Targeted Oncology最新文献

Background: Adavosertib is a highly selective, small molecule Wee1 inhibitor that sensitizes tumor cells to cytotoxic agents.

Objective: We report results from the lead-in cohorts of two phase II studies: carboplatin/pemetrexed plus adavosertib versus carboplatin/pemetrexed in first-line metastatic non-squamous non-small-cell lung cancer (NSCLC) (NCT02087241); and docetaxel plus adavosertib versus docetaxel in recurrent NSCLC (NCT02087176).

Patients and methods: Both lead-in cohorts assessed early safety and efficacy (objective response rate [ORR]). First-line metastatic treatment was carboplatin (area under the curve to 6 h [AUC₆]) plus pemetrexed 500 mg/m² intravenously on day 1, every 21 days; recurrent treatment was docetaxel 75 mg/m² intravenously on day 1 plus prophylactic granulocyte-colony stimulating factor 6 mg subcutaneously on day 4 every 21 days. All patients received adavosertib 225 mg twice daily orally on days 1-3 (five doses). After a planned safety analysis of the first-line trial, dose and schedule were modified to reduce toxicity.

Results: First-line: 14 patients were enrolled in four treatment cohorts. Median time on trial was 17.3 weeks, with an ORR of 29%. The most common adverse events were diarrhea (50%), nausea (50%), vomiting (50%), anemia (43%), neutropenia (43%), decreased appetite (43%), and dehydration (43%). Recurrent: 32 patients were enrolled. The ORR was 9%. The most common adverse events were diarrhea (66%), anemia (50%), nausea (47%), fatigue (47%), vomiting (44%), and thrombocytopenia (41%).

Conclusions: Both studies terminated early; the recurrent study after an interim analysis showed increased toxicity and limited efficacy, and the first-line study after a change in first-line standard of care.

Trial registrations: ClinicalTrials.gov, NCT02087241 and NCT02087176.

The advent of comprehensive genomic sequencing has catalysed the emergence of paediatric precision medicine platforms globally. These have established the feasibility of profiling tumours at scale, enhancing our understanding of the genetic landscape of paediatric tumours and enabling identification of driver mutations and actionable targets. In turn, this has created the opportunity for development of novel precision-guided therapies (PGT). This commentary synthesizes evidence from major collaborative trials with a focus on outcome reporting, particularly in the relapsed/refractory and high-risk patient cohorts. Patients receiving PGT in these cohorts demonstrate meaningful responses and survival benefit, particularly when treatment is based on high-level clinical evidence and administered early in the disease course. However, challenges remain in addressing low uptake of PGT, likely hindered by substantial barriers in access and complex pharmaceutical regulatory constraints. Furthermore, heterogeneity in recommendation and outcome reporting hinders data harmonisation and generalisability of results. In addition to improving outcomes, comprehensive profiling can contribute to diagnostic refinement and identification of germline variant detection in a subset of patients. Emerging studies, conducted through national initiatives, signify the potential benefit of precision medicine for all patients with childhood cancer regardless of risk. A dynamic approach to address challenges and ensure cost-benefit is necessary to embed precision oncology as a standard of care for all children with cancer.

Background: In the PAPILLON study, first-line amivantamab-chemotherapy in epidermal growth factor receptor (EGFR) exon 20 insertion-mutated non-small cell lung cancer demonstrated significantly prolonged progression-free survival and favorable overall survival over chemotherapy; a consistent benefit was also observed across some secondary endpoints. However, the complete clinical benefit of first-line amivantamab-chemotherapy is not fully understood, nor is the survival advantage in the presence of per-protocol crossover from chemotherapy to amivantamab after progression.

Objective: We aimed to assess time to treatment discontinuation (TTD) and time to subsequent therapy (TTST), at the time of primary analysis for progression-free survival, and the effect of the crossover design on overall survival at the time of interim analysis.

