Vijay Patil

PURPOSE: Immune checkpoint inhibitors (ICIs) achieve sufficient receptor occupancy at much lower than standard approved doses. We hypothesized that ultra-low-dose nivolumab would retain clinical efficacy. PATIENTS AND METHODS: In this phase III randomized superiority trial, patients with advanced solid tumors (Eastern Cooperative Oncology Group 0-1) and progression on ≥1 prior line of systemic therapy were randomly assigned 1:1 to ultra-low-dose nivolumab (20 mg intravenously once every 2 weeks) or standard chemotherapy (docetaxel or paclitaxel, as per tumor type). Treatment continued until progression or intolerable toxicity. The primary end point was overall survival (OS). RESULTS: From June 2020 to February 2024, we enrolled 500 patients: 250 per arm; 52% had head and neck and 36% lung cancers. The median number of prior lines of therapy was 1 (range, 1-8); 29% had received ≥2 prior lines. Median OS was significantly longer with ultra-low-dose nivolumab: 5.88 months (95% CI, 4.99 to 7.13) versus 4.70 months (95% CI, 3.91 to 5.65; hazard ratio [HR], 0.80 [95% CI, 0.66 to 0.97]; P = .022). One-year OS was 27.3% versus 16.9%. Median progression-free survival was similar: 2.04 months (95% CI, 2.00 to 2.10) with ultra-low-dose nivolumab and 2.09 months (95% CI, 2.04 to 2.17) with chemotherapy (HR, 1.03 [95% CI, 0.86 to 1.23]; P = .77). Grade ≥3 treatment-related adverse events were less frequent with ultra-low-dose nivolumab (42.5% v 60.8%; P < .001). Quality of life (QoL) was significantly better with ultra-low-dose nivolumab. CONCLUSION: Ultra-low-dose nivolumab significantly improves OS versus chemotherapy in pretreated solid tumors, with fewer severe toxicities and better QoL. These findings support re-evaluation of ICI dosing strategies and may enhance global access.

PURPOSE: Abiraterone acetate (AA) is widely used for metastatic castration-resistant prostate cancer (mCRPC), but the standard dose (1000 mg fasting) imposes challenges in resource-constrained settings due to strict fasting requirements and financial toxicity. Pharmacokinetic (PK) studies suggest that low-dose AA (250 mg with a low-fat meal) may provide comparable drug exposure, although clinical evidence remains limited. This trial compared the clinical efficacy of low-dose versus standard-dose AA. MATERIALS AND METHODS: This multicenter, open-label, phase III, noninferiority trial randomly assigned patients with mCRPC, 1:1, to low-dose or standard-dose AA. The primary end point was prostate-specific antigen progression-free survival (PSA-PFS). Secondary/exploratory end points included PSA ₃₀ /PSA ₅₀ responses (% of patients with ≥30% or ≥50% reduction in PSA), radiographic PFS, overall PFS, overall survival (OS), quality of life (QoL), and PK. Planned sample size of 314 (on the basis of a noninferiority margin of hazard ratio, 1.37) was not achieved because of slow accrual, so the noninferiority hypothesis could not be tested. RESULTS: A total of 164 patients were enrolled between September 2020 and January 2025 (median age 65 years; 64.0% received prior docetaxel). PSA ₃₀ and PSA ₅₀ responses were 50.0% and 38.5% with low-dose AA versus 55.4% ( P = .505) and 45.9% ( P = .350) with standard-dose AA, respectively. Median follow-up was 17.5 months. Median PSA-PFS was 5.7 months with low-dose versus 3.8 months ( P = .830) with standard-dose AA. Median OS was 18.1 versus 15.8 months ( P = .976). Grade ≥3 toxicities occurred in 38.3% versus 30.0% ( P = .269), respectively. PK analyses demonstrated approximately 8-fold higher AA exposure with standard dose. QoL scores were comparable between arms. CONCLUSION: Although underpowered to prove noninferiority, low-dose AA with food yielded outcomes broadly similar to standard dosing, with maintained safety and QoL. This cost-conscious regimen may be a feasible alternative, supporting further confirmatory evaluation.

