INTRODUCTION:In the phase 3 CASPIAN study, first-line durvalumab plus etoposide combined with either carboplatin or cisplatin (EP) significantly improved overall survival (OS) versus EP alone in treatment-naïve extensive-stage small-cell lung cancer (ES-SCLC). We report exploratory subgroup analyses from CASPIAN. METHODS:Patients with untreated ES-SCLC were randomized to durvalumab plus EP or EP alone. We analyzed OS and safety in subgroups defined by age, sex, and planned platinum agent, and patient-reported outcomes (PROs) by age. RESULTS:Of 537 patients (durvalumab plus EP: n = 268; EP alone: n = 269), 80.6% versus 19.4% were aged <70 versus ≥70 years; 69.6% versus 30.4% were male versus female; and planned platinum was cisplatin versus carboplatin in 25.1% versus 74.9%. The OS HRs for durvalumab plus EP versus EP were 0.71 (95% CI, 0.58-0.88) versus 0.74 (95% CI, 0.49-1.11) for patients aged <70 versus ≥70 years; 0.76 (95% CI, 0.62-0.95) versus 0.60 (95% CI, 0.42-0.84) for males versus females; and 0.65 (95% CI, 0.45-0.94) versus 0.74 (95% CI, 0.60-0.91) for planned cisplatin versus carboplatin. With durvalumab plus EP, rates of grade 3/4 adverse events (AEs) were similar across subgroups; serious AEs were more frequent in patients aged ≥70 versus <70 years; and immune-mediated AEs were more common in females versus males. Adding durvalumab to EP had no detrimental effect on PROs in either age subgroup. CONCLUSIONS:These findings support the use of durvalumab plus EP as first-line standard of care for ES-SCLC. Additional trials focused on elderly populations would be informative.

For patients with advanced stage non-small cell lung cancer (NSCLC), treatment strategies have changed significantly due to the introduction of targeted therapies and immunotherapy. In the last few years, we have seen an explosive growth of newly introduced targeted therapies in oncology and this development is expected to continue in the future. Besides primary targetable aberrations, emerging diagnostic biomarkers also include relevant co-occurring mutations and resistance mechanisms involved in disease progression, that have impact on optimal treatment management. To accommodate testing of pending biomarkers, it is necessary to establish routine large-panel next-generation sequencing (NGS) for all patients with advanced stage NSCLC. For cost-effectiveness and accessibility, it is recommended to implement predictive molecular testing using large-panel NGS in a dedicated, centralized expert laboratory within a regional oncology network. The central molecular testing center should host a regional Molecular Tumor Board and function as a hub for interpretation of rare and complex testing results and clinical decision-making.

Background: TTFields are electric fields that disrupt cancer cell viability. TTFields therapy is approved for glioblastoma and mesothelioma. The randomized, pivotal (phase 3) LUNAR study (NCT02973789) assessed the efficacy and safety of TTFields therapy with investigator's choice of standard systemic therapy (ST; immune checkpoint inhibitor [ICI] or docetaxel [DTX], standard of care at time of study design) for metastatic non-small cell lung cancer (mNSCLC) progressing on/after platinum-based therapy.

OBJECTIVES:IMbrella A is a Phase III extension study that allowed rollover from Roche/Genentech-sponsored atezolizumab trials, including IMpower133, a Phase I/III trial of first-line atezolizumab or placebo plus carboplatin/etoposide in extensive-stage small cell lung cancer. We report outcomes from an exploratory analysis of IMpower133 with extended time-to-event data for patients who rolled over to IMbrella A. MATERIALS AND METHODS:IMpower133 patients could roll over to IMbrella A to receive atezolizumab 1200 mg intravenously every three weeks if they continued to receive atezolizumab at IMpower133 closure or were in survival follow-up after atezolizumab discontinuation. Overall survival and safety were assessed; only serious adverse events and AEs of special interest were collected in IMbrella A. RESULTS:Eighteen of 26 eligible patients rolled over to IMbrella A. At clinical cutoff (March 16, 2023), median follow-up in the atezolizumab plus carboplatin/etoposide arm (IMpower133 and IMbrella A) was 59.4 months. The three-, four-, and five-year overall survival (95 % CI) estimates were 16 % (11 %-21 %), 13 % (8 %-18 %), and 12 % (7 %-17 %), respectively. In IMbrella A, serious adverse events occurred in three patients (16.7 %), and one adverse event of special interest was reported (grade two hypothyroidism). CONCLUSION:This long-term analysis of patients from IMbrella A previously enrolled in IMpower133 provides the first report of five-year overall survival outcomes in patients with extensive-stage small cell lung cancer treated with first-line cancer immunotherapy and chemotherapy. While limited by small patient numbers and lack of long-term data for the IMpower133 control arm, exploratory overall survival analyses in patients treated with atezolizumab plus carboplatin/etoposide compared favorably with historical data with chemotherapy alone. NCT03148418.

