Antibody-drug conjugates (ADCs) have emerged as an important class of anticancer therapeutics. Their highly modular design offers multiple opportunities to refine their properties and improve clinical performance by tuni...Antibody-drug conjugates (ADCs) have emerged as an important class of anticancer therapeutics. Their highly modular design offers multiple opportunities to refine their properties and improve clinical performance by tuning individual components, including the antibody, linker, and payload. Recent ADC optimization efforts have focused on more stable linker designs, apparently based on the assumption that premature payload release, rather than ADC uptake and intracellular catabolism, is the primary driver of off-target toxicity and limited antitumor activity. However, clinical data highlight a more complex picture. Several clinically successful ADCs employ relatively unstable linkers, including some with short systemic half-lives. In contrast, ADCs with increased linker stability have not consistently demonstrated improved clinical outcomes and, in many cases, have been associated with unexpected toxicities. In this article, we examine common assumptions regarding ADC linker stability, highlight limitations of preclinical models in predicting human payload exposure, address appropriate methods to assess ADC stability, and discuss the clinical implications of altering ADC linker stability. By re-evaluating the role of linker stability in ADC design, this review aims to inform more rational strategies for the development of next-generation ADCs.
BACKGROUND: IO102-IO103, an investigational, immune-modulatory cancer vaccine, targets both tumor cells and immune-suppressive cells within the tumor microenvironment through activation and expansion of T cells against i...BACKGROUND: IO102-IO103, an investigational, immune-modulatory cancer vaccine, targets both tumor cells and immune-suppressive cells within the tumor microenvironment through activation and expansion of T cells against indoleamine 2,3-dioxygenase 1-positive and/or programmed death ligand 1 (PD-L1)-positive cells. PATIENTS AND METHODS: This open-label, phase III trial randomly assigned 407 patients with untreated advanced melanoma in a 1:1 ratio to receive subcutaneous IO102-IO103 (85 μg each) plus pembrolizumab 200 mg intravenously every 3 weeks or pembrolizumab alone for up to 2 years. The primary endpoint was progression-free survival (PFS) by blinded independent central review per RECIST v1.1. RESULTS: The median PFS was 19.4 months [95% confidence interval (CI) 9.7 to not reached] for IO102-IO103 plus pembrolizumab versus 11.0 months (95% CI 6.0-14.8) for pembrolizumab [hazard ratio (HR) (95% CI) 0.77 (0.58-1.00), P = 0.0558]; the statistical significance threshold (P ≤ 0.045) was missed. A longer PFS was observed in the combination arm across most subgroups, notably in patients with PD-L1-negative tumors [median PFS 16.6 versus 3.0 months (HR 0.54, 95% CI 0.35-0.85)], anti-PD-1 naïve patients [24.8 versus 11.0 months (HR 0.74, 95% CI 0.56-0.98)], proto-oncogene B-Raf (BRAF)-mutated tumors, or elevated lactate dehydrogenase. There was no increase in the frequency of treatment-related adverse events grade ≥3 (14.5% versus 15.6%) or of serious adverse events (32.0% versus 32.3%) in the vaccine arm. Local vaccine-related injection site reactions were reported in 56.0% of patients and were mostly grade 1/2. CONCLUSIONS: IO102-IO103 plus pembrolizumab prolonged PFS compared with pembrolizumab alone in patients with advanced melanoma in the first-line setting; however, statistical significance was missed for the primary endpoint. The combination was well tolerated with no added significant systemic toxicity. These data show the potential benefit of this combination in untreated advanced melanoma.
