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Introduction Cancer of unknown primary remains a challenging clinical entity. Despite receiving empiric chemotherapy, median overall survival is approximately 6-12 months. Site-specific therapy based on molecular characterization has been shown to improve outcomes; however, feasibility outside of clinical trials, especially in community centers, is lacking. This study explores the application of rapid next-generation sequencing in defining cancer of unknown primary and to identify therapeutic biomarkers. Methods A retrospective chart review was performed by identifying pathological samples designated cancer of unknown primary. Next-generation sequencing testing was based on an automated workflow utilizing the Genexus integrated sequencer, validated for clinical use. Genomic profiling was further integrated within a routine immunohistochemistry service, with results reported directly by anatomic pathologists. Results Between October 2020 and October 2021, 578 solid tumor samples underwent genomic profiling. Among this cohort, 40 were selected based on an initial diagnosis of cancer of unknown primary. The median (range) age at diagnosis was 70 (42-85) and 23 (57%) were female. Genomic data were used to support a site-specific diagnosis in 6 patients (15%). Median turnaround time was 3 business days (IQR: 1-5). Most common alterations identified were KRAS (35%), CDKN2A (15%), TP53 (15%), and ERBB2 (12%). Actionable molecular targeted therapies were identified in 23 (57%) patients, including alterations in BRAF, CDKN2A, ERBB2, FGFR2, IDH1, and KRAS. Immunotherapy-sensitizing mismatch repair deficiency was identified in 1 patient. Conclusion This study supports the adoption of rapid next-generation sequencing among patients with cancer of unknown primary. We also demonstrate the feasibility of integration of genomic profiling with diagnostic histopathology and immunohistochemistry in a community practice setting. Diagnostic algorithms incorporating genomic profiling to better define cancer of unknown primary should be considered for future study. Cancer of unknown primary is a challenging clinical entity. This study explored the application of rapid next-generation sequencing to define cancer of unknown primary and identify therapeutic biomarkers.

Non-small-cell lung cancer (NSCLC) is a highly heterogeneous disease that is frequently associated with a host of known oncogenic alterations. Advances in molecular diagnostics and drug development have facilitated the targeting of novel alterations such that the majority of NSCLC patients have driver mutations that are now clinically actionable. The goal of this review is to gain insights into clinical research and development principles by summary, analysis, and discussion of data on agents targeting known alterations in oncogene-driven, advanced NSCLC beyond those in the epidermal growth factor receptor (EGFR) and the anaplastic lymphoma kinase (ALK). A search of published and presented literature was conducted to identify prospective trials and integrated analyses reporting outcomes for agents targeting driver gene alterations (except those in EGFR and ALK) in molecularly selected, advanced NSCLC. Clinical efficacy data were extracted from eligible reports and summarized in text and tables. Findings show that research into alteration-directed therapies in oncogene-driven, advanced NSCLC is an extremely active research field. Ongoing research focuses on the expansion of new agents targeting both previously identified targets (particularly hepatocyte growth factor receptor (MET), human epidermal growth factor receptor 2 (HER2), and Kirsten rat sarcoma viral oncogene homolog (KRAS)) as well as novel, potentially actionable targets (such as neuregulin-1 (NRG1) and phosphatidylinositol 3-kinase (PI3K)). The refinement of biomarker selection criteria and the development of more selective and potent agents are allowing for increasingly specific and effective therapies and the expansion of clinically actionable alterations. Clinical advances in this field have resulted in a large number of regulatory approvals over the last 3 years. Future developments should focus on the continued application of alteration therapy matching principles and the exploration of novel ways to target oncogene-driven NSCLC.

Osimertinib is a third-generation, irreversible, oral EGFR tyrosine kinase inhibitor. We report real-world effectiveness and safety data. T790M positive advanced non-small-cell lung cancer adults, who received ≥1 prior EGFR tyrosine kinase inhibitor, received osimertinib 80 mg daily. Primary effectiveness outcome: overall survival. Secondary effectiveness outcomes included: investigator-assessed clinical response, progression-free survival, time-to-treatment discontinuation. At data cutoff, 3015 patients had enrolled: 57.1% had investigator-assessed response (95% CI: 55.2-58.9). Median progression-free survival: 11.1 months (95% CI: 11.0-12.0) and median time-to-treatment discontinuation: 13.5 months (95% CI: 12.6-13.9). Interstitial lung disease/pneumonitis-like events reported in 28 (1%) patients. Osimertinib demonstrated clinical effectiveness similar to efficacy observed in the clinical trial program with no new safety signals.