Subgroup analysis of PFS by tTMB for (A) durvalumab plus tremelimumab plus EP versus EP and (B) durvalumab plus EP versus EP. In each panel, the shaded band shows the confidence interval for the ITT population; circle sizes are proportional to the number of events.

Baseline patient demographics and disease characteristics for the PD-L1 and tTMB BEPs and the ITT population.

Summary of adverse events of any cause in the PD-L1, tTMB, and overall safety populations.

AbstractPurpose: In the CASPIAN trial, first-line durvalumab plus platinum-etoposide (EP) significantly improved overall survival (OS) versus EP alone in extensive-stage small cell lung cancer (ES-SCLC). We report exploratory analyses of CASPIAN outcomes by programmed cell death ligand-1 (PD-L1) expression and tissue tumor mutational burden (tTMB). Experimental Design: Patients were randomized (1:1:1) to durvalumab (1,500 mg) plus EP, durvalumab plus tremelimumab (75 mg) plus EP, or EP alone. Treatment effects in PD-L1 and tTMB subgroups were estimated using an unstratified Cox proportional hazards model. Results: The PD-L1 and tTMB biomarker-evaluable populations (BEP) comprised 54.4% (438/805) and 35.2% (283/805) of the intention-to-treat population, respectively. PD-L1 prevalence was low: 5.7%, 25.8%, and 28.3% had PD-L1 expression on ≥1% tumor cells (TC), ≥1% immune cells (IC), and ≥1% TCs or ICs, respectively. OS benefit with durvalumab plus EP versus EP was similar across PD-L1 subgroups, with HRs all falling within the 95% confidence interval (CI) for the PD-L1 BEP (0.47‒0.79). OS benefit with durvalumab plus tremelimumab plus EP versus EP was greater in PD-L1 ≥1% versus <1% subgroups, although CIs overlapped. There was no evidence of an interaction between tTMB and treatment effect on OS (durvalumab plus EP vs. EP, P = 0.916; durvalumab plus tremelimumab plus EP vs. EP, P = 0.672). Conclusions: OS benefit with first-line durvalumab plus EP in patients with ES-SCLC was observed regardless of PD-L1 or tTMB status. PD-L1 expression may prove to be a useful biomarker for combined treatment with PD-(L)1 and CTLA-4 inhibition, although this requires confirmation with an independent dataset. See related commentary by Rolfo and Russo, p. 652

