Acquired resistance (AR) to immune checkpoint inhibitors (ICIs) remains a major obstacle to durable clinical benefit in non-small cell lung cancer (NSCLC). Emerging after initial responses, AR reflects tumor evolution, i...Acquired resistance (AR) to immune checkpoint inhibitors (ICIs) remains a major obstacle to durable clinical benefit in non-small cell lung cancer (NSCLC). Emerging after initial responses, AR reflects tumor evolution, immune escape, and metabolic reprogramming. Key mechanisms may include impaired antigen presentation (β2-microglobulin, human leukocyte antigen mutations), T-cell exhaustion, and remodeling of the tumor microenvironment (TME). In this review, we summarize the current understanding of ICIs resistance and highlight therapeutic strategies under investigation to overcome it. Novel approaches include next-generation ICIs targeting TIGIT and LAG-3, epigenetic modulators (HDAC, DNMT inhibitors), and metabolic agents relevant to and mutations. Additional strategies aim to reprogram the TME through AXL or multikinase inhibition, tumor-treating fields, and cytokine- and/or gene-based therapies. Cellular immunotherapies (tumor-infiltrating lymphocytes, T-cell receptors, chimeric antigen receptor-T), antibody-drug conjugates, and vaccines offer complementary means to restore antitumor immunity. Advancing the field will require biomarker-driven patient selection and rational combinations to overcome AR and achieve more durable, personalized immunotherapy outcomes in NSCLC.
Mass spectrometry (MS) offers a minimally invasive approach for detecting monoclonal proteins in multiple myeloma (MM), but large prospective evaluations remain limited. We analyzed 3,301 serum samples from 617 patients...Mass spectrometry (MS) offers a minimally invasive approach for detecting monoclonal proteins in multiple myeloma (MM), but large prospective evaluations remain limited. We analyzed 3,301 serum samples from 617 patients enrolled in the phase III GMMG-HD7 trial to characterize the analytical performance and clinical relevance of MS-based measurable residual activity. MS reliably distinguished therapeutic antibodies, tracked diagnostic M proteins longitudinally, and demonstrated strong prognostic value across defined time points. MS negativity was associated with superior progression-free survival (PFS), with the greatest separation at later time points (12 months of maintenance: hazard ratio, 0.25 [95% CI, 0.15 to 0.43]; adjusted < .001). Combined assessment with bone-marrow measurable residual disease (MRD) further refined risk stratification: MS/MRD double-positive patients exhibited the worst PFS, whereas all other groups showed comparably favorable outcomes. MS/MRD concordance increased over time and was influenced by immunoglobulin isotype, with expected immunoglobulin G-recycling-associated early discordance. MS provided accurate M-protein detection and outperformed serum protein electrophoresis at low concentrations, reliably quantifying low-level residual disease. These findings establish serum MS as a sensitive, reproducible, and practical biomarker that complements MRD and supports minimally invasive disease monitoring in MM, with potential integration into future response assessment and risk-adapted treatment strategies.
PURPOSE: To report the primary analysis of a multicenter, phase III randomized trial of adjuvant radiotherapy (RT) after chemotherapy and radical cystectomy (RC) in patients with high-risk muscle-invasive bladder cancer...PURPOSE: To report the primary analysis of a multicenter, phase III randomized trial of adjuvant radiotherapy (RT) after chemotherapy and radical cystectomy (RC) in patients with high-risk muscle-invasive bladder cancer (MIBC). METHODS: Patients with nonmetastatic urothelial MIBC at high risk after RC (any one of: T3-4, N1-3, margin positive, ≤10 nodes dissected) were randomly assigned 1:1 to adjuvant RT or observation (Obs), stratified by nodal involvement (yes/no) and chemotherapy (neoadjuvant/adjuvant/none). Stoma-sparing IG-IMRT 50.4Gy in 28 fractions was prescribed to the cystectomy bed and pelvic nodes. The primary end point was 2-year locoregional recurrence-free survival (LRFS), and the secondary end points were disease-free survival (DFS), bladder cancer-specific survival (BCSS), and overall survival (OS). RESULTS: From June 2016 to May 2024, 153 patients were randomly assigned (Obs = 76, RT = 77), with 62% and 41% of patients having pT3-T4 and pN+ stages, respectively. Over 90% of the patients received systemic chemotherapy (71% neoadjuvant and 20% adjuvant), and none received immunotherapy. After a median follow-up of 47 months, the 2-year LRFS was significantly higher with adjuvant RT versus observation (87.1% 76.0%, hazard ratio [HR], 0.43 [95% CI, 0.20 to 0.96], = .04). The DFS was 71.6% versus 58.7% (HR, 0.62 [95% CI, 0.36 to 1.05]), BCSS was 79.6% versus 65.0% (HR, 0.59 [95% CI, 0.33 to 1.10]), and OS was 70.4% versus 57.4% (HR, 0.78 [95% CI, 0.49 to 1.26]) for RT and Obs, respectively. CONCLUSION: Adjuvant pelvic IMRT after radical cystectomy and perioperative chemotherapy suggests an improvement in locoregional control in patients with high risk urothelial MIBC with no additional severe toxicity.