Liquid biopsy is rapidly becoming an indispensable tool in the oncologist’s arsenal; however, this technique remains elusive in a publicly funded healthcare system, and real-world evidence is needed to demonstrate utility and feasibility. Here, we describe the first experience of an in-house point of care liquid biopsy program at a Canadian community hospital. A retrospective review of consecutive cases that underwent plasma-based next-generation sequencing (NGS) was conducted. Liquid biopsy was initiated at the discretion of clinicians. Sequencing followed a point of care workflow using the Genexus™ integrated sequencer and the Oncomine precision assay, performed by histotechnologists. Results were reported by the attending pathologist. Eligible charts were reviewed for outcomes of interest, including the intent of the liquid biopsy, results of the liquid biopsy, and turnaround time from blood draw to results available. A total of 124 cases, with confirmed or suspected cancer, underwent liquid biopsy between January 2021 and November 2023. The median turnaround time for liquid biopsy results was 3 business days (range 1–12 days). The sensitivity of liquid biopsies was 71%, compared to tissue testing in cases with matched tissue results available for comparison. Common mutations included EGFR (29%), in 86 lung cancer patients, and PIK3CA (22%), identified in 13 breast cancer patients. Healthcare providers ordered liquid biopsies to inform diagnostic investigations and treatment decisions, and to determine progression or resistance mechanisms, as these reasons often overlapped. This study demonstrates that rapid in-house liquid biopsy using point of care methodology is feasible. The technique facilitates precision treatment and offers many additional advantages for cancer care.

Background: Adjuvant platinum-based chemotherapy is standard of care for patients with resected stage IIA/B or IIIA NSCLC. Overall survival is suboptimal due to the high metastatic potential of early-stage NSCLC and there is substantial clinical need for additional efficacious adjuvant treatment options. Methods: PubMed (all time to 4 February 2021) and related conference databases were searched using the key search terms ‘NSCLC’ AND ‘Adjuvant’ AND ‘EGFR inhibitor’ OR respective aliases. Results: The literature search identified five adjuvant phase III trials of EGFR inhibitors in early NSCLC. The earlier BR19 and RADIANT trials failed to demonstrate statistically significant improvements in either OS or DFS for gefitinib and erlotinib, respectively, compared with placebo in patients with EGFR mutation-unselected NSCLC. Three subsequent phase III trials, ADAURA, CTONG1104, and IMPACT, were conducted in EGFR-mutant NSCLC. IMPACT showed no statistically significant DFS benefit for adjuvant gefitinib, and although CTONG1104 did report improved DFS for gefitinib (HR = 0.56, p = 0.001), this benefit was not enduring, resulting in comparable 5-year DFS rates. Statistically significant and clinically meaningful DFS benefits were observed in ADAURA for osimertinib compared with placebo in patients with stage IB-IIIA and II-IIIA disease (7th Edition Staging), and these benefits, coupled with a meaningful improvement in 2-year CNS DFS and favorable HRQoL, make osimertinib an important new treatment option for the adjuvant treatment of EGFR exon 19 deletion or exon 21 L858R-mutated stage II-IIIA NSCLC (UICC/AJCC 8th Edition Staging), with final mature OS data eagerly awaited. Conclusion: Adjuvant osimertinib used alone or following platinum-based chemotherapy is now recommended in patients with stage II-IIIA EGFR-mutated NSCLC.

