Long-term effectiveness and treatment sequences in patients with extensive stage small cell lung cancer receiving atezolizumab plus chemotherapy: Results of the IFCT-1905 CLINATEZO real-world study.

BACKGROUND: Small cell lung cancer (SCLC) has a tendency towards recurrence and limited survival. Standard-of-care in 1st-line is platinum-etoposide chemotherapy plus atezolizumab or durvalumab,based on landmarkclinical trials. METHODS: IFCT-1905 CLINATEZO is a nationwide, non-interventional, retrospectivestudy of patients with extensive-SCLC receivingatezolizumab plus chemotherapy as part of French Early Access Program. Objectives were to analyse effectiveness,safetyand subsequent treatments. RESULTS: The population analyzed included 518 patients who received atezolizumabin 65 participating centers. There were 66.2% male,mean age was 65.7 years; 89.1% had a performance status (PS) 0/1 and 26.6% brain metastases. Almost all(95.9%) were smokers. Fifty-five (10.6%) received at least 1 previous treatment. Median number of atezolizumab injections was 7.0 (range [1.0-48.0]) for a median duration of 4.9 months (95% CI 4.5-5.1). Atezolizumab was continued beyond progression in 122 patients (23.6%) for a median duration of 1.9 months (95% CI: [1.4-2.3]). Best objective response was complete and partialin 19 (3.9%) and 378 (77.1%)patients. Stable diseasewas observed in 50 patients (10.2%). Median follow-up was30.8 months (95% CI: [29.9-31.5]). Median overall survival (OS), 12-, 24-month OS rates were 11.3 months (95% CI: [10.1-12.4]), 46.7% (95% CI [42.3-50.9]) and 21.2% (95% CI [17.7-24.8]). Median real-world progression-free survival, 6-, 12-month rates were 5.2 months (95% CI [5.0-5.4]), 37.5% (95% CI [33.3-41.7]) and 15.2% (95% CI [12.2-18.6]). For patients with PS 0/1, median OS was 12.2 months (95% CI [11.0-13.5]). For patients with previous treatment, median OS was 14.9 months (95% CI [10.1-21.5]). Three-hundred-and-twenty-six patients(66.4%) received subsequent treatment and27 (5.2%) were still underatezolizumabat date of last news. CONCLUSIONS: IFCT-1905 CLINATEZO shows reproductibility, in real-life,ofIMpower-133survival outcomes, possibly attributed to selection of patients fit for this regimen, adoption of pragmatic approaches,including concurrent radiotherapy and treatment beyond progression.

VEGFR2 and CD34 expression associated with longer survival in patients with pleural mesothelioma in the IFCT-GFPC-0701 MAPS phase 3 trial.

OBJECTIVES: VEGF/VEGFR autocrine loop is a hallmark of pleural mesothelioma (PM). We thus assayed the prognostic and predictive values of VEGFR-2 [vascular endothelial growth factor receptor 2 or Flk-1] and CD34, a marker of endothelial cells, in samples from patients accrued in the Mesothelioma Avastin Cisplatin Pemetrexed Study ('MAPS', NCT00651456). MATERIALS AND METHODS: VEGFR2 and CD34 expression were assayed using immunohistochemistry in 333 MAPS patients (74.3%), and their prognostic value was evaluated in terms of overall survival (OS) and progression-free survival (PFS) in univariate and multivariate analyses, before validation by bootstrap methodology. RESULTS: Positive VEGFR2 or CD34 staining was observed in 234/333 (70.2%) and 322/323 (99.6%) of tested specimens, respectively. VEGFR2 and CD34 staining correlated weakly, yet significantly, with each other (r = 0.36, p < 0.001). High VEGFR2 expression or high CD34 levels were associated with longer OS in PM patients in multivariate analysis (VEGFR2: adjusted [adj.] hazard ratio [HR]: 0.91, 95% confidence interval [CI] [0.88; 0.95], p < 0.001; CD34: adj. HR: 0.86, 95 %CI [0.76; 0.96], p = 0.010), with only high VEGFR2 expression resulting in significantly longer PFS (VEGFR2: adj. HR: 0.96, 95 %CI [0.92; 0.996], p = 0.032). Stability of these results was confirmed using bootstrap procedure. Nevertheless, VEGFR2 expression failed to specifically predict longer survival in bevacizumab-chemotherapy combination trial arm, regardless of whether the VEGFR2 score was combined or not with serum VEGF concentrations. CONCLUSION: VEGFR2 overexpression independently correlated with longer OS or PFS in PM patients, such biomarker deserving prospective evaluation as stratification variable in future clinical trials.