Gluz O, Nitz U, Christgen M
… +30 more, Kuemmel S, Braun M, Thill M, Wuerstlein R, Link T, Aktas B, Lüdtke-Heckenkamp K, Zaiss M, Bjelic-Radisic V, Just M, Veselinovic K, Vincent M, Baehner R, Wujak L, Warm M, Schumacher C, Schem C, Forstbauer H, Krauss K, Hoffmann O, Graeser M, Hartkopf A, Kates R, Zu Eulenburg C, Jóźwiak K, Burmeister S, Schmid P, Kreipe HH, Harbeck N, WSG ADAPT investigators
BACKGROUND: Low Ki67 after short preoperative endocrine therapy (ET) indicates a favorable prognosis in hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (eBC). We inv...BACKGROUND: Low Ki67 after short preoperative endocrine therapy (ET) indicates a favorable prognosis in hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (eBC). We investigated predictors of ET response in the West German Study Group (WSG) ADAPT-HR+/HER2- and ADAPTcycle trials. PATIENTS AND METHODS: ET response (Ki67 ≤10%) after 2- to 4-week standard ET, recurrence score (RS), and nodal status were used for treatment allocation. In ADAPT-HR+/HER2-, patients at high clinical risk received ET alone if N0-1 and RS 0-11 or RS 12-25 and ET response. In ADAPTcycle, N0-1 patients with RS > 25 and ET response and those with RS < 25 and e.g. ET nonresponse, N2-3 patients with RS ≤ 25 and ET response, were randomly assigned to receive (neo)adjuvant chemotherapy or aromatase inhibitor (AI)+ribociclib. Predictors of ET response were identified through multivariable logistic regression models. RESULTS: Three thousand six hundred seventy-five patients from the ADAPT-HR+/HER2- cohort (≤50 years and premenopausal, ≤50 years: N = 1250; >50 years or postmenopausal, >50 years: N = 2425) and 4239 from the ADAPTcycle screening cohort (≤50 years: N = 1336; >50 years: N = 2903) were analyzed. ET response rates were higher after AI (ADAPT-HR+/HER2-/ADAPTcycle: 81.4%/76.7%) versus tamoxifen (ADAPT-HR+/HER2-/ADAPTcycle: 40.1%/34.7%) in both age groups, with further improvement by ovarian function suppression (OFS) in premenopausal patients. Premenopausal patients with GnRH plus AI had similar ET response rates as postmenopausal patients. ET response predictors included AI use (plus OFS in premenopausal), age >50 years, lower RS and baseline Ki67 levels, and higher expression of estrogen receptor (by immunohistochemistry) and HER2 (by Oncotype DX™). In ADAPT-HR+/HER2-, 5-year distant disease-free survival in ET responders was markedly higher than in nonresponders and also in chemotherapy-treated N0-1 patients with RS > 25 (87.0 versus 80.7%), and it was only slightly lower than that in the RS 12-25 group. CONCLUSIONS: We observed similar ET response rates in two large phase III trials. Postmenopausal patients (mostly receiving AI) had higher ET response rates than younger patients. However, young patients with GnRH+AI had ET response rates comparable with those of postmenopausal patients, suggesting that therapy rather than biology accounts for the difference. Combining ET response and gene expression assessment could help more patients with luminal eBC avoid chemotherapy.
BACKGROUND: We summarize final results of the NCI/SWOG S1609 trial, the objective of which was to evaluate efficacy signals across 53 refractory rare cancer cohorts treated with dual cytotoxic T-lymphocyte-associated ant...BACKGROUND: We summarize final results of the NCI/SWOG S1609 trial, the objective of which was to evaluate efficacy signals across 53 refractory rare cancer cohorts treated with dual cytotoxic T-lymphocyte-associated antigen 4 and programmed cell death protein 1 inhibition. PATIENTS AND METHODS: A prospective, open-label, multicenter phase II trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks) was conducted (N = 53 cohorts). A statistical framework was established to evaluate each cohort in a two-stage design. The primary endpoint was objective response rate (ORR), with progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR, ORR plus stable disease >6 months), immune-related (i)-outcomes, and toxicity as secondary and exploratory endpoints. RESULTS: Overall, 798 previously treated patients were enrolled onto S1609/Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors (DART); 727 eligible patients received treatment; 1083 national (United States) sites opened the trial. Twenty-four of 53 cohorts (45%) demonstrated clinical activity, defined as ≥2 patients with confirmed response. Median (range) ORR was 12% (0%-75%); CBR was 27% (0%-75%). Median (range) 2-year PFS was 10% (0%-75%); 3-year OS was 23% (0%-100%). PFS at 6 months was moderately correlated with 1- and 3-year OS. Patients who attained an iOR versus OR had similar OS. Altogether, 82 patients (11% of the 727 enrolled patients) had an iPFS of ≥2 years. i-toxicity rates were comparable with those reported in prior studies. Adverse events led to treatment discontinuation in 102 patients (14%). The most common adverse events were fever, diarrhea, and rash/pruritus. Patients alive at 6 months who discontinued treatment due to i-toxicity had longer OS than those who discontinued treatment for other reasons. CONCLUSION: Patients with multiple refractory rare cancer types derived meaningful response to ipilimumab plus nivolumab treatment. More robust characterization of biologically defined subsets is underway to optimize therapeutic selection.