PURPOSE: Platinum-refractory advanced head and neck squamous cell carcinoma (HNSCC) has poor outcomes and limited treatment options, especially in resource-constrained settings. Triple oral metronomic chemotherapy (OMCT), involving low-dose continuous administration of chemotherapeutic agents, has shown promise in phase II studies but lacks evidence from randomized controlled trials. This study evaluated whether triple OMCT improves overall survival (OS) compared with chemotherapy of physician discretion (CPD). PATIENTS AND METHODS: In this phase III randomized open-label study, 214 patients with advanced HNSCC who had previous platinum-based chemotherapy were randomly assigned 1:1 to receive either triple OMCT (arm A) with erlotinib, celecoxib, and methotrexate, or CPD (arm B). The primary end point was OS, with secondary end points including progression-free survival (PFS), quality of life (QOL), and safety. Kaplan-Meier and log-rank tests were used for OS and PFS, and Cox-proportional hazard models estimated hazard ratios. QOL was evaluated using European Organisation for Research and Treatment of Cancer QLQ-C30 and FACT H&N. RESULTS: Median OS was 5 months in arm A and 3.1 months in arm B (hazard ratio [HR], 0.63 [95% CI, 0.47 to 0.83]; P = .00011). Median PFS was 4.8 months in arm A and 2.7 months in arm B (HR, 0.67 [95% CI, 0.52 to 0.87]; P < .0001). Previous treatment was a significant prognostic factor for OS, while age, tumor site, and previous treatment were significant for PFS. Triple OMCT improved global health status, physical functions, fatigue, and insomnia. It was well tolerated, with fewer grade 3 or higher adverse events than CPD (28.0% v 39.3%, P = .03). CONCLUSION: Triple OMCT is an effective and safe treatment for advanced HNSCC after platinum-based chemotherapy.

PURPOSE: Lineage-specific cellular plasticity is one of the emerging hallmarks of cancer. The undifferentiated state of anaplastic thyroid cancer (ATC) represents an instance of cellular plasticity where lineage-specific molecular markers are underacknowledged. In this study, we identified recurrent mutations in the thyroid hormone receptor α ( THRA ) gene, which may play a role in lineage-specific cellular plasticity in ATC. MATERIALS AND METHODS: We performed whole-exome sequencing and targeted sequencing of 68 formalin-fixed paraffin-embedded orphan tumors of ATC from Indian patients. RESULTS: Our analysis reveals the hallmark mutations in TP53 (approximately 42%), BRAF (approximately 10.3%), KRAS (approximately 2.9%), NRAS (29.4%), HRAS (23.5%), NF1 (1.5%), AKT1 (approximately 2.9%), and PIK3CA (approximately 1.5%) genes. Interestingly, we found significant mutations in THRA (approximately 11%) in our cohort, unlike the White population, which is a substantial gene in the thyroid cell's differentiation process. THRA mutations co-occur with TP53 and other hallmark genes, which suggests a synergetic molecular mechanism in phenotypic change in ATC. CONCLUSION: Our data reveal the significant association of THRA mutations potentially influencing cellular plasticity in a subset of patients with ATC.

PURPOSE: Thyroid dyshormonogenesis, a form of congenital hypothyroidism, is characterized by defects in thyroid hormone synthesis genes, affecting both children and adults. However, the potential link between such genetic defects and the development of papillary thyroid cancer (PTC) remains unclear. METHODS: We conducted whole-exome sequencing on 100 (N = 100) tumor-normal paired and orphan tumor samples of PTC from Indian patients, characterizing both germline and somatic molecular alterations. RESULTS: We identified significant germline mutations in the DUOX2 gene (approximately 8.8%), commonly associated with congenital hypothyroidism and thyroid dyshormonogenesis, and found these mutations to correlate with poor prognosis in PTC. Additionally, hallmark somatic mutations were detected in genes such as BRAF (35.4%), KRAS (3.8%), HRAS (5.1%), and NRAS (17.7%), which are well-known drivers of PTC. Importantly, we identified a distinct molecular subtype termed independent of BRAF-RAS (iBR), characterized by nonhallmark alterations and associated with a higher recurrence rate and poorer recurrence-free survival in Indian patients with PTC, highlighting the clinical significance of these molecular insights in prognosis and treatment strategies. CONCLUSION: Our analysis of PTC among Indians revealed novel genetic alterations and molecular subtypes. We identified a germline mutation in the DUOX2 gene, associated with congenital hypothyroidism, as a potential risk factor of PTC. Additionally, we characterized distinct molecular subtypes, BRAF-RAS driven and iBR driven, and their clinical implications. These findings provide valuable insights into the genetic landscape of thyroid cancer in Indian patients and offer potential avenues for targeted therapies.