In FLAURA2 (NCT04035486), 1L osi + platinum-pemetrexed (pem) chemotherapy (CTx) (n=279) significantly improved PFS vs osi alone (n=278) in EGFRm advanced NSCLC (HR 0.62; 95% CI 0.49, 0.79; p<0.0001 per investigator). Safety of osi + CTx was consistent with individual Tx profiles and was associated with higher incidence of G≥3 AEs vs osi. Most G≥3 AEs occurred during platinum-based CTx induction phase (pem + platinum CTx, 4 cycles Q3W) but reduced during maintenance. We report FLAURA2 PROs. Symptoms, function and HRQoL were measured using EORTC QLQ-C30/LC13 questionnaires (Table). Score (range 0–100) changes from baseline (BL) to progression/19 mos were analysed by a mixed-effects model. A clinically meaningful within-pt change was defined as ≥10 point change from BL. Tolerability was assessed with PRO-CTCAE items. EORTC questionnaire completion/PRO-CTCAE visit compliance was ≥80/≥75% to Wk 82. Non-clinically meaningful improvements in global health status/quality of life (GHS/QoL) and physical function were seen in both arms: average least-squares mean (LSM) change in GHS/QoL from BL (95% CI) over all visits was 3.32 (1.67, 4.98) with osi + CTx and 7.38 (5.70, 9.07) with osi. Non-clinically meaningful worsening of fatigue/appetite loss (LSM change from BL [95% CI]) was seen with osi + CTx in induction (10 wks: 2.98 [0.65, 5.32]/9.30 [6.13, 12.46]), but improved during maintenance (28 wks: -0.33 [-2.66, 2.00]/5.52 [2.60, 8.44]). A trend to improvement in dyspnoea, chest pain and cough was seen in both arms; clinically meaningful improvement for cough from Wks 5 (osi + CTx) and 6 (osi). PRO-CTCAE results showed osi + CTx and osi were similarly well tolerated except nausea/vomiting (more common with osi + CTx). A trend to improved HRQoL and several symptoms was seen after induction CTx. Negative changes in HRQoL from adding CTx to osi were not clinically meaningful and were mostly transient (trended back to BL post-induction CTx).Table: 9PMedian total study drug exposure, mos (range) at data cut-off 3 Apr 2023Osi + CTx: Platinum CTx, 2.8 (0.7, 4.1); Pem, 8.3 (0.7, 33.8); Osi, 22.3 (0.1, 33.8)Osi alone: 19.3 (0.1, 33.8)PRO toolPrespecified primary scalesScheduleEORTC QLQ-C30GHS/QoL, physical function, fatigue, appetite lossBL, Q3W to Wk 10 & Q6W to second-PFS (PFS2)EORTC QLQ-LC13Cough, dyspnoea, chest painBL, QW to Wk 10 & Q3W to PFS2PRO-CTCAE (exploratory endpoint)Mouth/throat sores, nausea, vomiting, diarrhoea, abdominal pain, loss of bowel movement control, dry skin, hair loss, numbness/tingling in hands/feetChange from BL: increased GHS/QoL = improved GHS/QoL & function; decreased symptom score = improved symptom burden Open table in a new tab

Les TTFields sont des champs électriques qui perturbent la viabilité des cellules cancéreuses, avec des effets démontrés dans des modèles précliniques, notamment l'induction d'une mitose anormale et d'un stress cellulaire, conduisant à une mort cellulaire immunogène et à une réponse immunitaire antitumorale renforcée. La thérapie TTFields délivrée de manière non invasive par un dispositif médical portable est approuvée pour le glioblastome et le mésothéliome. L'étude de phase 3 pivotale LUNAR (NCT02973789) a évalué les TTFields en combinaison avec, au choix de l'investigateur, un inhibiteur de point de contrôle immunitaire (ICI) ou le docétaxel (DTX), le protocole de soins (SOC) standard au moment de la conception de l'étude pour les cancers du poumon non à petites cellules (CBNPC) métastatiques ayant progressé après une thérapie à base de platine. Les patients adultes atteints d'un CBNPC métastatique progressant après un traitement à base de platine et dont le score ECOG est ≤ 2 ont été randomisés 1:1 entre TTFields/SOC et SOC. Le critère d'évaluation principal était la survie globale (SG). Les principaux critères d'évaluation secondaires étaient la SG dans les sous-groupes ICI et DTX. Les autres critères d'évaluation secondaires comprenaient la survie sans progression (SSP) et les événements indésirables (EI). Au total, 276 patients (TTFields + SOC, n = 137 ; SOC seul, n = 139) ont été inclus. L'âge médian (m) était de 64 ans (intervalle, 22–86), 65 % étaient des hommes, 56 % avaient un CBNPC non squameux, 96 % avaient un ECOG PS 0–1, 11 % avaient > 1 ligne antérieure de thérapie systémique, et 31 % avaient déjà reçu un ICI. Les caractéristiques étaient équilibrées entre les bras. La SG a été significativement prolongée avec TTFields + SOC par rapport à SOC : SGm (IC 95 %) 13,2 (10,3–15,5) mois (mo) vs 9,9 (8,1–11,5) mo ; HR 0,74 (IC 95 % 0,56–0,98) ; p = 0,035. La survie à 1 an (IC 95 %) était de 53 % (44–61) et 42 % (34–50), respectivement, et la SSPm (IC 95 %) était de 4,8 (4,1–5,7) mois vs 4,1 (3,1–4,6) mois (HR 0,85 ; IC 95 % 0,67–1,11 ; p = 0,23). Chez les patients traités par ICI (n = 134), les TTFields ont significativement amélioré la SG par rapport à l'ICI seul : SGm (IC 95 %) 18,5 (10,6–30,3) vs 10,8 (8,2–18,4) mois ; HR 0,63 (IC 95 % 0,41–0,96) ; p = 0,03. Dans le sous-groupe DTX (n = 142), la survie moyenne des patients traités par TTFields était de 11,1 (IC à 95 % 8,2–14,1) mo contre 8,7 (IC à 95 % 6,3–11,3) mo pour les patients recevant DTX seul ; HR 0,81 (IC à 95 % 0,55–1,19) ; p = 0,28. Les événements indésirables (EI) étaient similaires pour les patients recevant les TTFields + SOC (97 %) vs SOC seul (91 %). 71 % des patients ont signalé un EI lié au dispositif, la plupart étaient des dermatites de grade 1/2 (39 %) ou des prurits (12 %) ; 8 patients (6 %) ont signalé un EI de grade 3. Aucun EI de grade 4 ni aucun décès n'ont été attribués aux TTFields. La thérapie TTFields ajoutée au SOC a prolongé la SG par rapport au SOC seul, sans exacerber les toxicités systémiques, chez les patients atteints de CBNPC métastatique en progression après une thérapie à base de platine. Ces résultats justifient l'utilisation de la thérapie TTFields dans la prise en charge du CBNPC métastatique précédemment traité.

