Abstract Background: RET fusions occur in ∼1-2% of advanced NSCLC (aNSCLC). Selective RET inhibitors (SRIs) significantly improve outcomes, yet ∼10% of patients progress by 6 months and ∼30% by 12 months. Predictors of response or early progression remain poorly defined. Methods: A multicenter retrospective analysis (RET-MAP) of RET+ aNSCLC from 47 international centers evaluated clinical/genomic correlates of SRI outcomes. Multivariable Cox models estimated progression-free (PFS) and overall survival (OS) and tested interactions with first-line (1L) SRI versus chemotherapy ± immune checkpoint inhibitor (CH±ICI). In parallel, genomic/transcriptomic features were characterized in an external Caris Life Sciences (CLS) RET+ aNSCLC cohort. Results: Among 510 RET-MAP patients (median age 63; 59% female; 36% ever-smokers; 92% adenocarcinoma), 401 received an SRI (1L n=151; later lines n=250). Median PFS on SRI (any line) was 17.1 months (95% CI, 14.5-21.1), median OS 30.4 months (95% CI, 27.0-41.1). TP53 co-mutation was present in 27% (78/292 tested) and was associated with shorter PFS (8.9 vs 19.2 months; p<0.001) and OS (22.7 vs 30.9 months; p=0.002), without a significant treatment-by-TP53 interaction for 1L SRI versus CH±ICI (p=0.22). Fusion partner contributed with additional signal: KIF5B (73%, 274/373) had inferior PFS (13.4 vs 60.2 months; p<0.001) and OS (26.6 vs 73.0 months; p=0.002) compared with CCDC6 (17%, 65/373), and a significant treatment-by-fusion interaction favored SRI over CH±ICI in CCDC6 versus KIF5B (p=0.007). On multivariate analysis, shorter PFS and OS were independently associated with TP53 mutation (HR 1.74, p<0.001; HR 1.77, p=0.001), KIF5B fusion (HR 1.98, p=0.002; HR 1.64, p=0.040), ECOG ≥2 (HR 2.20, p<0.001; HR 3.06, p<0.001), and brain metastases (HR 1.59, p=0.003; HR 1.88, p<0.001); worse OS was associated with non-adenocarcinoma histology (HR 1.74, p=0.049) and smoking (HR 1.42, p=0.034). Notably, KIF5B fusions were enriched for TP53 mutations versus CCDC6 (40% vs 19.6%, p=0.011), suggesting partially overlapping biology. In the CLS cohort (N=211), TP53-mutant tumors (74/211) were enriched for RB1 mutations, had higher PD-L1 expression and tumor mutational burden, and demonstrated increased M1 macrophage/B-cell infiltration with reduced neutrophils; by fusion partner, CCDC6 showed higher PD-L1, while global transcriptomes were otherwise similar to KIF5B. Conclusions: In RET+ aNSCLC, TP53 mutation is prognostic for inferior outcomes on SRIs but not predictive of differential benefit versus CH±ICI. Fusion partner carries both prognostic and predictive relevance; CCDC6 is associated with a more indolent course and greater relative benefit from SRI. External profiling supports an inflammatory microenvironment in TP53-mutant disease, reinforcing biologically distinct—and clinically meaningful—subsets within RET-driven lung cancer. Citation Format: Daniela Miliziano, Julia K. Rotow, Meghanne Lomibao, Tolulope Adeyelu, Arianna Marinello, Helena Bote-de Cabo, Jamie Feng, Andrea De Giglio, Mariana Brandão, Florian Guisier, Michael Duruisseaux, Christina Falcon, Massimiliano Cani, Francesca Colamartini, Barliz Waissengrin, Isabelle Monnet, Anna Eisert, Emilio Bria, Amin H. Nassar, Ayesha Aijaz, Patricia Iranzo, Colin R. Lindsay, Elizabeth Fabre, Vladmir Cordeiro de Lima, Judith Raimbourg, Laura Mezquita, Nicolas Minatta, Sophie Cousin, Katarzyna Szymczak, Vincent Fallet, Clarisse Audigier-Valette, Helene Doubre, Philippe Rochigneux, Annarita Avanzo, Antonio Calles, Marco Tagliamento, Diego Cortinovis, Balazs Halmos, Nicholas Girard, Andrew Elliott, Jair Bar, Alessio Cortellini, Diana N. Ionescu, Frances A. Shepherd, Fabrice Barlesi, Karen L. Reckamp, David Planchard, Benjamin Besse, Alexander Drilon, Mihaela Aldea. Prognostic and predictive effects of TP53 co-mutations and RET fusion partners in RET-rearranged advanced NSCLC [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 2434.