Juric D, Rugo HS, Reising A
… +14 more, Vervier K, Ma C, Ciruelos EM, Loibl S, Singer CF, Sohn J, Campone M, Conte P, Iwata H, Ghaznawi F, Miller M, Taran T, Su F, André F
BACKGROUND: Approximately 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) have PIK3CA alterations, which contributes to endocrine...BACKGROUND: Approximately 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) have PIK3CA alterations, which contributes to endocrine therapy resistance. Alpelisib, an α-selective phosphatidylinositol 3-kinase inhibitor and degrader, given in combination with fulvestrant, is approved for the treatment of PIK3CA-mutated, HR-positive, HER2-negative ABC, based on the results of the SOLAR-1 trial (NCT02437318). Aside from PIK3CA, other gene alterations are associated with poor prognosis and limited response to treatment in this patient population. PATIENTS AND METHODS: In this retrospective analysis, we carried out tissue-based next-generation sequencing of 398 patients (237 PIK3CA-altered, 161 PIK3CA-wild type) from SOLAR-1. Progression-free survival (PFS) correlative analysis was carried out in the PIK3CA-altered cohort. RESULTS: PIK3CA-altered and PIK3CA-wild type tumors had distinct genomic profiles. In the PIK3CA-altered cohort, patients who received alpelisib plus fulvestrant had a median PFS of 11.01 months versus 5.55 months for those receiving placebo plus fulvestrant (P = 0.0004). Patients in the lowest tumor mutational burden quartile as well as those with FGFR1 or FGFR2 alterations derived greater PFS benefit from alpelisib plus fulvestrant versus placebo plus fulvestrant [18.5 versus 3.22 months: hazard ratio (HR) 0.38, 95% confidence interval (CI) 0.21-0.68; FGFR1 12.71 versus 3.75 months: HR 0.38, 95% CI 0.17-0.81, P = 0.32; FGFR2 9.63 versus 2.78 months: HR 0.31, 95% CI 0.1-0.94, P = 0.29]; patients with MYC or RAD21 alterations derived limited PFS benefit. Cox and multitask machine learning models identified lower Eastern Cooperative Oncology Group performance status, prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) treatment, and PTEN or TP53 alterations among the most deleterious factors for PFS in the PIK3CA-altered cohort. CONCLUSIONS: Alpelisib plus fulvestrant provides clinical benefit for patients with PIK3CA-altered, HR-positive, HER2-negative ABC across a range of concomitant alterations, including those previously implicated in endocrine therapy or CDK4/6i resistance. Machine learning models can identify factors including gene mutations that influenced PFS.
