CI: 77-97%) for enco + bini and 82% (95% CI: 55-93%) for placebo. CONCLUSION:EORTC 2139 - Columbus-AD demonstrated a consistent and manageable safety profile and encouraging efficacy results for the combination of enco and bini in resected stage IIB/C BRAF V600E/K-mutated cutaneous melanomas.

Abstract The most common platelet-derived growth factor receptor α (PDGFRA) alteration in gastrointestinal stromal tumors (GIST) is the exon 18 activation loop mutation D842V, which is resistant to imatinib and other type II tyrosine kinase inhibitors (TKI) but sensitive to type I TKI avapritinib. Avapritinib is FDA-approved for first-line treatment of all PDGFRA exon 18–mutant GIST cases but is only available for D842V-mutant cases outside the United States. Non-D842V exon 18–mutant GIST cases are understudied and lack evidence-based treatment guidelines. However, there are a few previous reports describing non-D842V exon 18–mutant patients with GIST who responded well to imatinib therapy. Given that imatinib is more tolerable, globally accessible, and significantly less expensive than avapritinib, we sought to define which patients could be treated with imatinib rather than avapritinib. We assembled a cohort of more than 1,000 PDGFRA exon 18–mutant GIST cases and identified that 78% of these mutations involved a key autoinhibitory aspartic acid residue at position 842. Using cell-based models, we demonstrated that imatinib sensitivity was dependent on the amino acid class of the 842-position residue, with all hydrophobic amino acids except alanine conferring resistance. In contrast, all 842-position mutations were avapritinib-sensitive. Structural modeling supported our biochemical results and revealed how 842-position mutations induce changes that can interfere with imatinib binding. Lastly, our biochemical data were validated using imatinib response data for first-line metastatic disease; patients with predicted exon 18–sensitive mutations had longer progression-free survival than patients with predicted imatinib-resistant mutations. These results provide key evidence that should be used to guide therapy selection for PDGFRA-mutant GIST. Significance: Biochemical and structural modeling of PDGFRA exon 18 842-position mutations allows for the prediction of clinical TKI responses. These data can be used to generate new treatment guidelines for PDGFRA exon 18–mutant GISTs and select optimal therapies for patients.

Merkel cell carcinoma (MCC) is a highly aggressive yet profoundly immunotherapy-sensitive skin cancer characterized by early nodal and systemic dissemination. Historically, aggressive locoregional treatment was considered essential because therapeutic options for advanced disease were limited. The advent of immune checkpoint inhibitors has fundamentally transformed outcomes in MCC and, for the first time, enabled critical reassessment of established surgical and radiotherapeutic paradigms. Contemporary evidence suggests that intensified locoregional therapy does not consistently improve survival, which appears to be driven primarily by occult systemic disease. Emerging perioperative immunotherapy data therefore support more individualized, biology-driven strategies, including potential de-escalation of local therapy in selected patients while maintaining effective oncologic control.

Chondrosarcoma (ChS) is a rare bone malignancy with heterogeneous behavior, the molecular and immunological background of which remains unknown. No effective systemic treatment for advanced ChS patients is available. The aim of this study was to develop an immune-mutational classification of ChS and to search for novel prognostic factors and molecular targets. We performed an immunological-molecular profiling of 99 patients diagnosed with primary ChS G1-G3 and dedifferentiated ChS. An expression of 20 immune response markers was assessed by IHC and targeted the next-generation sequencing of 409 genes was performed. Immunological and mutational profiles were correlated with overall survival using a multivariate LASSO-penalized Cox model. Three immunophenotypes were described-"cold" (IMP1), "hot" (IMP2), and "intermediate" (IMP3). IMP1 was the most prevalent in G1 cases, while IMP2 was the most prevalent in dedifferentiated cases. IDH1/2 or TP53 mutations were associated with high-grade ChS (FDR < 0.05). IMP2 was characterized by a higher number of immune infiltrates in the central region of the tumor (HR: 3.3; CI: 1.13-9.8; p < 0.05). IDH1 mutations were present most often in IMP2 cases (HR: 3.8; CI: 1.75-8.1; p < 0.001). Tumor size, dedifferentiated subtype, IDH1 mutation and the presence of IMP2 were identified as independent negative prognostic survival factors in ChS. An immune-mutational classification system for ChS patients was proposed, which may be used to identify those potentially suited for immunotherapy combined with IDH-mutant inhibitors in future research.