Antibody-drug conjugates (ADCs) are an emerging class of therapeutics for lung cancer, and several are currently in development for this malignancy. The structure of these molecules is based on an antibody that targets a protein on the lung cancer cell surface and a cytotoxic payload attached by a linker. Many protein targets, including TROP2, c-MET, CEACAM5, HER2, and HER3 have been identified. In metastatic non-small cell lung carcinoma (NSCLC) without alterations in oncogenic drivers, platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) targeting the programmed death-1/programmed death-ligand 1 (PD1/PDL1) interaction are the standard first-line treatments. In patients with EGFR-mutated or ALK-rearranged NSCLC, tyrosine kinase inhibitors (TKIs) are recommended. However, although the prognosis of patients with metastatic NSCLC differs between such with and without alterations in oncogenic drivers, most patients eventually experience disease progression. A novel therapeutic class is needed in routine practice to overcome the mechanisms of resistance to ICIs and EGFR/ALK TKIs. Several ADCs have already been approved for other cancers, such as breast cancer and urothelial carcinoma. This review summarizes the knowledge about the efficacy and tolerance profiles of ADCs targeting TROP2, HER2, HER3, CEACAM5 and c-MET in metastatic NSCLC with and without alterations in oncogenic drivers.

Metastatic non-small-cell lung carcinoma (mNSCLC) first-line therapy is based on the combination of chemotherapy with immune checkpoint inhibitors (ICIs). Early assessment of long-term outcomes may be crucial to guide clinician's decisions. Whether radiological depth of response (DpR) could be a surrogate of survival remains unsolved. This study aims to evaluate the correlation between the DpR at 6 months and survival in patients presenting an mNSCLC treated with ICI chemotherapy in a first-line metastatic setting. This retrospective multicenter study included mNSCLC patients treated with ICI chemotherapy, still on first-line therapy at 6 months, with measurable disease. Patients were classified into four groups according to radiological assessment at 6 months of the beginning of first-line therapy using RECIST criteria 1.1: group 1: -100% to -60%, group 2: -59% to -30%, group 3: 0% to -29% and group 4: 0% and more. We evaluate the impact of DpR on survival with the Cox model using group 3 (0% to -29%) as the reference. The analysis included 175 patients: (median age: 61 years, adenocarcinoma: 82.3%; brain metastasis: 25.7%, PD-L1 ≥ 1%: 56.0%. Patients were in groups 1, 2, 3 and 4 in 21.1%, 31.5%, 29.7% and 17.7% of cases, respectively. Median overall survival and progression-free survival were 35.0 months [95% confidence interval (CI), 31.0-NA], and 17.1 months (95% CI, 14.0-23.9 months), respectively. Patients in group 1 and 2 had a significantly lower risk of death compared with group 3 [Hazard ratio (HR) = 0.31, 95% CI, 0.14-0.68, P = 0.003, and HR = 0.53, 95% CI, 0.30-0.92, P = 0.025, respectively]. Depth of response at 6 months according to RECIST 1.1 criteria for patients with mNSCLC still on first-line therapy is a predictor of overall survival.

Urothelial carcinoma is three to four times more common in men than in women, with a 73-year old mean age at diagnosis which is older than the average age at diagnosis of all cancers. Urothelial carcinoma is rare in people under 40 years of age. Smoking, exposure to industrial chemicals, and family history influence the development of bladder cancer, but age remains one of the most important risk factors. It is well established that women are more likely to be diagnosed with an advanced disease, impacting the prognosis and a higher stage-for-stage mortality compared to men. A gender difference is also observed when considering molecular features; for example, there a higher male/female ratio in Fibroblast Growth Factor Receptor 3 (FGFR3)-mutated bladder cancer. Epidermal Growth Factor Receptor (EGFR) amplifications, which are roughly depicted in 25–50% of urothelial carcinoma, have been correlated with a worse prognosis. Genomic alterations of clinical interest are mainly Human Epidermal Growth Factor Receptor 2 mutations and amplifications, as well as FGFR 3 alterations; however, no EGFR mutation has been routinely reported despite the frequency of its amplifications. Recurrently, no targeted inhibitors have demonstrated a benefit compared to platinum-based chemotherapy. We report a rare case of a 35-year-old woman presenting bone, hepatic, and lymph node metastatic urothelial carcinoma, harboring a deletion of 24 nucleotides in exon 19 of the EGFR gene with a 5-month response to osimertinib, a third-generation EGFR tyrosine kinase inhibitor.