Methods: In the phase III PAPILLON study, 308 participants were randomized (amivantamab-chemotherapy, n = 153; chemotherapy, n = 155). Intravenous amivantamab was administered every 3 weeks. Chemotherapy was administered as carboplatin for four cycles and pemetrexed until disease progression. TTD and TTST were evaluated using Kaplan-Meier and Cox proportional hazards models. Crossover-adjusted survival estimates were generated using three established statistical methods.

Results: At a median follow-up of 14.9 months, median TTD was 13.2 versus 7.5 months for amivantamab-chemotherapy versus chemotherapy (hazard ratio [HR] 0.38 [95% confidence interval 0.28-0.51]; nominal p < 0.0001). Median TTST was 17.7 versus 9.9 months (HR 0.35 [95% confidence interval 0.25-0.49]; nominal p < 0.0001). A total of 65/155 participants crossed over from chemotherapy to amivantamab after progression. The crossover-adjusted overall survival continued to demonstrate a favorable survival benefit for amivantamab-chemotherapy versus chemotherapy with HRs of 0.52-0.60, which is more pronounced than the planned interim intention-to-treat overall survival (HR of 0.67; 95% confidence interval 0.42-1.09).

Conclusions: In PAPILLON, TTD and TTST were substantially longer for amivantamab-chemotherapy versus chemotherapy at primary analysis (cut-off on 3 May 2023). Crossover-adjusted analyses of the planned interim overall survival demonstrated a greater benefit for amivantamab-chemotherapy versus chemotherapy, further supporting amivantamab-chemotherapy as the first-line standard of care in EGFR exon 20 insertion-mutated non-small cell lung cancer.

Clinical trial registration: ClinicalTrials.gov Identifier: NCT04538664.

Targeted therapies have transformed outcomes of patients with advanced non-small cell lung cancer. Amivantamab, a bispecific antibody targeting epidermal growth factor receptor (EGFR) and MET, and lazertinib, a third-generation EGFR tyrosine kinase inhibitor, were approved in 2024 for the first-line treatment of EGFR-mutated (exon 19 deletion/exon 21 L858R substitution) locally advanced or metastatic non-small cell lung cancer. While EGFR-targeted therapies have demonstrated clinical efficacy, they are associated with on-target dermatologic adverse events (AEs). This vodcast aims to educate on strategies to mitigate and manage dermatologic AEs associated with amivantamab + lazertinib. The MARIPOSA study assessed amivantamab + lazertinib versus osimertinib in previously untreated patients with EGFR-mutated locally advanced or metastatic non-small cell lung cancer. In the same population, the COCOON study assessed the impact of enhanced versus standard dermatologic management on the incidence of grade ≥ 2 dermatologic AEs. In MARIPOSA, amivantamab + lazertinib significantly improved overall survival (median not reached vs 36.7 months) and progression-free survival (median 23.7 vs 16.6 months) versus osimertinib. The most common EGFR-associated dermatologic AEs were rash and paronychia. To address these AEs, the COCOON study evaluated enhanced dermatologic management strategies (including prophylactic oral and topical antibiotics and moisturizer) versus standard of care dermatologic management, which resulted in a two-fold reduction in grade ≥ 2 dermatologic AEs with COCOON versus standard dermatologic management. We further discuss the COCOON prophylactic regimen together with reactive and expert-recommended dermatologic management approaches. In conclusion, amivantamab + lazertinib is an effective treatment that significantly improves overall survival. While dermatologic AEs are common, effective proactive management strategies, as demonstrated in the COCOON study, can help reduce the incidence and severity of dermatologic AEs. Prioritizing education for healthcare providers and patients will facilitate timely identification and proactive and reactive management of these events, ultimately improving the treatment experience for patients undergoing therapy with amivantamab and lazertinib.

