Over the past 20 years, there has been a paradigm shift in the care of patients with non-small cell lung cancer (NSCLC), who now have a range of systemic treatment options including targeted therapy, chemotherapy, immunotherapy (ICI), and antibody–drug conjugates (ADCs). A proportion of these cancers have single identifiable alterations in oncogenes that drive their proliferation and cancer progression, known as “oncogene-addiction”. These “driver alterations” are identified in approximately two thirds of patients with lung adenocarcinomas, via next generation sequencing or other orthogonal tests. It was noted in the early clinical development of ICIs that patients with oncogene-addicted NSCLC may have differential responses to ICI. The toxicity signal for patients with oncogene-addicted NSCLC when treated with ICIs also seemed to differ depending on the alteration present and the specific targeted agent used. Developing a greater understanding of the underlying reasons for these clinical observations has become an important area of research in NSCLC. In this review, we analyze the efficacy and safety of ICI according to specific mutations, and consider possible future directions to mitigate safety concerns and improve the outcomes for patients with oncogene-addicted NSCLC.

Early discontinuation of endocrine therapy (ET) is higher among patients with early breast cancer (EBC) compared to patients with metastatic hormone receptor-positive (HR+) breast cancer (MBC). In our clinical experience the reasons for this may include a significant burden of ET side effects impacting quality of life (QOL) in patients with EBC. We hypothesized that QOL is lower in patients with HR + EBC compared to patients with HR + MBC on ET. We conducted a cross-sectional observational study to assess QOL utilizing FACT-ES & EORTC QLQ C30 tools among patients with EBC and MBC receiving ET across 5 Irish hospitals. A total of 417 patients were enrolled—EBC (79% n = 331) and MBC 21% (n = 86). Using the FACT-ES, we found no difference in overall QOL by stage (139.2 vs 141, P = .33). Patients with HR + MBC had a lower symptom burden from ET compared to HR + EBC (61.4 vs 54, P < .01). In adjusted multivariate linear regression models, there was no difference in QOL for patients with EBC and MBC receiving ET. There was no significant difference in overall QOL for patients with EBC and MBC. However, patients with EBC experienced more endocrine symptoms. In adjusted multivariate linear regression models, the stage did not predict QOL. Our results suggest that endocrine symptoms are significant contributors to impaired QOL for patients with EBC but the role of other determinants of QOL (eg, stage) is less clear. Future work could include the development of stage-specific QOL tools and utilization of electronic patient-reported outcomes (ePROs) to identify and manage emergent toxicities.

Melanoma has become the poster child for transformative outcomes in advanced malignancy from the use of immunotherapy over the last 10-15 years with median survival improving from ~ 1 to > 5 years. With the increasing repertoire of immune checkpoint inhibitors (ICI) and other novel immunotherapeutic approaches, integrating and sequencing treatments to create new paradigms has gained prominence, with focus on optimizing toxicity management and complex scenarios such as immunotherapy resistance, brain metastases, fertility, and duration of follow-up. In this review, we summarize the progress and emerging evidence in melanoma treatments to date and consider management and possible future directions to improve outcomes for above-mentioned specific patient cohorts. Personalized care with integration of novel prognostic and predictive biomarkers is the way forward in tailoring not only patient selection and choice of therapy, but also duration of treatment and surveillance to allow for early recurrence detection and access to newer therapies such as tumor infiltrating lymphocytes (TIL) to maximize the curative fraction of melanoma patients. Further research is needed in optimizing ICI and other immunotherapy toxicity management, including reducing steroid exposure for better patient outcomes and preserving quality of life.

A number of drugs are in development for the treatment of ERBB2(HER2)-mutated NSCLC, including antibody-drug conjugates such as trastuzumab-deruxtecan and tyrosine kinase inhibitors such as zongertinib and sevabertinib. Herein, we report a case of relapsed advanced ERBB2-mutant NSCLC with acquired resistance to zongertinib potentially mediated through ERBB2 amplification and HER2 3+ immunohistochemistry overexpression with subsequent durable response to fifth-line trastuzumab-deruxtecan. We propose this as a mechanism for zongertinib resistance, one that may underpin a biological rationale for future ERBB2 tyrosine kinase inhibitor–antibody-drug conjugate combination therapy.

Objectives: We sought to identify factors associated with prognosis and bleeding in patients with melanoma brain metastases (BM). Objectives were median overall survival (mOS [months]) and bleeding incidence. Methods: We conducted a retrospective analysis of patients receiving stereotactic radiosurgery (SRS) at our centre 11/15-11/23. Analysis was performed on Prism 10.1.1. Extraction from electronic medical records was undertaken by authors, with local R&D approval (NEU012). Results: A total of 81 patients were evaluable. One hundred and nineteen treatment courses were delivered. There were no bleeding events (BEs) in the first 7 days, 1 within 28 days (0.8%) and 19 within 90 days (16%). Overall, 7.6% (N = 9) died within 90 days, and 25.2% (N = 30) died within 6 m. There were no deaths within 30 days or related to treatment. mOS was 17.6 m (95% confidence interval [CI] 9.20-35.05). Significantly inferior survival outcomes were observed for patients with elevated lactate dehydrogenase (LDH), poor performance status (Karnofsky performance status [KPS]), higher total treated intracranial volume (gross target volume [GTV]), and total number of BM. mOS of patients with a normal LDH was 37.0 m vs 5.2 m for those with LDH > upper limit of normal (ULN) (HR 4.40, P<.0001). This was also true on multivariable analysis including KPS, BM number, and BM size (HR 3.75 95% CI, 1.94-7.30, P ≤.0001). For patients with KPS ≥90, mOS was 35.0 m vs 7.7 m for KPS ≤80 (HR 2.55, P<.0004). This was significant using the multivariable analysis described above (HR 2.12 95% CI, 1.123-3.948, P = .0181). Conclusions: Despite theoretically high risk of bleeding after SRS in MM BM, incidence of bleeding in our cohort was low. mOS was comparable to historical controls of 16-23 months. Advances in knowledge: We novelly performed univariate and multivariate analysis demonstrating poor survival outcomes in patients with high LDH, poor performance status, and larger BM (both by BM size and number).