Neoadjuvant durvalumab for resectable non-small-cell lung cancer (NSCLC): results from a multicenter study (IFCT-1601 IONESCO).

BACKGROUND: The IONESCO (IFCT-1601) trial assessed the feasibility of neoadjuvant durvalumab, for early-stage resectable non-small-cell lung cancer (NSCLC). METHODS: In a multicenter, single-arm, phase II trial, patients with IB (≥4 cm)-IIIA, non-N2, resectable NSCLC received three doses of durvalumab (750 mg every 2 weeks) and underwent surgery between 2 and 14 days after the last infusion. The primary endpoint was the complete surgical resection rate. Secondary endpoints included tumor response rate, major histopathological response (MPR: ≤10% remaining viable tumor cells), disease-free survival (DFS), overall survival (OS), durvalumab-related safety, and 90-day postoperative mortality (NCT03030131). RESULTS: Forty-six patients were eligible (median age 60.9 years); 67% were male, 98% were smokers, and 41% had squamous cell carcinoma. Regarding tumor response, 9% had a partial response, 78% had stable disease, and 13% had progressive disease. Among the operated patients (n=43), 41 achieved complete resection (89%, 95% CI 80.1% to 98.1%)), and eight achieved MPR (19%). The 12-month median OS and DFS rates were 89% (95% CI 75.8% to 95.3%) and 78% (95% CI 63.4% to 87.7%), respectively (n=46). The median follow-up was 28.4 months (12.8-41.1). All patients in whom MPR was achieved were disease-free at 12 months compared to only 11% of those with >10% residual tumor cells (p=0.04). No durvalumab-related serious or grade 3-5 events were reported. The unexpected 90-day postoperative mortality of four patients led to premature study termination. None of these four deaths was considered secondary to direct durvalumab-related toxicity. CONCLUSIONS: Neoadjuvant durvalumab given as monotherapy was associated with an 89% complete resection rate and an MPR of 19%. Despite an unexpectedly high rate of postoperative deaths, which prevented us from completing the trial, we were able to show a significant association between MPR and DFS.

Chest CT scan plus x-ray versus chest x-ray for the follow-up of completely resected non-small-cell lung cancer (IFCT-0302): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Even after resection of early-stage non-small-cell lung cancer (NSCLC), patients have a high risk of developing recurrence and second primary lung cancer. We aimed to assess efficacy of a follow-up approach including clinic visits, chest x-rays, chest CT scans, and fibre-optic bronchoscopy versus clinical visits and chest x-rays after surgery for resectable NSCLC. METHODS: In this multicentre, open-label, randomised, phase 3 trial (IFCT-0302), patients aged 18 years or older and after complete resection of pathological stage I-IIIA NSCLC according to the sixth edition of the TNM classification were enrolled within 8 weeks of resection from 122 hospitals and tertiary centres in France. Patients were randomly assigned (1:1) to CT-based follow-up (clinic visits, chest x-rays, thoraco-abdominal CT scans, and fibre-optic bronchoscopy for non-adenocarcinoma histology) or minimal follow-up (visits and chest x-rays) after surgery for NSCLC, by means of a computer-generated sequence using the minimisation method. Procedures were repeated every 6 months for the first 2 years and yearly until 5 years. The primary endpoint was overall survival analysed in the intention-to-treat population. Secondary endpoints, also analysed in the intention-to-treat population, included disease-free survival. This trial is registered with ClinicalTrials.gov, NCT00198341, and is active, but not enrolling. FINDINGS: Between Jan 3, 2005, and Nov 30, 2012, 1775 patients were enrolled and randomly assigned to a follow-up group (888 patients to the minimal follow-up group; 887 patients to the CT-based follow-up group). Median overall survival was not significantly different between follow-up groups (8·5 years [95% CI 7·4-9·6] in the minimal follow-up group vs 10·3 years [8·1-not reached] in the CT-based follow-up group; adjusted hazard ratio [HR] 0·95, 95% CI 0·83-1·10; log-rank p=0·49). Disease-free survival was not significantly different between follow-up groups (median not reached [95% CI not estimable-not estimable] in the minimal follow-up group vs 4·9 [4·3-not reached] in the CT-based follow-up group; adjusted HR 1·14, 95% CI 0·99-1·30; log-rank p=0·063). Recurrence was detected in 246 (27·7%) of 888 patients in the minimal follow-up group and in 289 (32·6%) patients of 887 in the CT-based follow-up group. Second primary lung cancer was diagnosed in 27 (3·0%) patients in the minimal follow-up group and 40 patients (4·5%) in the CT-based follow-up group. No serious adverse events related to the trial procedures were reported. INTERPRETATION: The addition of thoracic CT scans during follow-up, which included clinic visits and chest x-rays after surgery, did not result in longer survival among patients with NSCLC. However, it did enable the detection of more cases of early recurrence and second primary lung cancer, which are more amenable to curative-intent treatment, supporting the use of CT-based follow-up, especially in countries where lung cancer screening is already implemented, alongside with other supportive measures. FUNDING: French Health Ministry, French National Cancer Institute, Weisbrem-Benenson Foundation, La Ligue Nationale Contre Le Cancer, and Lilly Oncology. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Lorlatinib for advanced anaplastic lymphoma kinase-positive non-small cell lung cancer: Results of the IFCT-1803 LORLATU cohort.

