Giuseppe Giaccone

Background: Manual endpoint assessment is labor-intensive and variable. This study evaluated artificial intelligence (AI)-powered intracranial response assessment and explored imaging prognostic factors in the phase III CROWN trial of advanced treatment-naive anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Methods: CROWN randomized patients to lorlatinib or crizotinib. Seventy-two with baseline brain metastases (BMs) had brain MRI every 8 weeks. We evaluated an FDA-cleared AI platform, VBrain, for automated lesion-level tracking of BMs and early tumor response (ETR) in relation to systemic progression-free survival (PFS), the primary endpoint of the trial. Progression-free survival was assessed by blinded central review, independent of AI. VBrain assessments were compared with 2 neuroradiologists (R1, R2). Early tumor response at the first on-treatment scan was derived from modified response evaluation criteria in solid tumors (mRECIST) target-lesion diameters and from AI-based all-lesion volumes (AI-ETR). Treatment-neutral Cox models related ETR to systemic PFS; discrimination was assessed using Uno’s C and time-dependent AUC(t) with bootstrap uncertainty. Results: Per mRECIST v1.1, VBrain, R1, and R2 measured 68, 32, and 51 targets, with high concordance (r = 0.94). Across 666 time-points, pairwise assessment discordance and time to intracranial progression did not differ between AI and readers. Beyond mRECIST, VBrain tracked 322 tumors. AI-ETR significantly stratified PFS (multivariable-adjusted hazard ratio [HR] 0.44, 95% CI, 0.23-0.86), whereas target-diameter ETR was not significant (adjusted HR 0.64, 95% CI, 0.29-1.41). Adding AI-ETR improved prediction vs a clinical base model (Δc-index +0.07; AUC(t) 0.71 vs 0.55). Conclusions: The AI and human readers reached a high agreement in endpoint evaluations. Volumetric all-BMs ETR outperforming target-only mRECIST offers early prognostic information in advanced ALK-positive NSCLC. Trial Registration: ClinicalTrials.gov identifier: NCT03052608.

Background: The surrogacy of progression-free survival (PFS) for overall survival (OS) at the trial-level in randomized clinical trials (RCTs) testing immune checkpoint inhibitors (ICIs) in patients with advanced non-small cell lung cancers (NSCLC) is influenced by several clinical-pathological factors. However, potential heterogeneity of PFS surrogacy according to patients’ sex has never been investigated. Methods: RCTs testing ICIs as monotherapy or combined with chemotherapy in patients with advanced NSCLC reporting hazard ratios (HRs) for PFS and OS according to patients’ sex were included. The main objective was to assess sex-based heterogeneity in the trial-level association between PFS (surrogate endpoint) and OS (reference endpoint), overall and in subgroups defined by treatment type (ICIs as monotherapy vs ICIs plus chemotherapy). We used the coefficient of determination (R2) to quantify surrogacy. Results: Twenty RCTs, for a total of 7528 male and 3008 female patients, were included. Overall, the association between OS-HR and PFS-HR was moderate: the R2 from a model adjusted by the type of treatment administered in the experimental arm was 0.69 (95% confidence interval [CI] = 0.34 to 0.88). Sex-disaggregated analysis showed heterogeneity in PFS surrogacy: the association was strong in male patients (adjusted R2 = 0.77; 95% CI = 0.56 to 0.89), but poor in female (adjusted R2 = 0.31, 95% CI = 0.03 to 0.63). Consistent results were obtained in subgroups analyses by treatment type, and in cross-validation analysis. Conclusions: In RCTs testing ICIs alone or combined with chemotherapy in patients with advanced NSCLC, PFS is a robust surrogate endpoint for OS in male patients but not in female.

Small-cell lung cancer (SCLC) accounts for 10–15% of lung cancers and is characterized by early metastasis, treatment resistance and rapid progression. Treatment advancements have been stagnant for decades, with chemotherapy as the mainstay and immune checkpoint inhibitors offering only modest survival extensions. However, new insights into tumor heterogeneity and recent practice-changing observations such as the identification of targetable cell surface proteins could effectively transform SCLC therapy. In this Review, we highlight key advances in SCLC biology, therapeutic innovation and biomarker development. Finally, we discuss the role of reverse translation in optimizing treatments, approaches to overcoming resistance and ensuring equitable access to care.

Background: The surrogacy of overall response rate (ORR) or progression-free survival (PFS) for overall survival (OS) at the trial-level in randomized clinical trials (RCTs) testing antibody-drugs conjugates (ADC) has never been investigated. Methods: RCTs testing ADCs in patients with advanced solid tumors and reporting data on OS and PFS and/or ORR were analyzed. The main objective was to assess the trial-level association between the surrogate endpoints (ORR or PFS) and the reference endpoint (OS), overall and in subgroups of trials defined by tumor type, number of previous lines of systemic treatments, and specific ADC features. Results: Twenty-five RCTs, for a total of 26 treatment comparisons and 11 729 patients, were included in the analysis. In 21 comparisons the ADC was administered as monotherapy, and in 16 was tested in patients with breast cancer. The association between the hazard ratio for OS and relative risk of ORR was moderate: the R2 from a model adjusted by tumor type was 0.47 (95% CI = 0.11 to 0.83). The association between the hazard ratios for OS and PFS was strong: the R2 from the adjusted model was 0.79 (95% CI = 0.66 to 0.92). Cross-validation analyses showed similar results. Consistent results were obtained across all the subgroups analyzed, with the notable exception of the subgroup of trials testing ADCs for breast cancer, where the association between OS and ORR appeared strong (R2 = 0.77; 95% CI = 0.51 to 0.90). Conclusions: In RCTs evaluating ADCs in advanced solid tumors, PFS serves as a robust surrogate endpoint for OS, offering greater reliability than ORR and adequately supporting accelerated approval of ADCs in future trials.

The antitumor activity of immunotherapy is strongly influenced by the presence of driver gene mutations/translocations. For this reason, knowledge of the predictive value of specific genetic alterations in relation to anti-PD(L)1 activity is highly useful for the clinical decision making process in many solid tumors, particularly in Non-Small Cell Lung Cancer. Although data on the correlation between genetic alterations and response to immunotherapy are available in the majority of common cancers, data are lacking in the subset of patients with KIT-mutated Thymic Carcinoma (TC). As a consequence, although immunotherapy is a standard treatment for TC patients, the lack of this knowledge leads to uncertainty when proposing immunocheckpoint inhibitors in this subset of patients. Here we describe the first report of a patient with KIT-mutated TC who received the anti-PD1 agent pembrolizumab, which caused a sustained partial response. This case report of a sustained partial response achieved with pembrolizumab in a patient with KIT-mutated TC after progression to chemotherapy and imatinib may be supportive during clinical decision making for this extremely rare disease.