IntroductionIn the context of the COVID-19 pandemic, scientific societies of oncology issued guidelines to limit the spread of the virus, in particular by limiting the prescription of cancer treatments with palliative intent. This qualitative study adopts a psychosocial perspective to explore how oncologists experienced these guidelines, and what this reveals about their representations and practices concerning end-of-life treatments.MethodsConducted in a comprehensive cancer center, the study is based on a mixed-method strategy involving 10 semistructured interviews with oncologists and observation of 13 consultations.ResultsThe oncologists stated that they were complying with the guidelines, which was perceived as an external argument of authority that made it easier to announce the cessation of treatment. The analysis highlights the sacralization of chemotherapy, a shared feeling of guilt at the idea of stopping cancer treatments, and a representation of palliative care as the moment when there is "nothing more to be done."DiscussionThe fact that the oncologists reported that previous practices had been reinstated once the health crisis had passed reveals the psychosocial logics at work in their decision-making and communication practices. This study recommends the creation of workshops to raise awareness of the psychosocial factors that influence chemotherapy prescriptions in the advanced stages of the disease.

PURPOSE:Mismatch repair deficiency (dMMR) or microsatellite instability (MSI) represents a distinct phenotype among solid tumors resulting in the generation of highly immunogenic neoantigens. Pembrolizumab has been approved in first-line unresectable or metastatic dMMR/MSI colorectal cancers (CRC). We aimed to assess efficacy and tolerance of perioperative pembrolizumab in dMMR/MSI CRC. PATIENTS AND METHODS:The prospective multicenter phase II trial IMHOTEP enrolled patients with localized resectable dMMR/MSI CRC to receive one or two cycles of IV pembrolizumab 400 mg once every 6 weeks before surgery and 1-year total duration thereafter. The primary end point was pathologic complete response (pCR) rate (ypT0N0). Secondary objectives included safety, event-free survival, and overall survival. RESULTS:IMHOTEP enrolled 81 patients with dMMR/MSI CRC who received at least one cycle of pembrolizumab from November 26, 2021, to February 22, 2023: median age was 66 (21-89) years, 46 (52%) were women, and 63 (71%) had clinical stage III disease at baseline. Out of the 72 patients included in the efficacy population, 38 patients (52.7% [95% CI, 41.4 to 63.9]) achieved a pCR. The exploratory post hoc analysis showed a pCR rate increased from 46% (23/50) after one cycle to 68.2% (15/22) after two cycles of neoadjuvant pembrolizumab (P = .0125). With a median follow-up of 24.5 (95% CI, 23.3 to 25.6) months, three disease recurrences occurred. Grade ≥3 immune-related toxicities were reported in 14 (15.7%) patients including one grade 5 (myasthenia). CONCLUSION:The IMHOTEP trial showed promising results, with pCR achieved after one or two cycles of neoadjuvant pembrolizumab in 53% of patients with dMMR/MSI CRC. To our knowledge, this prospective study is the first to demonstrate the feasibility and the safety of perioperative pembrolizumab.