Background: Osimertinib is the preferred treatment for patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) in several settings; however, disease progression is common, and treatment options after progression are limited. Datopotamab deruxtecan (Dato-DXd), an antibody-drug conjugate comprising a humanized anti-trophoblast cell-surface antigen 2 (TROP 2) monoclonal antibody conjugated to a potent topoisomerase I inhibitor via a plasma-stable linker, has demonstrated efficacy in advanced NSCLC, including previously treated EGFR-mutated advanced NSCLC. Combining osimertinib and Dato-DXd may overcome heterogeneous osimertinib resistance mechanisms and limit tumor progression. Objectives: TROPION-Lung15 is an ongoing, phase III, open-label, sponsor-blind, multicenter, randomized trial evaluating Dato-DXd ± osimertinib versus chemotherapy in patients with EGFR-mutated advanced NSCLC and disease progression on prior osimertinib. Methods and design: Approximately 630 patients with histologically/cytologically confirmed non-squamous NSCLC, documented epidermal growth factor receptor tyrosine kinase inhibitor-sensitive mutations, and radiologic progression on prior osimertinib monotherapy will be enrolled. Patients will be randomized 1:1:1 to Dato-DXd (6 mg/kg intravenously every 3 weeks), osimertinib (80 mg orally once daily) plus Dato-DXd, or platinum-doublet chemotherapy, stratified by the history/presence of brain metastases (yes vs no), prior osimertinib therapy (adjuvant vs post-chemoradiotherapy/first-line vs second-line), and race. Treatment will continue until radiological progression (per Response Evaluation Criteria in Solid Tumors version 1.1), unacceptable toxicity, or another discontinuation criterion is met. The dual primary endpoints are progression-free survival (PFS) by blinded independent central review (BICR) for osimertinib + Dato-DXd and PFS by BICR for Dato-DXd alone versus chemotherapy. Secondary endpoints include overall survival, central nervous system PFS by BICR, and safety/tolerability. Ethics: The study is approved by independent ethics committees/institutional review boards at each center. Patients will provide written informed consent. Discussion: TROPION-Lung15 will assess Dato-DXd ± osimertinib in patients with EGFR-mutated advanced NSCLC and disease progression on prior osimertinib. Data from this study could lead to a new treatment option in this setting. Trial registration: ClinicalTrials.gov identifier: NCT06417814 (date of registration: May 13, 2024). Plain language summary TROPION-Lung15: a clinical study comparing osimertinib in combination with datopotamab deruxtecan (Dato-DXd) or Dato-DXd alone versus standard chemotherapy in patients with non-small cell lung cancer (NSCLC) and mutations in the epidermal growth factor receptor (EGFR) gene whose disease has progressed after previous osimertinib therapy Osimertinib is an anticancer drug that blocks the activity of a protein called EGFR on cancer cells and prevents their growth. It is the recommended first treatment for people with EGFR-mutated advanced NSCLC, EGFR-mutated NSCLC where the cancer has been removed by surgery, and EGFR-mutated NSCLC that cannot be removed by surgery and whose disease has not got worse during or after chemoradiotherapy (chemotherapy and radiotherapy). Unfortunately, osimertinib eventually stops working in many people and the cancer returns or starts growing again. Studies are therefore looking for new treatment combinations that might overcome resistance to osimertinib. Datopotamab deruxtecan (Dato-DXd) is an antibody–drug conjugate consisting of an antibody (datopotamab) and an anticancer drug (DXd), joined via a stable, cleavable linker. Dato-DXd has shown promising antitumor efficacy in previous studies in patients with previously-treated advanced/metastatic NSCLC, and in combination with osimertinib in patients with EGFR-mutated NSCLC whose disease had gotten worse on initial osimertinib treatment. The TROPION-Lung15 study will compare Dato-DXd with and without osimertinib versus standard chemotherapy in patients with EGFR-mutated advanced NSCLC whose disease has progressed after previously taking osimertinib. Eligible patients will be randomly assigned to receive osimertinib plus Dato-DXd, Dato-DXd alone, or chemotherapy. Patients will receive treatment until their disease gets worse, side effects become unacceptable, or they choose to leave the study. The main aim of the study is to see how long patients in the two Dato-DXd treatment groups live without their cancer growing or spreading (progression-free survival) compared with patients receiving chemotherapy. About 630 patients with EGFR-mutated advanced NSCLC whose cancer has progressed after previously taking osimertinib are expected to take part. The study is expected to end in 2027, with the first results available in 2026.

PurposeAfatinib is a standard first-line therapy for advanced EGFR-positive NSCLC. We implemented a pharmacist-led proactive follow-up algorithm to identify and manage early afatinib-related adverse events (AEs).MethodsWe conducted a retrospective chart review of all patients treated with afatinib after implementation of the algorithm at the Sunnybrook Odette Cancer Centre (Toronto, ON, Canada) from April 1, 2015 to July 31, 2016. Our in-house algorithm involved consultations in person and proactive pharmacist-led callbacks on days 5, 10, and 17. All AEs were graded and documented in real time and management based on toxicity grade was standardized. This study evaluated the impact of our algorithm on real-world AEs.Results and discussionThirty-three patients were identified and reviewed. Median follow-up was 248 days. All patients experienced at least one drug-related AE; 18.2% were grade 3/4. The most common AEs were diarrhea 87.9%, rash 81.8%, stomatitis 57.6%, and paronychia 45.5%. Median dose of afatinib was 40 mg daily; 51.5% of patients had ≥ 1 dose reduction and 6.3% discontinued afatinib due to AEs. Proactive calls by the pharmacist identified 36.5% of all drug-related AEs, 33.3% of grade 3/4 AEs, 58.1% of first drug-related AEs and identified two patients that were non-compliant. Only 3.2% of AEs were identified by an emergency room/urgent clinic visit.ConclusionsThis proactive multi-disciplinary AE management algorithm resulted in a low rate of urgent assessments and discontinuation due to toxicity while maintaining afatinib at ideal dose, thus providing a useful tool for centers prescribing afatinib.

Considerable variety in how patients respond to treatments, driven by differences in their geno- and/ or phenotypes, calls for a more tailored approach. This is already happening, and will accelerate with developments in personalized medicine. However, its promise has not always translated into improvements in patient care due to the complexities involved. There are also concerns that advice for tests has been reversed, current tests can be costly, there is fragmentation of funding of care, and companies may seek high prices for new targeted drugs. There is a need to integrate current knowledge from a payer’s perspective to provide future guidance. Multiple findings including general considerations; influence of pharmacogenomics on response and toxicity of drug therapies; value of biomarker tests; limitations and costs of tests; and potentially high acquisition costs of new targeted therapies help to give guidance on potential ways forward for all stakeholder groups. Overall, personalized medicine has the potential to revolutionize care. However, current challenges and concerns need to be addressed to enhance its uptake and funding to benefit patients.