Distribution of tTMB scores by treatment arm in the tTMB BEP.

Representativeness of study participants.

In the past two decades, the treatment of metastatic non-small cell lung cancer (NSCLC), has undergone significant changes due to the introduction of targeted therapies and immunotherapy. These advancements have led to the need for predictive molecular tests to identify patients eligible for targeted therapy. This review provides an overview of the development and current application of targeted therapies and predictive biomarker testing in European patients with advanced stage NSCLC. Using data from eleven European countries, we conclude that recommendations for predictive testing are incorporated in national guidelines across Europe, although there are differences in their comprehensiveness. Moreover, the availability of recently EMA-approved targeted therapies varies between European countries. Unfortunately, routine assessment of national/regional molecular testing rates is limited. As a result, it remains uncertain which proportion of patients with metastatic NSCLC in Europe receive adequate predictive biomarker testing. Lastly, Molecular Tumor Boards (MTBs) for discussion of molecular test results are widely implemented, but national guidelines for their composition and functioning are lacking. The establishment of MTB guidelines can provide a framework for interpreting rare or complex mutations, facilitating appropriate treatment decision-making, and ensuring quality control.

Background:Stage III non-small cell lung cancer (NSCLC) is a highly heterogeneous stage due to its subgroups (IIIA-IIIC) comprising both resectable and unresectable tumors. Accurate determination of the extent of the disease is essential for excluding stage IV and choosing the optimal treatment regimen. Whole body positron emission tomography and computed tomography scan (PET/CT) is recommended as an initial staging imaging in locally advanced NSCLC. Despite international guidelines for NSCLC diagnosis and treatment, they are not always adhered to due to various reasons. Even in such a groundbreaking study, the phase 3 trial PACIFIC investigating the efficacy of durvalumab as consolidation therapy in patients with stage III NSCLC PET/CT was not mandatory. With the premise that whole body PET/CT of the trunk is essential for diagnosing stage III NSCLC, we performed a retrospective study evaluating the relationship of the use of PET/CT versus conventional staging with CT of the chest and abdomen, in terms of survival. Methods:This retrospective study of stage III NSCLC patients used the Czech lung cancer registry LUCAS, which was established in June 2018. As of the data export (up to February 9, 2022), a total of 703 patients were eligible for the analysis. Overall survival (OS) was compared using Kaplan-Meier analysis and a Cox regression model. Continuous variables were tested using the Mann-Whitney test, and categorical variables using the Pearson's Chi-square or Fisher's exact test. Results:A total of 703 patients were included in the cohort with an average age of 69 years. PET/CT was performed on 354 patients, and conventional staging using chest and abdominal CT on 349 patients. The median OS among patients with PET/CT was 20.9 months [95% confidence interval (CI): 18.1-23.7], and it was statistically significantly higher (P<0.001) than among patients without PET/CT, where the median OS was 9.0 months (95% CI: 7.3-10.6). The observed effect of PET/CT was also statistically significant when comparing individual stages (IIIA, IIIB, IIIC). The multivariate Cox model confirmed the use of PET/CT as an independent prognostic factor. The most common reason for omission of PET/CT was the local or time unavailability of the examination. Conclusions:Omission of PET/CT can mean a significant decrement in survival for the patients in stage III NSCLC, likely due to poor staging and suboptimal treatment. Routine use of PET/CT is strictly recommended for the optimal management of stage III NSCLC patients even outside the high-income countries.