Despite the introduction of immunotherapy and antibody-drug conjugates (ADCs), 5-year survival rates for advanced urothelial cancer (UC) remain unsatisfactory. Modest results with conventional systemic treatments have prompted the need for tailored therapies that exploit actionable mutations, such as those involving the human epidermal growth factor receptor (HER)-2 proto-oncogene, which plays a key role in regulating cell growth, differentiation, and survival. HER2-positive UC accounts for 13-25% of all locally advanced/metastatic UC. HER2 overexpression in UC varies widely by tumour stage and is usually a late phenomenon associated with poorer prognosis. Given the crucial biological role of HER2 in UC and the proven activity of anti-HER2 drugs in other solid tumours (e.g. breast and gastric cancer), in this comprehensive review, we analyse clinical trials using HER2-targeting strategies in HER2-positive metastatic UC. Clinical trials of anti-HER2 monoclonal antibodies and tyrosine kinase inhibitors in UC have shown limited efficacy. On the other hand, HER2-targeted ADCs such as trastuzumab deruxtecan and disitamab vedotin have shown encouraging results. However, the most interesting data come from the combination of HER2-targeted ADCs with immunotherapy because of the synergistic action of the two drugs: HER2-directed ADCs, with their cytotoxic effect, lead to the release of cancer antigens, enhancing the anti-tumour immune response, which is boosted by the immune checkpoint inhibitor. Moreover, this combination strategy may also offer some advantages in rewiring the tumour microenvironment, favouring an anti-cancer immune response. ADC and immune checkpoint inhibitor combinations are supported by solid preclinical evidence and are emerging as novel and promising tailored therapeutic approaches for advanced UC.

Background: Immune checkpoint inhibitors are standard treatment for advanced melanoma. Pembrolizumab (programmed cell death-1 inhibitor) monotherapy is recommended as first-line treatment. However, real-world evidence on its efficacy and safety in Australia, a region with the highest melanoma incidence, remains limited.

Objective: This study aimed to assess real-world outcomes of pembrolizumab in patients with advanced melanoma in Australia.

Methods: A retrospective cohort study was conducted using national Pharmaceutical Benefits Scheme and National Death Index data via the Australian Bureau of Statistics DataLab. Patients who initiated pembrolizumab monotherapy for stage III/IV unresectable melanoma (1 January, 2017-30 June, 2022) were included. Kaplan-Meier analyses and multivariate Cox regressions were performed to assess overall survival and time to treatment discontinuation. Immune-related adverse events were inferred from corticosteroid and levothyroxine prescriptions. Subgroup analyses were performed by age (18-64, 65-84, ≥ 85 years) and sex.

Results: Among 4127 patients, the median overall survival was 816 days. Mortality was higher in patients aged 65-84 years (adjusted hazards ratio 1.39, 95% confidence interval 1.24-1.56) and ≥85 years (adjusted hazards ratio 1.93, 95% confidence interval 1.69-2.21) versus 18-64 years. Median time to treatment discontinuation was 377 days, with a higher discontinuation rate in female individuals (adjusted hazards ratio 1.19, 95% confidence interval 1.09-1.29). Incident corticosteroid and levothyroxine prescriptions were observed in 19.3 and 7.6% of patients, respectively.

Conclusions: Our findings align with clinical trials, demonstrating similar survival outcomes. Younger patients benefited more from pembrolizumab, while female individuals had shorter treatment durations. Further research is required to explore immune checkpoint inhibitor efficacy, safety, and treatment disparities.

Background: Epidermal growth factor receptor (EGFR)-driven non-small cell lung cancer (eLC) is a leading cause of death. The FLAURA study showed that upfront osimertinib (U-OSI) led to better overall survival (OS) than gefitinib or erlotinib, regardless of T790M status in advanced disease. However, if sequenced optimally, sequential OSI (S-OSI) in T790M-positive patients after first- or second-generation EGFR-tyrosine kinase inhibitors (F-S-EGFR-TKI) should theoretically lead to better OS than U-OSI.