PURPOSE: The WSG TP-II trial (ClinicalTrials.gov identifier: NCT03272477) was designed to compare the impact of 12 weeks of neoadjuvant trastuzumab + pertuzumab combined with endocrine therapy (ET) versus chemotherapy (o...PURPOSE: The WSG TP-II trial (ClinicalTrials.gov identifier: NCT03272477) was designed to compare the impact of 12 weeks of neoadjuvant trastuzumab + pertuzumab combined with endocrine therapy (ET) versus chemotherapy (once per week paclitaxel) on the pathologic complete response (pCR) rate and survival in hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (eBC). Analysis of the primary end point revealed that the pCR rate in the paclitaxel + trastuzumab + pertuzumab arm was superior compared with that in the ET + trastuzumab + pertuzumab arm (56.4% 23.7%). METHODS: Here, we present the final 5-year survival analysis of this multicenter, randomized phase II, open-label trial, with 207 participants randomly assigned 1:1 to the two study arms. All patients received dual HER2 blockade in the adjuvant setting. Further standard chemotherapy was obligatory in all patients with non-pCR, but optional after pCR. RESULTS: After a 5-year follow-up, an overall survival rate of 100% (95% CI, 100.0 to 100.0) in the ET arm versus 97.9% (95% CI, 95.0 to 100.0) in the paclitaxel arm was estimated. The corresponding 5-year event-free survival-ductal carcinoma in situ rates were 92.1% (95% CI, 86.6 to 97.9) versus 94.8% (95% CI, 90.5 to 99.3), and 5-year invasive disease-free survival rates were 97.7% (95% CI, 94.5 to 100.0) versus 79.8% (95% CI, 55.6 to 100.0). CONCLUSION: Our results show excellent survival outcomes in patients with hormone receptor-positive/HER2-positive eBC who received either a de-escalated chemotherapy or ET in combination with trastuzumab and pertuzumab in the neoadjuvant setting. WSG TP-II confirms the safety and efficacy of a de-escalated and well-tolerated neoadjuvant therapy approach with pCR-guided adjuvant therapy in hormone receptor-positive/HER2-positive eBC.