Treatment exposure by PD-L1 subgroup (PD-L1 safety population).

Prevalence of PD-L1 expression on TC and IC in the PD-L1 BEP. *Includes patients whose tumors had <1% PD-L1 expression on TCs or ICs, but not absolute zero.

Relationship between PD-L1 expression and tTMB score. (A) Box plots showing the distribution of tTMB score in patients by PD-L1 subgroup; (B) Venn diagram showing overlap between the tTMB ≥10 mut/Mb and PD-L1 TC or IC ≥1% subgroups. Percentages are calculated from the PD-L1 and tTMB BEP, i.e., patients who had both a PD-L1 and a tTMB result (n=275); samples from 171 patients had tTMB ≥10 mut/Mb and/or PD-L1 TC or IC ≥1%, while samples from 104 patients (37.8%) had both tTMB <10 mut/Mb and PD-L1 TC and IC <1%.

In the Phase III IMpower133 trial (NCT02763579), first-line treatment with atezolizumab + carboplatin/etoposide (A+CE) improved OS and PFS vs placebo + carboplatin/etoposide (P+CE) in patients with ES-SCLC. At the time of IMpower133 study closure, patients treated with A+CE were eligible to enrol in the Phase IV, single-arm IMbrella A extension and long-term observational study (NCT03148418). Given the interest in long-term OS data for immunotherapy in ES-SCLC, we report patient outcomes from IMbrella A as an extension of the IMpower133 results.

Background: In CheckMate 227 Part 1, first-line nivolumab plus ipilimumab prolonged overall survival (OS) in patients with metastatic non-small-cell lung cancer (NSCLC) and tumor programmed death-ligand 1 (PD-L1) expression >1% versus chemotherapy. We report results from CheckMate 227 Part 2, which evaluated nivolumab plus chemotherapy versus chemotherapy in patients with metastatic NSCLC regardless of tumor PD-L1 expression.Patients and methods: Seven hundred and fifty -five patients with systemic therapy-naive, stage IV/recurrent NSCLC without EGFR mutations or ALK alterations were randomized 1 : 1 to nivolumab 360 mg every 3 weeks plus chemotherapy or chemotherapy. Primary endpoint was OS with nivolumab plus chemotherapy versus chemotherapy in patients with nonsquamous NSCLC. OS in all randomized patients was a hierarchically tested secondary endpoint.Results: At 19.5 months' minimum follow-up, no significant improvement in OS was seen with nivolumab plus chemotherapy versus chemotherapy in patients with nonsquamous NSCLC [median OS 18.8 versus 15.6 months, hazard ratio (HR) 0.86, 95.62% confidence interval (CI) 0.69-1.08, P = 0.1859]. Descriptive analyses showed OS improvement with nivolumab plus chemotherapy versus chemotherapy in all randomized patients (median OS 18.3 versus 14.7 months, HR 0.81, 95.62% CI 0.67-0.97) and in an exploratory analysis in squamous NSCLC (median OS 18.3 versus 12.0 months, HR 0.69, 95% CI 0.50-0.97). A trend toward improved OS was seen with nivolumab plus chemotherapy versus chemotherapy, regardless of the tumor mutation status of STK11 or TP53, regardless of tumor mutational burden, and in patients with intermediate/poor Lung Immune Prognostic Index scores. Safety with nivolumab plus chemotherapy was consistent with previous reports of first-line settings.Conclusions: CheckMate 227 Part 2 did not meet the primary endpoint of OS with nivolumab plus chemotherapy versus chemotherapy in patients with metastatic nonsquamous NSCLC. Descriptive analyses showed prolonged OS with nivolumab plus chemotherapy in all-randomized and squamous NSCLC populations, suggesting that this combination may benefit patients with untreated metastatic NSCLC.