Felip E, Rojas CI, Schenker M
… +16 more, Kowalski DM, Casarini IA, Csöszi T, Şendur MAN, Martins J, Calles Blanco A, Wang CC, Wang M, Ramirez Fallas RAL, Yoshioka H, Nair S, Song X, Deng X, Lala M, Eiras R, Takahashi T
BACKGROUND: Prognosis is poor, and treatment options are limited for patients with previously untreated, advanced triple-negative breast cancer (TNBC), especially for those who are not candidates for immunotherapy. PATIE...BACKGROUND: Prognosis is poor, and treatment options are limited for patients with previously untreated, advanced triple-negative breast cancer (TNBC), especially for those who are not candidates for immunotherapy. PATIENTS AND METHODS: In the randomised, open-label, phase III TROPION-Breast02 trial, patients with previously untreated, locally recurrent inoperable or metastatic TNBC for whom immunotherapy was not an option were randomly assigned 1:1 to datopotamab deruxtecan (Dato-DXd; 6 mg/kg intravenously every 3 weeks) or investigator's choice of chemotherapy. Randomisation was stratified by geographic location, disease-free interval, and programmed cell death ligand-1 status. Dual primary endpoints were progression-free survival (PFS; blinded independent central review per RECIST version 1.1) and overall survival (OS). Efficacy analyses were performed in the intention-to-treat population. Safety analyses included all patients who received ≥1 dose of study treatment. RESULTS: Between 16 May 2022 and 11 June 2024, 644 patients were randomly assigned to receive Dato-DXd (n = 323) or chemotherapy (n = 321). Median PFS was 10.8 months [95% confidence interval (CI) 8.6-13.0] with Dato-DXd and 5.6 months (95% CI 5.0-7.0) with chemotherapy [hazard ratio 0.57 (99% CI 0.44-0.73); P < 0.0001]. Median OS was 23.7 months (95% CI 19.8-25.6) and 18.7 months (95% CI 16.0-21.8) with Dato-DXd and chemotherapy, respectively [hazard ratio 0.79 (95.01% CI 0.64-0.98); P = 0.029]. Treatment-related adverse events (TRAEs) of grade ≥3 were reported in 105 (33%) and 89 (29%) patients who received Dato-DXd and chemotherapy, respectively, and TRAEs led to treatment discontinuation in 14 (4%) and 23 (7%) patients. There were no treatment-related deaths in either arm. CONCLUSIONS: Dato-DXd demonstrated significantly improved PFS and OS versus chemotherapy in patients with previously untreated, locally recurrent inoperable or metastatic TNBC for whom immunotherapy was not an option. Safety was consistent with the known profile for Dato-DXd.
BACKGROUND: T-cell redirecting therapies, notably chimeric antigen receptor T cells and bispecific antibodies, have revolutionized the treatment of hematologic malignancies. Their rapid expansion into solid tumors, along...BACKGROUND: T-cell redirecting therapies, notably chimeric antigen receptor T cells and bispecific antibodies, have revolutionized the treatment of hematologic malignancies. Their rapid expansion into solid tumors, alongside the emergence of next-generation agents, such as immunocytokines and CD28-costimulatory bispecifics, has brought cytokine release syndrome (CRS) to the forefront of clinical oncology. However, the absence of a unified grading system for these novel constructs remains a critical barrier to drug development and patient safety. Current toxicity management relies on disparate grading scales, leading to inconsistent reporting and hindering cross-trial comparisons. A fundamental challenge lies in the diagnostic ambiguity created by the significant clinical and temporal overlap among CRS, infusion-related reactions, and other diagnoses. Although fever, hypotension, and hypoxia are common denominators, their distinct pathophysiological drivers necessitate divergent therapeutic interventions. DESIGN: We advocate for a paradigm shift from aggregate syndromic grading toward a granular, longitudinal reporting framework. This approach prioritizes the precise documentation of symptom kinetics, specific interventions (e.g. exact vasopressor requirements and oxygen flow rates), and real-time biomarker integration. By capturing high-fidelity data, researchers can retrospectively apply evolving criteria and develop more tailored, evidence-based management algorithms. CONCLUSION: Transitioning to a standardized, symptom-driven reporting model is essential to navigate the complexities of 'Immuno-oncology 2.0.' Such a framework will harmonize safety assessments across global trials and ultimately optimize the therapeutic index of next-generation immunotherapies.
