Nandini Menon

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: Intermediate-risk and poor-risk nonseminomatous germ cell tumors (NSGCTs) have inferior survival outcomes compared with earlier stages. This study reports the survival outcomes and proposes a prognostic reclassification to identify the poorest risk subset within these groups. METHODS: A retrospective analysis was conducted on consecutive patients 15 years and older with intermediate-risk or poor-risk NSGCTs, as per the International Germ Cell Cancer Collaborative Group classification, treated at a tertiary cancer center in western India from 2015 to 2021. Survival outcomes were analyzed using the Kaplan–Meier method, with multivariate analyses identifying prognostic factors. A risk factor model and nomogram were developed and compared with the existing classification. RESULTS: A total of 400 patients were included with a median follow-up of 60.2 months; 5-year overall survival (OS) was 84.6% for intermediate-risk and 52.6% for poor-risk patients ( P < .001). Five-year relapse-free survival (RFS) was 77.0% and 45.6%, respectively ( P < .001). Age 35 years and older; mediastinal primary; and liver, lung, and brain metastases were significant factors for both RFS and OS by multivariate analyses. Additionally, lactate dehydrogenase >10× upper limit of normal was significant for RFS while alpha-fetoprotein >10,000 ng/mL was significant for OS. The risk factor model stratified patients (0, 1, 2, ≥3 factors) with 5-year OS of 90.3%, 69.6%, 53.8%, and 27.1%, respectively, outperforming existing classification (c-index: 0.668 v 0.629 for OS; 0.666 v 0.619 for RFS). A validated nomogram further enhanced prognostic precision. CONCLUSION: This largest single-center Indian cohort of intermediate-risk and poor-risk NSGCTs identifies a “poorest risk” subset who may benefit from treatment intensification and novel strategies.

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: Carica papaya leaf extract (CPLE) is known to increase platelet counts (PCs) in certain infections. METHODS: Patients were randomly assigned in a 2:1 ratio to the CPLE or placebo arm and continued treatment until the PC improved to 75,000 × 10 ⁹ /L or above, a platelet transfusion was required, or upto D+10. The primary outcome was to evaluate whether CPLE improves PC faster compared with placebo in a significant proportion of patients with a modified intention-to-treat protocol. RESULTS: Between March 2020 and October 2024, 219 patients were randomly assigned, of whom 198 patients (CPLE arm: 129; placebo arm: 69) were analyzed for outcomes. The primary end point with modified intention-to-treat analysis showed a statistically significant increase in PC to ≥75,000 × 10 ⁹ /L in a greater proportion of patients by D+4 compared with placebo (59% v 44%; P = .042). The primary outcome of increasing PC >75,000 × 10 ⁹ /L at D+4 was significantly improved by CPLE (83/129, 64% v 33/69, 48%; P = .034) compared with placebo as per protocol analysis. There was no grade 3 or grade 4 treatment-related adverse events associated with CPLE. About 43% of patients in the placebo arm versus 25% of patients in the CPLE arm needed dose reductions or delays in their subsequent chemotherapy treatment for patients with grade 2 chemotherapy-induced thrombocytopenia (CIT) at the baseline ( P 0.033) and not significant in grade 3 CIT. CONCLUSION: CPLE is a potential therapeutic intervention to improve CIT faster and to a greater extent than placebo in this phase III randomized trial without any safety concerns. It could be potentially used as a secondary prophylaxis to maintain the chemotherapy intensity.

Purpose: Phakomatoses‐associated primary central nervous system (CNS) tumors are therapeutically challenging due to young age of onset, multiple tumors, and prolonged morbidity from long‐term survival. This study evaluated demographics, survival, and prognostic factors of patients with phakomatoses‐associated CNS tumors treated at a specialized neuro‐oncology service in India. Materials and Methods: Consecutive patients diagnosed and managed between 2000 and 2022 were included in this retrospective study. Data were retrieved from electronic medical records. Treatment decisions were multidisciplinary and included maximal safe resection, radiation (RT), and systemic therapy as indicated. Kaplan–Meier survival analysis evaluated overall survival (OS) and progression‐free survival (PFS). Univariate analyses used the log‐rank test, and multivariate analyses the restricted mean survival time. Results: A total of 121 patients were analysed: NF1 (61.2%), NF2 (23.1%), VHL (10.7%), and TSC (5.0%). For NF1, median follow‐up was 36.5 months (95% CI: 1–254); 3‐year PFS and OS were 76.4% (95% CI: 66.5–87.8) and 87.7% (95% CI: 80.1–96.1) respectively. On univariate analysis, NF1 high‐grade glioma patients who did not receive RT had inferior outcomes, though not significant on RMST. For NF2, median follow‐up was 40.5 months (95% CI: 1–199); 5‐year PFS and OS were 37.3% (95% CI: 20.5–68.1) and 100% respectively. For VHL, median follow‐up was 66.5 months (95% CI: 3–426); 5‐year PFS and OS were 77.9% (95% CI: 54.6–100) and 100% respectively. For TSC, median follow‐up was 71 months (95% CI: 1–228); 5‐year PFS and OS were 75% (95% CI: 42.5–100) and 100% respectively. Conclusion: Phakomatoses‐associated CNS tumors show promising outcomes with multimodality management. Further research into targeted multimodality treatment is warranted.

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.