Objective: To identify the best sequencing strategy in this group of patients.

Patients and methods: A multicentre retrospective study was conducted on treatment-naive eLC patients who had received an F-S- EGFR-TKI between 1 January 2016 and 31 December 2020 in three tertiary NHS hospitals in the UK. Compliance to national recommendation of T790M testing was analysed. Survival outcomes of T790M testing and S-OSI were estimated with the Kaplan-Meier and Cox Proportional Hazard models.

Results: In 84/122 evaluable patients, after F-S-EGFR-TKI, only 50% of the patients were offered a T790M biopsy, owing to rapid progression and reduced fitness. Of which, 59.5% of the patients tested positive and had S-OSI. Median OS for the T790M-tested cohort, regardless of positivity and S-OSI, was 54.0 months vs 8.9 months in those not tested (P = < 0.001). Median OS of S-OSI in T790M-positive patients was 64.0 months vs 34.9 months in the T790M-negative cohort (P < 0.0001). On multivariable analysis, S-OSI was associated with better OS (HR 1.841; 95% CI 1.052-3.221; P = 0.0325), whereas performance status (HR 2. 256; 95% CI 1.151-4.422, P = 0.0178), presence of baseline intracranial disease (HR 2 .022; 95% CI 1.144-3.575, P = 0. 0115), the male sex (HR 2.265; 95% CI 1.302-3.939; P = 0.0038) and non-exon 19 deletion mutations (HR 1.610; 95% CI 1.112-2.331, P = 0.0116) were associated with a higher risk of death.

Conclusions: High performance status and intracranial disease should be indications for U-OSI for a higher chance of response. For fitter patients, F-S-EGFR-TKI followed by T790M biopsy +/- S-OSI appears to confer better-than-expected OS in the entire cohort in the real-world setting, regardless of T790M positivity. Given the clinical benefit and potential cost-effectiveness of this approach, S-OSI should be considered a favourable option in this group of patients, especially in resource-deprived settings.

Background: Population pharmacokinetic models can potentially provide suggestions for an initial dose and the magnitude of dose adjustment during therapeutic drug monitoring procedures of imatinib. Several population pharmacokinetic models for imatinib have been developed over the last two decades. However, their predictive performance is still unknown when extrapolated to different populations, especially children.

Objective: This study aimed to evaluate the predictive performance of these published models on an external real-world dataset containing data from both adults and children.

Methods: A real-world dataset was collected, containing observations from adult and pediatric patients with Philadelphia chromosome-positive/Philadelphia chromosome-like acute lymphoblastic leukemia and chronic myeloid leukemia (N = 39) treated with imatinib. A systematic review through PubMed was conducted to identify qualified population-pharmacokinetic models for external evaluation (i.e., prediction-based, simulation-based, and Bayesian forecasting diagnostics). Standard allometric scaling was used for models that were developed based on data from adults only.

Results: Fifteen published models were found for evaluation, of which only two were based on data from both children and adults. Prediction-based diagnostics showed that some models had an acceptable level of bias. The model by Shriyan et al. (with allometric scaling) performed best with a median prediction error of 1.24%. However, no models performed well on precision even when allometric scaling was used, where the lowest median absolute prediction error was 37.66% using the model by Schmidli et al. The models by Golabchifar et al. and Schmidli et al. (both with allometric scaling) performed the best of all tested models, with a median prediction error ≤ 15%, median absolute prediction error ≤ 40%, fraction of prediction error within ± 20% (F₂₀) ≥ 0.3, and within ± 30% (F₃₀) nearly 0.4. Simulation-based diagnostics showed that most of the observations outside the 90% prediction interval were from children. Bayesian forecasting showed that the model prediction could be improved using one prior sample, particularly in adults.

Conclusions: Current models fail to accurately predict imatinib plasma concentrations in our real-world dataset, especially for children. Future pharmacokinetic studies should focus on developing better models for pediatric populations.