Sherry AD, Haymaker C, Wang S
… +27 more, Liu S, Bathala TK, Medina-Rosales MN, Seo A, Hara K, Reddy J, Chun SG, Mayo LL, Walker G, Pant S, Zhao D, Kovitz CA, Ramirez D, Ha CS, Smith BD, Gomez D, Cohen L, Koong AC, Reuben A, Tannir N, Corn PG, Tran PT, Siddiqui BA, Subudhi SK, Msaouel P, Ludmir EB, Tang C
PURPOSE: We tested the hypothesis that adding metastasis-directed therapy (MDT) to standard-of-care (SOC) systemic therapy improves progression-free survival (PFS) among patients with oligometastatic disease. METHODS: EX...PURPOSE: We tested the hypothesis that adding metastasis-directed therapy (MDT) to standard-of-care (SOC) systemic therapy improves progression-free survival (PFS) among patients with oligometastatic disease. METHODS: EXTEND was a multicenter randomized phase II trial. Patients with 1-5 metastases were randomly assigned to MDT + SOC versus SOC in one of the six baskets (breast, pancreas, kidney, two prostate baskets, and an other basket) with basket-specific stratification and powering. PFS, the primary end point, was prespecified in the per-protocol set within each basket, across all baskets, and across all baskets excluding the prostate baskets. Exploratory end points included circulating tumor DNA (ctDNA) and immune profiling. RESULTS: From 2018 through 2023, 521 patients were screened, 350 were randomly assigned, and 334 were analyzed per protocol (MDT + SOC, n = 166; SOC, n = 168). Radiotherapy was used as MDT for 98% of metastases (370/379). Overall, after a median follow-up of 53 months, PFS was improved with MDT + SOC (hazard ratio [HR], 0.54 [95% CI, 0.41 to 0.72], < .001). Similarly, PFS was improved when excluding the prostate baskets (HR, 0.60 [95% CI, 0.40 to 0.89]). Within each basket, PFS superiority was identified for the pancreas, prostate, and other baskets, whereas the breast and kidney baskets were inconclusive. At enrollment, detectable ctDNA correlated with shorter PFS and survival; by contrast, ctDNA clearance 3 months postenrollment correlated with improved survival. MDT + SOC-induced systemic immune activation was most pronounced among baskets demonstrating PFS superiority. CONCLUSION: The phase II EXTEND trial supports the addition of MDT to SOC for oligometastatic disease. Histology-specific efficacy signals were identified for phase III testing. Translational insights suggest the potential for optimizing the definition of oligometastasis using ctDNA and point to systemic immune responses as a possible mechanism of benefit from MDT.
Moon AM, Yanagihara TK, Dawson LA
… +35 more, Yu JI, Lawrence TS, Kim TH, Yan M, Iwata H, Nabavizadeh N, Apisarnthanarax S, Dunne EM, Lock MI, Chuong MD, Chiang CL, Scorsetti M, Katoh N, Sioshansi S, Numata K, Liu HY, Iwamoto H, Wakatsuki M, Chen Y, Pollom EL, Gkika E, Jabbour SK, Munoz-Schuffenegger P, Dutta D, Hajj C, Ueno M, Hallemeier CL, Feldman AM, Méndèz Romero A, Tan X, Molla M, Tepper JE, Torres F, Reig M, EBRT Collaboration Group
J Clin Oncol
· 2026 Jul · PMID 42139645
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PURPOSE: External beam radiation therapy (EBRT) has gained delayed acceptance as a recommended first-line treatment modality for patients with hepatocellular carcinoma (HCC), given limited evidence that it improves overa...PURPOSE: External beam radiation therapy (EBRT) has gained delayed acceptance as a recommended first-line treatment modality for patients with hepatocellular carcinoma (HCC), given limited evidence that it improves overall survival (OS). We analyzed individual patient data (IPD) from an international cohort to assess OS among patients with HCC treated with EBRT. METHODS: We performed a systematic review of publications that assessed EBRT, met prespecified technical standards for HCC, and reported OS (search date December 15, 2022). Corresponding authors were invited to submit IPD for the study. We performed Kaplan-Meier survival analyses to determine OS and restricted mean survival time (RMST) stratified by Barcelona Clinic Liver Cancer (BCLC) stage and treatment status (ie, treatment-naïve and experienced). We performed random effects Cox proportional hazards modeling to assess clinical characteristics associated with OS. RESULTS: Data were provided on 4,913 patients treated with EBRT with a median follow-up time of 5.0 years. The median OS was 6.8 years (95% CI, 5.7 to 8.7) for BCLC-0 and 4.6 years (95% CI, 4.1 to 5.1) for BCLC-A. Among treatment-naïve patients, the median OS was not reached (95% CI, 8.6 to not reached) for BCLC-0 and was 5.4 years (95% CI, 4.5 to 6.7) for BCLC-A. In multivariable models, more advanced BCLC stage, higher tumor burden, worse performance status, and Child-Pugh class B or C were associated with a higher risk of mortality. Ablative radiation dose and more recent year of treatment were associated with a reduced risk of death. CONCLUSION: To our knowledge, this study represents the largest multinational cohort of patients with HCC treated with EBRT. OS outcomes with EBRT for very early- and early-stage HCC appear to be comparable with resection, thermal ablation, and other ablative locoregional therapies. These data support the inclusion of EBRT in the BCLC HCC clinical decision-making process.