Background: Transcriptomic FOLFIRINOX-component sensitivity signatures have been clinically evaluated in resected and advanced PDAC, but their relevance and longitudinal stability in the neoadjuvant BR/LA setting are unknown. Patients and methods: We retrospectively studied 77 patients with borderline resectable or locally advanced PDAC treated with neoadjuvant FOLFIRINOX followed by resection. Pretreatment sensitivity to 5-fluorouracil, oxaliplatin and irinotecan was determined using previously developed locked transcriptomic classifiers and integrated into a regimen-level FOLFIRINOX classification. The primary molecular cohort comprised 53 patients whose pretreatment biopsies had ≥10% tumour cellularity. Cox models assessed associations with survival. Longitudinal changes were assessed in 35 paired tumours. Results: Thirty-one pretreatment tumours were classified as FOLFIRINOX-sensitive (FFX-Sens), and 22 were not classified as FOLFIRINOX-sensitive (FFX-Res). FFX-Sens status was associated with longer overall survival (OS; hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.25-0.93; p=0.029). In the complete-case model adjusted for baseline carbohydrate antigen 19-9 (CA19-9) and tumour size (n=50), the association with OS persisted (adjusted HR 0.47, 95% CI 0.23-0.96; p=0.037), whereas the adjusted association with disease-free survival was not statistically significant (adjusted HR 0.55, 95% CI 0.28-1.10; p=0.090). Among paired tumours, 15 changed from FFX-Sens to FFX-Res and four in the opposite direction (exact McNemar p=0.019). The OS association also persisted after adjustment for postoperative pathological factors (adjusted HR 0.40; p=0.015). Conclusions: Pretreatment FOLFIRINOX sensitivity was associated with OS under neoadjuvant FOLFIRINOX, while matched pretreatment and residual-tumour analyses revealed significant directional reclassification after treatment. These findings extend the clinical evaluation of validated drug-specific FOLFIRINOX sensitivity classifiers to the neoadjuvant setting and provide a longitudinal assessment of their stability during treatment. They support prospective evaluation of both pretreatment stratification and molecular reassessment of residual disease.

Immune checkpoint inhibitors (ICIs) have revolutionized the management of multiple malignancies, offering durable clinical benefit in a subset of patients. However, the emergence of distinct response patterns has revealed two major challenges: primary resistance, observed in patients who fail to respond from the outset, and acquired resistance, which develops after an initial period of disease control. These two resistance phenotypes likely arise from divergent biological mechanisms, involving both tumour-intrinsic and tumour-extrinsic factors. A comprehensive understanding of these processes is essential to optimize therapeutic strategies, particularly through rational combinations of ICIs with novel immunomodulators, targeted therapies, or conventional treatments. In this review, we provide an integrative overview of the key molecular and cellular mechanisms underlying both primary and acquired resistance to ICIs, encompassing alterations in antigen presentation, interferon signalling, oncogenic and metabolic pathways, as well as immune exclusion within the tumour microenvironment. We also highlight emerging predictive biomarkers of response and resistance—ranging from genomic and transcriptomic signatures to soluble immune checkpoints and non-immune circulating markers—aimed at refining patient selection and guiding personalized immunotherapy. Ultimately, deciphering these mechanisms will be pivotal for designing the next generation of immune-based combinations to overcome therapeutic resistance and expand the population of patients who can benefit from immune checkpoint blockade.

PURPOSE For elderly patients with pancreatic ductal adenocarcinoma (PDAC), FOLFIRINOX (FFX) is often contraindicated due to frequent grade III adverse events (AEs) limiting available data on this population. MATERIALS AND METHODS This retrospective single-center study identified patients older than70 years treated with FFX for PDAC (2011-2022). Tumor, G8 score calculation (score <14/17 indicates geriatric examination), geriatric, and nutritional parameters were collected. The primary end point was toxicity, defined as grade ≥3 GI AEs or unplanned hospitalization. Overall survival (OS) and toxicity associated factors were analyzed using Cox regression with stepwise selection. RESULTS We included 142 patients: 73 with metastatic PDAC (mPDAC) and 69 with non-mPDAC (nmPDAC). Median age was 74 years (71-84), with 43% age 75 years and older. 80% had Eastern Cooperative Oncology Group 0-1. G8 score ≤14 and severe malnutrition were more frequent in mPDAC (82% and 51%) than in nmPDAC (64% and 27%). Low muscle mass was present in >80% of cases. Median FFX exposure was four cycles in mPDAC and 4.5 in nmPDAC. Overall, 56% experienced toxicity, including two treatment-related deaths. Frequent grade ≥3 AEs included infections (26%), nausea/vomiting (22%), and diarrhea (18%). Early toxicity within 2 months was associated with worse OS. Factors linked to toxicity included metastatic status (hazard ratio [HR], 2.41) and psychiatric comorbidities (HR, 6.96), while cardiovascular disease (HR, 0.35) and history of cancer (HR, 0.22) were protective. In nmPDAC, multidimensional geriatric assessment (MGA) reduced toxicity in G8 ≤ 14 patients. CONCLUSION FFX is feasible in highly selected elderly patients with PDAC. Severe toxicity remains frequent and proactive supportive care—including MGA in cases of G8 ≤ 14—to avoid early severe toxicity that impact significantly survival.