Real-world data regarding patients with non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion (ex20ins) mutations receiving mobocertinib are limited. This study describes these patients' characteristics and outcomes. A chart review was conducted across three countries (Canada, France, and Hong Kong), abstracting data from eligible patients (NCT05207423). The inclusion criteria were: ≥ 18 years old; diagnosis of stage IIIB-IV NSCLC with EGFR ex20ins between January 1, 2017 and November 30, 2021; received mobocertinib. Data on demographics, clinical parameters, treatment patterns, mobocertinib exposure, real-world outcomes, and adverse events (AEs) were collected. Results are also reported by Asian/Non-Asian races. Overall, 105 patients were enrolled (median [IQR] age at initial diagnosis: 64.0 years [56, 71]; women: 62.9%). The most common first-line of therapy (LoT) was chemotherapy; the most common second LoT was EGFR tyrosine kinase inhibitors. Most patients received mobocertinib during LoT two and three (74.3%); the maximum dose was 160 mg/day for 67.6% of the cohort (mean [SD] daily dose: 130.6 mg [36.68]). The median real-world progression-free survival (PFS) on mobocertinib was 4.76 months (95% CI: 3.98, 6.21). The overall response rate and disease control rate were 20.0% and 48.6%, respectively (median duration of response: 8.34 months [95% CI: 3.61, 9.49]). The median overall survival (OS) was 26.28 months (95% CI: 20.21, 36.44). Asian patients had numerically superior PFS and OS compared with non-Asian patients. Regarding safety analysis, 73 patients (69.5%) experienced any AE. The most common AE was diarrhea (any grade) (52 patients; 49.5%). These data illustrate the real-world effectiveness of mobocertinib.

BackgroundThe HUDSON platform study (NCT03334617) explores investigational therapies in patients (pts) with NSCLC who progressed on immune checkpoint inhibitors (ICIs) to overcome immune resistance in the post-ICI setting. HUDSON allocated treatment based on biomarker selection or on time (<24 vs. ≥ 24 weeks) before progression on prior ICI. Here, we report on the results of Durvalumab (anti-PD-L1) + T-DXd (anti-HER2 antibody drug conjugate) treatment (module 6) in pts with HER2 overexpressing or HER2 mutant tumours.MethodsPts had documented advanced/metastatic NSCLC with centrally confirmed HER2 overexpression (HER2e) or activating mutations (HER2m), received platinum-based therapy and progressed on prior ICI. Pts received durvalumab 1120 mg iv and T-DXd 5.4 mg/kg iv every 3 weeks until disease progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR) per RECIST 1.1 criteria; secondary endpoints included progression-free survival (PFS), overall survival (OS) and frequency of adverse events (AEs).ResultsA total of 43 pts (HER2e n=23, HER2m n=20) started therapy between 23/6/2020 and 16/9/2021. Differences in main demographic and disease characteristics at study entry were observed between HER2e and HER2m pts (sex, smoking status, extent of disease, primary resistance to prior ICI; extended report of the characteristics at the conference). Confirmed ORR was 26.1% (80% CI, 14.3–41.3) in HER2e pts and 35% (80% CI, 20.7–51.8) in HER2m pts. Median PFS was 2.8 mo (80% CI, 2.2–5.5) in HER2e pts and 5.7 mo (80% CI, 5.5–6.5) in HER2m pts. Median OS was 9.5 mo (80% CI, 6.6–12.4) in the HER2e group and 10.6 mo (80% CI, 8.9-NC) in the HER2m group. Median duration of follow-up in censored subjects was 16.5 mo (range, 7.3–24.2) in the HER2e pts and 17.1 mo (range, 4.4–27.6) in HER2m pts. Grade (G) ≥3 treatment emergent AEs (TEAEs) occurred in 55% of all pts (61% of HER2e pts, 50% of HER2m pts); the most common G ≥3 AEs were pneumonitis (none were fatal), pulmonary embolism and anemia. All grade and G≥3 treatment-related pneumonitis occurred in 9.3% (8.7% of HER2e pts, 10% of HER2m pts) and in 7% (8.7% of HER2e pts, 5% of HER2m pts) of all pts, respectively.ConclusionsDurvalumab+T-DXd combination was tolerated and showed antitumor activity in HER2 altered NSCLC in the post-ICI setting, with a trend toward higher response in HER2m pts. The small sample size limits the overall conclusions of the study.