PURPOSE: The optimal second-line strategy for patients with extensive-stage small cell lung cancer (ES-SCLC) developing brain-only progression (BOP) after first-line therapy remains undefined. We aimed to evaluate the ef...PURPOSE: The optimal second-line strategy for patients with extensive-stage small cell lung cancer (ES-SCLC) developing brain-only progression (BOP) after first-line therapy remains undefined. We aimed to evaluate the efficacy of continuing the original systemic therapy versus switching strategies. METHODS: This multicenter cohort study screened 889 patients with ES-SCLC. A total of 203 patients developing BOP were assigned to 3 second-line strategies: continuation of original systemic therapy plus brain radiotherapy (OTP + BRT), substitution therapy plus BRT (ST + BRT), or substitution therapy alone (ST). Inverse probability of treatment weighting was used to balance baseline characteristics. The primary end point was overall survival from second-line initiation (OS2). RESULTS: In the inverse probability of treatment weighting-weighted analysis of 203 BOP patients, OTP + BRT demonstrated significantly superior median OS2 (14.7 months) compared with ST (10.2 months; hazard ratio [HR], 1.68; = .028) and ST + BRT (9.8 months; HR, 1.67; = .023). OTP + BRT also yielded improved median second-line progression-free survival (PFS) (8.0 months) versus ST (4.0 months; = .024). Multivariable analysis confirmed OTP + BRT as an independent prognostic factor for improved survival. The benefit was most pronounced in patients with prior immunotherapy and longer initial PFS (≥7.5 months). No significant survival differences were observed among radiotherapy modalities (whole-brain radiotherapy stereotactic radiosurgery). CONCLUSION: For ES-SCLC patients with BOP, continuing the original systemic regimen plus BRT yields superior survival compared with switching systemic therapy. This supports a site-of-progression-directed strategy, effectively controlling the CNS sanctuary while maintaining an effective systemic backbone.
Yang C, Jia Q, Zhao C
… +22 more, Yang X, Wei H, Liu T, Jiao J, Wu Z, Zhao J, Xu W, Zhou Z, Wan W, Zou W, Zhu Z, Ma X, Chen Q, Guo W, Zhu D, Tan T, Lou Y, Ye J, Xing J, Zhang H, Yuan Z, Xiao J
PURPOSE: Limited efficacy of current treatments for chordoma calls for novel therapeutic options. Combination of immune checkpoint inhibitors and antiangiogenic drugs has altered the landscape of cancer treatment but has...PURPOSE: Limited efficacy of current treatments for chordoma calls for novel therapeutic options. Combination of immune checkpoint inhibitors and antiangiogenic drugs has altered the landscape of cancer treatment but has rarely been investigated in chordoma. METHODS: An investigator-initiated, single-center, phase II trial was conducted on camrelizumab (a PD-1 inhibitor, 200 mg once every 2 weeks) plus apatinib (an antiangiogenic drug, 250 mg and 500 mg on alternate days, that is, 250 mg one day, 500 mg the next day, alternating) in patients with refractory chordoma for 4-week cycles. The primary end point was the objective response rate (ORR) per RECIST version 1.1. Secondary end points included ORR per Choi criteria, progression-free survival (PFS), overall survival, the disease control rate, median duration of response (mDoR), safety, and quality of life. The trial is registered with Chictr.org.cn (ChiCTR2100042938). RESULTS: Of the 38 patients initially screened between September 2021 and October 2024, 33 were enrolled. Median follow-up duration was 20.8 months (IQR, 13.35-26.55). ORR was 24.2% (8/33 [95% CI, 11.1 to 42.3]) per RECIST 1.1 and 48.5% (16/33 [95% CI, 30.8 to 66.5]) per Choi criteria. The median PFS was 28.4 months (95% CI, 13.53 to 43.28). The mDoR was not reached per RECIST 1.1 and was 22.2 months (95% CI, 12.5 to not reached) per Choi criteria. copy-number deletion or homozygous deletion was found to associate with worse prognosis. The most common grade 3 or 4 treatment-related adverse events included increased aspartate aminotransferase (13 [39.4%]) and increased alanine aminotransferase (11 [33.3%]). No treatment-related deaths occurred. CONCLUSION: Combination of camrelizumab and apatinib offered encouraging efficacy with manageable toxicity in chordoma treatment. alterations are associated with worse prognosis and may prove to be a potential biomarker for treatment selection.