cDC_monocyte_macrophage subpopulations gene features, related to Figure 1

GSEA outputs based on the differentially expressed genes between pre–αPD–1 versus post–αPD–1 Vg9Vd2 T cells in primary breast tumors, related to Figure 5

Inferred pseudotime gene features, related to Figure 1

Mass cytometry panels, related to Figure 1

BACKGROUND:While the use of chemotherapy near the end of life (EOL) has been identified as a relevant criterion for assessing quality of cancer care and has been estimated as non-beneficial, a trend of aggressiveness in cancer care during the last period of life remains. Both patients' sociodemographic characteristics and physicians' practice setting are associated with this use. The role of patients' psychosocial characteristics has however been understudied. The objectives were to study oncologists' intention to recommend chemotherapy or therapeutic abstention in an EOL patient's case and to examine the factors associated with this decision. METHODS:A clinical vignette-based questionnaire survey was conducted. While the case presented to the participating oncologists of a patient with EGFR-mutated lung cancer, progressing after osimertinib, ECOG 3, with leptomeningeal disease (N = 146), was strictly equivalent in terms of medical aspects and age, 4 patients' non-medical characteristics were manipulated: gender, marital status, parenthood, and psychosocial characteristics ("nice" patients, patients "making strong demands," or control patients). RESULTS:77.4% of the oncologists surveyed stated that they would recommend chemotherapy in this situation. Only scenarios with nice patients or patients making strong demands were associated with less recommendation of chemotherapy (70.8% for the nice/making strong demands scenarios together vs 87.7%, for the control scenario P = .017). Medical oncologists with previous experience of similar cases were also less keen to recommend chemotherapy (73% vs 100%, P = .007). Of the 76.7% of respondents declaring that they would think of other therapeutic options, 49.1% mentioned "other treatments" without mentioning palliative care. CONCLUSION:Developing physicians' awareness of the psychosocial aspects at stake in their medical decisions in these sensitive situations may improve EOL care.

Differentially expressed genes between intratumoral TNFRSF9+ eTregs versus TNFRSF9- eTregs, related to Figure 1

PURPOSE:Immune checkpoint inhibitor (ICI)-induced thyroid dysfunction is a common endocrine immune-related adverse event. Although rates during therapy are well documented, data on post-treatment thyroid dysfunction are limited. We hypothesized that post-ICI thyroid dysfunction is under-recognized because of inadequate surveillance. METHODS:A retrospective analysis of 3,626 patients treated with ICIs for various malignancies within a single health system was conducted. Clinically acted-upon thyroid dysfunction (diagnosis or thyroid-directed medication) was evaluated before, during, and after ICI therapy, alongside rates of thyroid laboratory surveillance. RESULTS:Clinically acted-upon thyroid dysfunction occurred in 8.1% (294/3,626) during treatment and 4.4% (159/3,626) after treatment. Among the 1,170 patients with post-ICI thyroid laboratory results and no prior dysfunction, 11.6% (136/1,170) developed post-ICI thyroid dysfunction. However, 48.6%% (1,764/3,626) had no post-ICI thyroid laboratory results. Thirty percent of patients with abnormal thyroid stimulating hormone (TSH) values and no clinically acted-upon thyroid dysfunction before therapy discontinuation subsequently developed clinically acted-upon thyroid dysfunction, and the rate of post-ICI clinically acted-upon thyroid dysfunction was higher in patients who received 9 or less months of ICI therapy. CONCLUSION:Post-ICI thyroid dysfunction is frequent, with 11.6% of monitored patients being affected, and patients with abnormal TSH before ICI discontinuation and those who received treatment for 9 months or less may benefit from more stringent post-ICI surveillance.