Background: Amivantamab, an epidermal growth factor receptor-MNNG-HOS transforming gene (EGFR-MET) bispecific antibody with immune cell-directing activity, plus platinum-based polychemotherapy improved survival outcomes in patients with classical EGFR-mutant metastatic lung cancer previously treated by osimertinib. However, its efficacy in the context of uncommon EGFR alterations, particularly the Thr751_Ile759delinsAsp deletion in exon 19, which directly impacts the αC helix, remains uncertain. Case Description: This report presents a rare case of a patient with metastatic lung adenocarcinoma (involving bone and lymph nodes) harboring an uncommon exon 19 deletion (Thr751_Ile759delinsAsp) in the EGFR gene. The patient demonstrated a one-year response to osimertinib and a deep and prolonged response to amivantamab plus chemotherapy as second line with a high-grade cutaneous toxicity. Conclusions: In non-smoker patients diagnosed with metastatic lung adenocarcinoma, comprehensive genetic profiling is essential to identify EGFR alterations and provide tailored treatment strategies. The detection of uncommon EGFR mutations requires the expertise and advanced technological platforms available in specialized centers. Data evaluating the efficacy of the news therapies mainly bispecific anti-EGFR/MET in patients with lung cancer harboring uncommon EGFR alterations are needed, as well as the relationship between toxicity and efficacy.

Glioblastoma (GBM) is the most common malignant brain tumor in adults. The current treatment is surgery followed by chemoradiotherapy (CRT) and adjuvant temozolomide (TMZ). Three out of four patients experience recurrence within the year following diagnosis. The management of first GBM recurrence remains challenging with no standardized guidelines. This study aimed to evaluate multimodal strategies combining systemic therapy, radiotherapy, surgery as a potential promising approach to enhance patient outcomes. The FROST study is a real-life multicenter study. All patients with primary GBM treated for recurrence after prior CRT were included. The Kaplan-Meier method, Cox regression model, and propensity score were employed. Two hundred seventy-one patients were included. One hundred ninety (70%) patients benefited from systemic treatment. Fifty-six patients (21%) received a multimodal approach, and 25 (9%) either radiotherapy (n = 14) or surgery (n = 11) alone. The median OS was 9.9 months (8.2-11.2) from first recurrence. The median OS for systemic treatment was 7.9 months (7.1-10.4) and 12.7 months (10.8-19.6) for the local/multimodal approach (p = 1e^- 03). Using local/multimodal treatment as reference, the Cox-stratified hazard ratio (HR) for systemic treatment was 2.64 (1.42-4.89). The multimodal approach was more effective than the local strategy alone, with an OS of 16.2 months (11.2-22.9) versus 9.3 months (8.2-18.7) (p = 0.03), and a multivariate HR of 1.88 (1.05-3.4) for local strategy alone. Integrating systemic therapy, radiotherapy and surgery within a multimodal framework at first GBM recurrence seems to offer meaningful clinical benefit. Not applicable.

Background: Biliary tract cancer (BTC) management has undergone tremendous changes, benefiting from the identification of highly actionable molecular alterations. Among these, IDH1 mutations and FGFR2 fusions are the most common alterations detected and are classified as ESCAT tier 1 in BTC. However, their prognostic value in real-world settings remains uncertain. Objective: To explore overall survival (OS) in patients harbouring locally advanced or metastatic BTC (mBTC) with IDH1 or FGFR2 alterations, compared to those with wild-type tumours. Methods: This retrospective, multicentre study included patients with mBTC treated between 2020 and 2023 across five French centres. Patients were categorized into two cohorts based on molecular profiling: those with IDH1 or FGFR2 alterations, and those with wild-type tumours (WT-mBTC). Results: 119 consecutive patients were included. 18 were classified as altered (IDH1 = 13; FGFR2 = 5). Sixty-four pts underwent no molecular testing. The median OS of the entire cohort was 11.9 months (10.3–14.3). The median OS was 24.2 months (12.3–NA) versus 10.8 months (7.9–12.9), p = 0.02, in the altered and WT-mBTC cohorts, respectively. The Cox regression model conducted depicted an HR for death of 0.46 (CI95%, 0.2–0.9) for IDH1 or FGFR2 alterations. There were no diffence in PFS for first-line. Conclusions: Our cohort suggests that IDH1 or FGFR2 alterations may be associated with prognostic differences in patients with metastatic BTC, although they do not appear to influence outcomes under first-line treatment. These findings are consistent with trends observed in clinical trials. Whether improved survival is solely attributable to targeted therapies remains questionable. In line with ESMO recommendations, systematic molecular profiling should be considered in patients with mBTC.