A poignant reflection on loss and growth, this piece traces how a medical student transforms the grief of losing her aunt in Room 402 into a compassionate and humanistic approach to caring for patients facing the end of...A poignant reflection on loss and growth, this piece traces how a medical student transforms the grief of losing her aunt in Room 402 into a compassionate and humanistic approach to caring for patients facing the end of life.
Vicini FA, Winter K, Freedman GM
… +22 more, Arthur DW, Rosenstein BS, Bentzen SM, Li XA, Halyard MY, Woodward WA, Bleicher RJ, Taghian A, Lyons J, Tomberlin JK, Seaward SA, Cheston SB, Hoover AC, Anderson BM, Perera FE, Poppe MM, Petersen IA, Jhawar S, Hijal T, Moughan J, Movsas B, White JR
J Clin Oncol
· 2026 Jul · PMID 42114027
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PURPOSE: For patients with breast cancer undergoing breast conservation, escalating the dose (boost) of radiation to the lumpectomy cavity after whole-breast irradiation (WBI) reduces ipsilateral breast recurrence (IBR)...PURPOSE: For patients with breast cancer undergoing breast conservation, escalating the dose (boost) of radiation to the lumpectomy cavity after whole-breast irradiation (WBI) reduces ipsilateral breast recurrence (IBR) but extends treatment duration. This phase III trial investigated whether boost delivery during WBI versus after WBI provides noninferior IBR and preserves cosmetic appearance. METHODS: NRG/RTOG 1005 randomly assigned patients at higher risk for IBR after lumpectomy and axillary surgery to either a sequential boost of 12 Gy in six fractions(F) or 14 Gy in 7F after WBI of 50 Gy in 25F or 42.7 Gy in 16F (sequential arm) or a concurrent boost of 8 Gy in 15F of 0.53 Gy per day with WBI of 40 Gy in 15F (concurrent arm) using 3-dimensional conformal radiation therapy (RT) or intensity-modulated RT. Based on 1.59% 5-year IBR for the sequential arm, defining the noninferiority margin as a hazard ratio upper limit on the 90% CI of 2.12, 2,312 patients provide 80% power for noninferiority of IBR as first recurrence for the concurrent arm. Secondary end points included disease-free survival and overall survival, adverse events (AEs), and cosmetic outcomes. RESULTS: Between May 24, 2011, and June 20, 2014, 2,354 patients were randomly assigned, with 2,255 eligible for analysis (sequential arm, n = 1,118; concurrent arm, n = 1,137). With median follow-up of 7.3 years, there were 56 IBR events; 5- and 7-year IBR were 2.1% and 2.2% on the sequential arm and 1.9% and 2.6% on the concurrent arm, respectively. The noninferiority criterion was met: HR (90% CI): 1.31 (0.84 to 2.04), = .037. No differences were observed in AEs, cosmetic outcomes, or survival between arms. CONCLUSION: Concurrent boost during WBI results in noninferior IBR compared with sequential boost without worsening toxicity or cosmetic outcomes and reduces overall treatment time.