PURPOSE: Gene fusions are critical oncogenic mutations that drive cancer development and serve as diagnostic and prognostic biomarkers. Despite the increasing cancer burden in India, large-scale analyses of molecular landscapes, particularly gene fusions, have been relatively scarce. MATERIALS AND METHODS: This retrospective study used RNA-exome data from 1,392 Indian patients with cancer across 15 major cancer types to explore gene fusions. The study used a comprehensive framework that integrated open-source and proprietary tools to detect gene fusions from formalin-fixed paraffin-embedded tumor samples. The process involved RNA extraction, RNA-exome library preparation, and analysis using tools such as FastQC, DRAGEN RNA Pipeline, STAR-Fusion, and FusionInspector. We validated and filtered potential false-positive fusion calls using AGFusion and FusionAnnotator to annotate fusion breakpoints and their functional impact through various in silico tools. RESULTS: The study found a notable prevalence of FGFR fusions across cancer types, especially FGFR3, with FGFR3::TACC3 as the most recurrent. Kinase fusions were prevalent in the cohort accounting for 37% of incidence in the patients. We also identified 91 novel potential driver fusions, including those involving FGFR2 , MET , ESR1 , and PDGFRA. CONCLUSION: This study underscores the critical role of gene fusions as biomarkers in cancer, extending beyond fusion-driven malignancies to encompass all cancer types. Gene fusions serve as both diagnostic markers and tumor-agnostic therapeutic targets within the current cancer treatment paradigm. Our insights into the prevalence of oncogenic drivers and novel targets expand the understanding of gene fusions, shedding new light on their mechanisms and clinical implications.

PURPOSE: Medullary thyroid cancer (MTC) is a rare cancer originating from parafollicular C cells of the thyroid gland. Therapeutically relevant alterations in MTC are predominantly reported in RET oncogene, and lower-frequency alterations are reported in KRAS and BRAF . Nevertheless, there is an unmet need existing to analyze the MTC in the Indian cohort by using in-depth sequencing techniques that go beyond the identification of known therapeutic biomarkers. MATERIALS AND METHODS: Here, we characterize MTC using integrative whole-exome and whole-transcriptome sequencing of 32 MTC tissue samples. We performed clinically relevant variant analysis, molecular pathway analysis, tumor immune-microenvironment analysis, and structural characterization of RET novel mutation. RESULTS: Mutational landscape analysis shows expected RET mutations in 50% of the cases. Furthermore, we observed mutations in known cancer genes like KRAS , HRAS , SF3B1 , and BRAF to be altered only in the RET -negative cohort. Pathway analysis showed differential enrichment of mutations in transcriptional deregulation genes in the RET -negative cohort. Furthermore, we observed novel RET kinase domain mutation Y900S showing affinity to RET inhibitors accessed via molecular docking and molecular dynamics simulation. CONCLUSION: Altogether, this study provides a detailed genomic characterization of patients with MTC of Indian origin, highlighting the possible utility of targeted therapies in this disease.

PURPOSE: Desmoid fibromatosis (DF) is a locally aggressive tumor with low mortality but significant morbidity. There is a lack of standard of care, and existing therapies are associated with significant barriers including access, cost, and toxicities. This study aimed to explore the efficacy and safety of the metronomic therapy (MT) in DF in a large, homogenous cohort from India. PATIENTS AND METHODS: This study involved histologically confirmed DF cases treated with MT comprising vinblastine (6 mg) and methotrexate (15 mg) both once a week, and tamoxifen (40 mg/m²) in two divided doses once daily between 2002 and 2018. RESULTS: There were 315 patients with a median age of 27 years; the commonest site was extremity (142 of 315; 45.0%). There were 159 (50.1%) male patients. Of the 123 (39.0%) prior treated patients, 119 had surgery. Of 315 patients, 263 (83.5%) received treatment at our institute (MT—151, 77—local treatment, 9—tyrosine kinase inhibitor, and 26 were observed). Among the MT cohort (n = 163, 61.2%), at a median follow-up of 36 (0.5-186) months, the 3-year progression-free and overall survival were 81.1% (95% CI, 74.3 to 88.4) and 99.2% (95% CI, 97.6 to 100), respectively. There were 35% partial responses. Ninety-two patients (56.4%) completed 1-year therapy, which was an independent prognosticator ( P < .0001; hazard ratio, 0.177 [95% CI, 0.083 to 0.377]). MT was well tolerated. Predominant grade ≥3 toxicities were febrile neutropenia, 12 (7.4%) without any chemotoxicity-related death. The annual cost of MT was $130 US dollars. CONCLUSION: The novel, low-cost MT qualifies as one of the effective, less toxic, sustainable, standard-of-care options for the treatment of DF with global reach and merits wide recognition.

The study depicts significance of TMB as a biomarker, variable across cancers and populations/ethnicities.