Bipinesh Sansar

KRAS mutations represent the most common oncogenic driver in Western NSCLC and a major therapeutic challenge historically deemed “undruggable.” The approval of allele-specific KRAS G12C inhibitors has transformed management, yet overall survival gains remain modest and resistance is inevitable. Rapid advances in next-generation KRAS inhibitors, rational combinations, and mutant-specific strategies (G12D, G12V) necessitate an updated synthesis of evolving evidence. To critically review the therapeutic landscape of KRAS-mutant NSCLC, covering biological underpinnings, clinical efficacy of approved and investigational inhibitors, mechanisms of resistance, combination strategies, and emerging paradigms likely to redefine future standards of care. A comprehensive narrative review of published clinical trials, translational studies, resistance-mechanism analyses, and real-world datasets focusing on KRAS-mutant NSCLC. Key sources include phase I–III trials of sotorasib, adagrasib, next-generation G12C inhibitors, mutant-specific G12D inhibitors, and ongoing combination studies integrating KRAS blockade with immunotherapy, MAPK-axis inhibitors, SHP2/SOS1 inhibitors, EGFR/MET inhibitors, and chemotherapy. Sotorasib and adagrasib achieve ORRs of 37–43% and median PFS ~ 6–7 months in previously treated KRAS G12C NSCLC, with improved tolerability over docetaxel. Next-generation inhibitors (olomorasib, divarasib, glecirasib, D-1553, IBI351) demonstrate ORRs 45–55% and, in some studies, PFS exceeding first-generation agents, while emerging KRAS G12D inhibitors show early proof-of-concept activity. Resistance arises through on-target KRAS alterations, RTK-RAS bypass signaling, MAPK/PI3K pathway reactivation, and co-mutation–driven phenotypic remodeling. Combination strategies—particularly KRAS inhibitor + PD-1 blockade, SHP2/SOS1 inhibition, EGFR/MET inhibition, or platinum doublets—are yielding higher response rates and deeper, more durable suppression in early trials. KRAS-mutant NSCLC is transitioning from historically untargetable disease to a therapeutically actionable subset. Future progress hinges on resistance-directed combinations, biomarker-guided personalization, expansion to non-G12C mutants, and evaluation in earlier disease settings.

PURPOSE: Homologous recombination repair (HRR) pathway defects are critical drivers of hereditary cancers, yet population-specific prevalence data from India remain limited. Current testing practices disproportionately focus on BRCA1/2 , potentially underidentifying patients with other HRR gene variants who could benefit from targeted therapies. METHODS: A retrospective observational cohort study was conducted, analyzing 950 consecutive patients who underwent next generation sequencing-based germline testing at the Cancer Genetics Clinic, Mahamana Pandit Madanmohan Malaviya Cancer Centre, Varanasi. The core HRR panel included BRCA1 , BRCA2 , PALB2 , RAD51C , RAD51D , ATM , CHEK2 , BRIP1 , BARD1 , RAD50 , NBN , MRE11 , and FANCC . RESULTS: Of 950 patients analyzed, 364 (38.3%) harbored variants in HRR genes, with 266 (28%) carrying pathogenic/likely pathogenic (P/LP) variants . BRCA1 was the most frequently altered gene (182/266, 68.4% of P/LP variants), followed by BRCA2 (37/266, 13.9%). Combined BRCA1/2 genetic variants accounted for 219/266 (82.3 17%) of all P/LP variants. Non- BRCA HRR genes contributed 47/266 (17.6%) P/LP variants, with PALB2 being the most common (14/266, 5.2%). The study identified 98 variants of uncertain significance across the HRR genes. CONCLUSION: This large Indian cohort demonstrates a high prevalence of HRR gene alterations, with significant contribution from non- BRCA genes. These findings support the implementation of comprehensive HRR gene panels in Indian populations and highlight the therapeutic implications for poly (ADP-ribose) polymerase inhibitor and platinum-based treatment strategies.

PURPOSE: Biliary tract cancers (BTCs), particularly gallbladder carcinoma (GBC), are highly aggressive and exhibit significant geographical disparity, with a high incidence in Northern India. Human epidermal growth factor receptor 2 (HER2) amplification represents a key targetable alteration in a subset of patients. This study evaluates the real-world outcomes of trastuzumab in combination with chemotherapy for HER2-positive BTCs. METHODS: A retrospective analysis of 91 patients with HER2-positive (immunohistochemistry 2+ amplified or 3+) BTCs was conducted. Patient characteristics and treatment details were summarized using descriptive statistics. The primary end points were progression-free survival (PFS) and overall survival (OS), estimated using the Kaplan-Meier method and compared with the log-rank test. RESULTS: The median age was 50 years, with a female predominance (70.3%). Nearly all patients had GBC (98.9%) and HER2 3+ positivity (91.2%); 76.9% had metastatic disease. Trastuzumab was administered to 49 patients (53.8%), mostly in the first line (38.5%). The median PFS was 11.8 months (95% CI, 7.7 to 15.8) with trastuzumab versus 2.8 months (95% CI, 2.4 to 3.1) without ( P < .001). The median OS was 17.3 months (95% CI, 13.5 to 21.1) with trastuzumab versus 5.8 months (95% CI, 4.3 to 7.3) without ( P < .001). The 2-year OS rate was 32.7% for the trastuzumab group versus 11.8% for the control group. CONCLUSION: In this real-world cohort from a high-incidence region, trastuzumab-based therapy was associated with a significant and clinically meaningful improvement in survival outcomes for HER2-positive BTCs. These findings strongly support routine HER2 testing and the integration of trastuzumab into the treatment arsenal for this molecularly defined subgroup.