Xu B, Jeong H, Sun T
… +18 more, Sohn J, Zhang Q, Kostic S, Wang X, Tong Z, Wang S, Wang J, Li W, Lee KS, Moon YW, Kang MJ, Hu X, Kim TY, Milenković D, Seo JH, Kim JH, Lee J, Kim SB
BACKGROUND: Intravenous (i.v.) paclitaxel (Taxol) requires prolonged infusion and is associated with hypersensitivity reactions and peripheral neuropathy. This study evaluated the efficacy and safety of DHP107, a novel o...BACKGROUND: Intravenous (i.v.) paclitaxel (Taxol) requires prolonged infusion and is associated with hypersensitivity reactions and peripheral neuropathy. This study evaluated the efficacy and safety of DHP107, a novel oral formulation of paclitaxel, compared with i.v. paclitaxel in patients with HER2-negative, recurrent, or metastatic breast cancer. PATIENTS AND METHODS: This multinational, multicenter, open-label, randomized phase III trial evaluated the noninferiority of DHP107 compared with i.v. paclitaxel, with a predefined noninferiority margin of 1.33. Eligible patients had recurrent or metastatic breast cancer and had received no prior chemotherapy in the metastatic setting. Patients were randomly assigned to receive either DHP107 (200 mg/m orally twice daily on days 1, 8, and 15) or paclitaxel (80 mg/m i.v. on days 1, 8, and 15) in a 28-day cycle. The primary endpoint was investigator-assessed progression-free survival (PFS) in the per-protocol set (PPS). Secondary endpoints included independent central review-assessed PFS, overall survival (OS), tumor response, quality of life, and safety. RESULTS: Between January 2018 and December 2023, 549 patients were randomly assigned to receive either DHP107 (n = 277) or paclitaxel (n = 272); 519 patients were included in the PPS. DHP107 demonstrated noninferiority in PFS with a median PFS of 10.0 months compared with 8.5 months for paclitaxel (hazard ratio [HR] 0.869; 95% confidence interval [CI] 0.707-1.068). The median OS was 32.6 months for DHP107 and 31.8 months for paclitaxel (HR 0.967, 95% CI 0.762-1.227). DHP107 was associated with higher rates of neutropenia, febrile neutropenia, nausea, diarrhea, and vomiting, whereas peripheral neuropathy and hypersensitivity reactions were more common with paclitaxel. No treatment-related death occurred in the DHP107 group, and one (0.4%) in the paclitaxel group. Quality of life was comparable between the two groups. CONCLUSIONS: DHP107 demonstrated noninferior efficacy compared with i.v. paclitaxel, with a manageable safety profile, supporting its use as an effective and convenient alternative in HER2-negative breast cancer.
Aldea M, Lenahan SM, Locquet MA
… +45 more, Liao L, Gasparro M, Gokhale PC, Ghigna MR, Ionescu DN, Odintsov I, Ngo K, Wang X, Aziz S, Pecci F, Garbo E, Ivanova E, Nakazawa S, Kulesza J, Tsai JA, Zullo L, Lee J, Zielinska M, Simon S, Han D, Marinello A, Li G, Rossato de Almeida G, Huang J, Paoloni F, Gariazzo E, Santo V, Remon J, Marks JA, LoPiccolo J, Florez N, Nishino M, Ricciuti B, Luo J, Barbie DA, Planchard D, Rotow JK, Barlesi F, Graf RP, Feng WW, Besse B, Paweletz C, Sholl L, Shaw AT, Jänne PA
BACKGROUND: Homozygous loss of methylthioadenosine phosphorylase (MTAP) occurs in ∼15% of cancers and leads to partial PRMT5 inhibition, creating a selective vulnerability to PRMT5 inhibitors. The frequency and therapeut...BACKGROUND: Homozygous loss of methylthioadenosine phosphorylase (MTAP) occurs in ∼15% of cancers and leads to partial PRMT5 inhibition, creating a selective vulnerability to PRMT5 inhibitors. The frequency and therapeutic relevance of MTAP loss in oncogene-driven non-small-cell lung cancers (NSCLCs) remain underexplored. METHODS: MTAP status was assessed by next-generation sequencing (NGS) or immunohistochemistry (IHC) in >13 000 NSCLC samples in four cohorts. Prevalence was assessed across oncogenic drivers and temporal dynamics in pre- and post-treatment biopsies. Clinical outcomes were analyzed in EGFR- and ALK-rearranged NSCLC treated with first-line osimertinib and alectinib, respectively. The methylthioadenosine (MTA)-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor BMS-986504 was tested alone and in combination with