12116 Background: Immune checkpoint inhibitor (ICI)-induced thyroid dysfunction is the most common endocrine immune-related adverse event. While ICI-induced thyroid dysfunction rates during therapy are well documented, data on post-treatment dysfunction is limited. Describing these rates is important as ICIs are increasingly used in the curative treatment setting. This study aimed to evaluate the rates of post-ICI thyroid dysfunction, evaluate for predictors of post-ICI thyroid dysfunction and assess adequacy of post-ICI thyroid function surveillance. Methods: A retrospective analysis of 3626 patients treated with ICIs for various malignancies and cancer stages within a single health system from March 2013 to December 2022 was conducted. Rates of clinically acted upon thyroid dysfunction (diagnosis or thyroid-directed medication) were evaluated before, during, and after ICI therapy, alongside rates of thyroid laboratory surveillance in the post treatment setting. A multivariate analysis evaluated the odds of developing clinically acted upon post-ICI thyroid dysfunction based on patient/treatment characteristics. Rates of clinically acted upon thyroid dysfunction were evaluated based on therapy duration. Statistical analyses were carried out using R V4.1.0. Results: Clinically acted upon thyroid dysfunction occurred in 8.1% of patients (294/3626) during treatment and 4.4% (159/3626) after treatment. However, in patients alive two months after ICI cessation, 53.9% (989/1834) had no post-ICI thyroid function tests performed. Among the 1170 patients with post-ICI thyroid labs and no prior dysfunction, 11.6% (136/1170) developed post-ICI thyroid dysfunction. Thirty percent of patients with abnormal TSH values and no clinically acted upon thyroid dysfunction prior to therapy discontinuation subsequently developed clinically acted upon thyroid dysfunction. The rate of post treatment thyroid dysfunction in patients who underwent thyroid test surveillance and received <9 months of therapy was 13.3% compared to 6.5% in those who received therapy >9 months. The odds ratio for developing post-ICI dysfunction were 1.76 (95% CI, 1.03 to 2.95) for patients with urologic malignancies compared to patients with respiratory malignancies as the reference group. Conclusions: Post-ICI thyroid dysfunction is frequent, with 11.6% of patients who undergo thyroid function surveillance being affected. Patients with abnormal TSH before ICI discontinuation and those who received treatment for < 9 months as well as those with urologic malignancies may benefit from more stringent post-ICI surveillance.

Percentage of immune cell types in primary TNBC, related to Figure 2

Clinical characteristics of patients with breast cancer

Supplementary_Materials_and_Methods_Figures_and_Figure_legends

Supplementary Figure 1: Graphical Abstract Supplementary Figure 2: Overall Survival in NSCLC patients treated with pembrolizumab in KEYNOTE-001 according to EGFR mutation Supplementary Figure 3: Recursive partitioning identified classical monocytes and NK as the main immune populations whose frequency splits patients into distinct patterns of overall survival Supplementary Figure 4: Classical monocytes, NK cells and ICOS+ CD4+ T cells are associated with improved pembrolizumab efficacy in advanced NSCLC patients. Supplementary Figure 5: Gating strategy of the 3 main immune populations associated with pembrolizumab efficacy. Supplementary Figure 6: Comparison side by side of Maxstat cut-offs with cut-off from Younden index for overall survival in the 3 populations of interest. Supplementary Figure 7: Survival outcomes in NSCLC patients treated with pembrolizumab in KEYNOTE-001 according to blood baseline frequency of classical monocytes. Supplementary Figure 8: Baseline immune peripheral score is also associated with PFS in melanoma patients treated with PD-1 inhibitors.