PURPOSE: Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) have a poor prognosis, particularly those with human papillomavirus (HPV)-negative disease, in which elevated epidermal gro...PURPOSE: Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) have a poor prognosis, particularly those with human papillomavirus (HPV)-negative disease, in which elevated epidermal growth factor receptor and transforming growth factor-β impair tumor penetration of immune cells and lessen immunotherapy responses. METHODS: We present results from an expansion cohort of a first-in-human phase I/Ib trial (ClinicalTrials.gov identifier: NCT04429542) evaluating first-line treatment with ficerafusp alfa 1,500 mg once every week in combination with pembrolizumab 200 mg once every 3 weeks administered intravenously in patients with R/M HNSCC overexpressing PD-L1 (combined positive score ≥1). The primary end point was safety. Secondary end points included objective response rate (ORR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS). RESULTS: Between February 2022 and April 2023, 42 patients received ≥1 dose of study drug and 39 were included in the efficacy-evaluable set (≥1 postbaseline scan). The median follow-up was 26.3 months. Nineteen of 42 patients (45%) had a grade 3 treatment-related adverse event (TRAE), and one (2%) had a grade 4 TRAE. The most common grade ≥3 TRAEs were anemia (14%) and acneiform dermatitis (12%). In efficacy-evaluable patients with HPV-negative (n = 28) or HPV-positive (n = 11) tumors, confirmed ORRs were 54% (complete response in 21%) and 27%, respectively. In the HPV-negative subgroup, median DOR was 21.7 months (95% CI, 6.0 to not estimable [NE]), median PFS was 9.9 months (95% CI, 4.4 to 22.7), and median OS was 21.3 months (95% CI, 9.9 to NE). CONCLUSION: Ficerafusp alfa plus pembrolizumab demonstrated favorable safety and tolerability with promising antitumor activity in the first-line treatment of R/M HNSCC, particularly in those with HPV-negative tumors.
McKay RR, Xie W, Ajmera A
… +19 more, Araneta A, Jamieson C, Folefac E, Hussain A, Kyriakopoulos CE, Manning DK, Olson A, Parikh M, Parikh R, Saraiya B, Pasquina LW, Madison R, Clifford S, Childress M, Gasco A, Ivy P, Van Allen E, Kochupurakkal B, Shapiro GI
PURPOSE: Radium-223 is an α-emitting radiopharmaceutical that improves survival in metastatic castration-resistant prostate cancer (mCRPC). Preclinical data suggest synergy between poly(ADP-ribose) polymerase (PARP) inhi...PURPOSE: Radium-223 is an α-emitting radiopharmaceutical that improves survival in metastatic castration-resistant prostate cancer (mCRPC). Preclinical data suggest synergy between poly(ADP-ribose) polymerase (PARP) inhibition and radiation. After phase I dose-finding, we conducted a randomized phase II trial to assess efficacy and safety of this combination versus radium-223. PATIENTS AND METHODS: Men with mCRPC and ≥2 bone metastases (BM) were randomly assigned 1:1 to olaparib (200 mg twice daily) plus radium-223 (55 kBq/kg intravenous once every 4 weeks × 6 doses) or radium-223. Crossover was allowed at progression. The primary end point was investigator-assessed radiographic progression-free survival (rPFS). RESULTS: A total of 120 patients were randomly assigned. Most had prior androgen receptor pathway inhibitor exposure (96%), 52% had received docetaxel, 47% had >20 BM, and 90% received bone-protecting agents. The combination significantly improved rPFS (median 8.9 4.7 months; hazard ratio [HR], 0.50 [one-sided 90% CI, 0.35 to 0.70]; one-sided = .0042). The benefit was most pronounced in patients without prior docetaxel (13.7 5.7 months; HR, 0.24 [90% CI, 0.15 to 0.40]) and those with ≤20 BM (13.4 4.2 months; HR, 0.21 [90% CI, 0.13 to 0.33]). The 1-year cumulative incidence of symptomatic skeletal-related events was lower with the combination (12.7% 22.9%). Median overall survival was similar (20.2 21.1 months). Grade ≥3 treatment-related adverse events occurred in 56% versus 33% (combination radium-223), primarily hematologic, including lymphopenia (31% 9.1%), anemia (22% 16%), and thrombocytopenia (6.8% 3.6%). CONCLUSION: Olaparib plus radium-223 significantly prolonged rPFS compared with radium-223 in men with mCRPC and BM. Despite increased hematologic toxicity, the regimen was manageable and supports further exploration of DNA damage-targeted strategies in this population.