Background: Carbapenem‐resistant gram‐negative infections pose a major public health challenge in India due to high antibiotic consumption, limited diagnostic access, and regional variation in resistance mechanisms. We systematically reviewed recent data to evaluate prevalence, diagnostics, and therapeutic strategies. Methods: Following PRISMA 2020 guidelines, we searched PubMed, Scopus, Embase, and Google Scholar for studies (January 2019–December 2024) reporting carbapenem resistance in clinical gram‐negative isolates from India. Data on prevalence, molecular mechanisms, diagnostics, and treatment outcomes were extracted. Study quality was assessed using the Joanna Briggs Institute (JBI) Checklist. Results: From 75 studies (> 25,000 isolates), pooled resistance rates were K. pneumoniae 42.3%, E. coli 35.6%, A. baumannii 58.9%, and P. aeruginosa 41.7%. NDM (65%) and OXA‐48‐like (20%) enzymes predominated. Only 38% of studies employed rapid molecular diagnostics. Treatment strategies included ceftazidime‐avibactam ± aztreonam, colistin‐based regimens, and cefiderocol, but outcomes were inconsistent. Conclusions: Carbapenem resistance in India remains alarmingly high, primarily driven by NDM and OXA‐type carbapenemases. Optimised diagnostics, improved access to effective antimicrobials, robust antimicrobial stewardship, and national surveillance are critical to mitigate its growing clinical and public health impact.

PURPOSE: The human microbiome is increasingly recognized as a key modifier of carcinogenesis, immune regulation, and treatment response. In lung cancer, characterization of both respiratory and gut microbiomes offers opportunities to identify biomarkers and therapeutic targets. However, methodologic variability limits reproducibility and clinical translation. The objective was to systematically evaluate current microbiome testing methodologies in lung cancer, focusing on sequencing-based profiling and short-chain fatty acid (SCFA) analysis. METHODS: A systematic search of PubMed, Scopus, and Web of Science identified human lung cancer studies (2014-2023) employing 16S rRNA gene sequencing, shotgun metagenomics, metatranscriptomics, or SCFA quantification. Eligible studies were assessed per PRISMA guidelines for design, analytic workflow, and key findings. RESULTS: Eighty-seven studies met inclusion criteria. Most (86%) used 16S rRNA sequencing, primarily on bronchoalveolar lavage, bronchial brushings, or stool. Shotgun metagenomics (9%) provided higher taxonomic and functional resolution, while SCFA analysis (14%), mainly via gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry, explored gut-lung interactions. Substantial heterogeneity was noted in DNA extraction, targeted 16S regions, sequencing platforms, and bioinformatic pipelines, complicating cross-study comparison. Across studies, lung cancer samples showed reduced alpha diversity and enrichment of taxa such as Streptococcus and Veillonella . SCFA studies suggested higher fecal butyrate and propionate levels were associated with favorable immunotherapy responses. CONCLUSION: Methodologic inconsistency across microbiome testing platforms remains a major barrier to validation of microbial biomarkers in lung cancer. Standardized protocols for sampling, sequencing, and SCFA quantification are essential for reproducibility. Incorporating harmonized microbiome assays into immuno-oncology trials could improve biomarker reliability, refine patient stratification, and advance precision cancer care.

ALK‐rearranged non–small cell lung cancer (NSCLC) represents a paradigm of precision oncology, but acquired resistance to second‐generation ALK tyrosine kinase inhibitors (TKIs) such as alectinib remains inevitable. We report a young, nonsmoker male with ALK‐positive metastatic NSCLC who achieved a sustained complete response (CR) to brigatinib following alectinib resistance mediated by the ALK I1171N mutation. After 22 months of response to alectinib, disease progression prompted repeat molecular profiling, which identified the I1171N alteration. Brigatinib was initiated, and a complete radiologic response was documented within 3 months and has been sustained for over 12 months, including durable intracranial disease control. Sustained CR in I1171N‐mediated alectinib resistance is rare and highlights the critical role of repeat molecular testing to guide ALK TKI sequencing.

Background: Establishing benchmarks for extravasation incidences with systemic anti-cancer therapy from various global regions is crucial. Reliable data can inform practices aimed at reducing both the occurrence and severity of extravasation events. Methods: This prospective observational study evaluated extravasation incidences in patients receiving systemic anti-cancer therapy for solid tumors at a tertiary oncology daycare center over a period of 15 months. Multiple risk factors potentially contributing to extravasation and influencing its severity were systematically recorded and analyzed. Results: Out of 66,540 infusions, a total of 58 extravasation cases were identified, resulting in an overall incidence of 0.087%. The extravasation incidence was 0.13% for vesicant drugs and 0.045% for irritant drugs. Specifically, DNA-binding vesicants had an incidence of 0.2%, while non-DNA binding vesicants had an incidence of 0.11%. The predominant symptom reported was infusion site swelling (86%), followed by pain (43%) and erythema (36%). Grade 3 extravasation occurred in 13 cases (22.4%), with vesicants responsible for all but one event. Median symptom resolution time was 20 days overall, extending to 40 days in grade 3 cases. Notably, the occurrence of symptoms either during infusion or within 6 h post-infusion significantly correlated with milder grade 1 extravasations, lower incidence of severe grade 3 cases, and quicker symptom resolution within three weeks. Conclusions: Daycare oncology centers should implement standardized protocols for systemic therapy administration, emphasizing preventive strategies and prompt identification and management of extravasation to reduce associated morbidity.

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.