targeted therapies (TT) in MTAP-deleted models in vitro, ex vivo, and in vivo. RESULTS: MTAP loss was frequent in ALK-rearranged (27% and 33% by NGS; 36% and 45% IHC), RET-rearranged (18.5% and 26% by NGS; 35% by IHC), and EGFR-mutant NSCLC (17% and 24% by NGS; 24% and 29% by IHC), with CDKN2A co-deletion in 98% of cases. MTAP loss was typically present before TT. MTAP loss did not significantly impact response or overall survival with first-line osimertinib or alectinib in EGFR-mutant and ALK-rearranged NSCLC, respectively. In preclinical studies, BMS-986504 showed nanomolar activity in 11/18 MTAP-deleted models, including 5/8 EGFR- and 5/5 ALK-driven models, regardless of TT sensitivity. Synergistic or additive effects with TT were observed in 11/18 models. In ex vivo ALK-rearranged spheroids resistant to crizotinib, the combination of BMS-986504 and alectinib improved antitumor activity over monotherapy. In an osimertinib-resistant, EGFR-mutant patient-derived xenograft model, BMS-986504 with or without osimertinib controlled tumor growth, without weight loss. CONCLUSIONS: MTAP loss is frequent in oncogene-driven NSCLC, particularly in ALK-, RET-, and EGFR-altered subtypes. MTA-cooperative PRMT5 inhibition demonstrates broad activity in MTAP-deleted, oncogene-driven models and, and may enhance targeted therapy efficacy in selected settings.
Cheng Y, Azouzi N, Laurent-Bellue A
… +26 more, Guo Z, Chung T, Zeng Q, Ghodsifard A, Albrecht T, Roessler S, Boulagnon-Rombi C, Vij M, Rela M, Akpinar R, Augustin J, Bazille C, Xu S, Kong S, Lechapt-Zalcman E, Tournigand C, Kempf E, Brustia R, Pawlotsky JM, Braconi C, Caruso S, Ziol M, Goeppert B, Di Tommaso L, Park YN, Calderaro J
BACKGROUND: Intrahepatic cholangiocarcinoma (ICCA) is a rare but highly lethal adenocarcinoma arising within the hepatic parenchyma. Diagnosis presents a significant clinical challenge as the histological features of ICC...BACKGROUND: Intrahepatic cholangiocarcinoma (ICCA) is a rare but highly lethal adenocarcinoma arising within the hepatic parenchyma. Diagnosis presents a significant clinical challenge as the histological features of ICCA substantially overlap with those of metastatic liver cancers. This diagnostic ambiguity often necessitates extensive and costly exclusionary investigations, such as upper and lower gastrointestinal endoscopy, to rule out an occult primary site. Consequently, this process results in treatment delays and an increased financial burden on health care systems. PATIENTS AND METHODS: We retrospectively analyzed 544 patients across five European centers, comprising cases of either ICCA or metastases from extrahepatic cancers. Three deep-learning architectures utilizing foundation models were investigated: CTranspath/HistoBistro, UNI/CLAM, and CONCH/TITAN. Performance was assessed using the area under the receiver operating characteristic curve (AUROC) and the false-positive rate (FPR). Furthermore, we implemented a confidence estimation system using the generalized-ODIN (G-ODIN) approach, utilizing predictive entropy as a metric. The final model, designated AICCA, was prospectively validated in 161 patients across four international centers in France, India, and Korea. RESULTS: In the retrospective test set, the CONCH/TITAN architecture yielded the best performance (AUROC 0.840). Predictive entropy derived via G-ODIN was significantly higher in misclassified cases, validating its utility as a confidence metric. Implementation of confidence thresholding improved the AUROC to 0.958 with an FPR of 0, while retaining 46% of samples for high-confidence prediction. In prospective validation, AICCA achieved AUROCs of 1.00 and 0.965 in the French and Asian cohorts, respectively (with only one misclassified case in the Asian series). CONCLUSIONS: Collectively, our study demonstrates the real-world clinical utility of a confidence-based artificial intelligence biomarker for assisting in the diagnosis of liver cancer. By accurately discriminating ICCA from metastasis, this tool offers the potential to reduce unnecessary investigations and accelerate therapeutic decision-making.