BACKGROUND: Anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC) represents a rare subset of lung cancer, with specific presentation, and multiple treatment options, including selective tyrosine kinase inhibitors (TKIs). Real-world evidence is insufficient regarding the actual real-life treatment sequences in the late line setting, and available clinical trials may not reflect real-world situation. Here, we took advantage of the French Expanded Access Program (EAP) of lorlatinib, a third-generation TKI targeting ALK and ROS1, to assess treatment sequencing, and lorlatinib efficacy and safety, in patients with ALK+ NSCLC. METHODS: All consecutive patients with advanced ALK+ NSCLC treated between October 2015 and June 2019 with lorlatinib as part of EAP were included. Data were collected and reviewed from medical records by independent research staff of the French Thoracic Cancer Intergroup. The primary endpoint was progression-free survival (PFS). RESULTS: Of the 208 patients included, 117 (56%) were female, 142 (69%) were never smokers, and 180 (87%) had stage IV NSCLC at diagnosis. The most frequent histology was adenocarcinoma (94%), and the median age was 60.9 years. At the time of lorlatinib initiation, 160 (77%) patients had brain metastases, and 125 (72%) were performance status 0/1. Lorlatinib was delivered as 2nd/3rd/4th/5th+ line in 4%/17%/30%/49% of patients. A total of 162 (78%) patients had previously been treated with chemotherapy, 194 (93%) with a first-generation ALK-TKI, 195 (94%) with a second-generation ALK-TKI. The median follow-up from lorlatinib initiation was 23.3 months. The median PFS, median overall survival (OS) from lorlatinib initiation and median OS from advanced NSCLC diagnosis were 9.9 months (95% confidence interval [CI] 6-12.3 months), 32.9 months (95% CI 18.7 months to not reached) and 97.3 months (95% CI 75.7-152.8 months), respectively. The median duration of treatment with lorlatinib was 11.8 months (95% CI 8.5-18.8 months). Overall response and disease control rate were 49% and 86%, respectively. Central nervous system objective response rate was 56%. Treatment was stopped due to toxicity in 28 patients (14%). The safety profile of lorlatinib was consistent with previously published data. CONCLUSIONS: Real-world evidence indicates that lorlatinib offers a significant clinical benefit and high intracerebral antitumour activity in heavily pretreated patients with ALK+ NSCLC. GOV IDENTIFIER: NCT03727477.

A defect of amphiregulin release predicted longer survival independently of YAP expression in patients with pleural mesothelioma in the IFCT-0701 MAPS phase 3 trial.

The Hippo pathway effector YAP is dysregulated in malignant pleural mesothelioma (MPM). YAP's target genes include the secreted growth factor amphiregulin (AREG), which is overexpressed in a wide range of epithelial cancers and plays an elusive role in MPM. We assayed the expression of YAP and AREG in MPM pathology samples and that of AREG additionally in plasma samples of patients from the randomized phase 3 IFCT-0701 Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) using immunohistochemistry and ELISA assays, respectively. MPM patients frequently presented high levels of tumor AREG (64.3%), a high cytosolic AREG expression being predictive of a better prognosis with longer median overall and progression-free survival. Surprisingly, tumor AREG cytosolic expression was not correlated with secreted plasma AREG. By investigating the AREG metabolism and function in MPM cell lines H2452, H2052, MSTO-211H and H28, in comparison with the T47D ER+ breast cancer cell line used as a positive control, we confirm that AREG is important for cell invasion, growth without anchorage, proliferation and apoptosis in mesothelioma cells. Yet, most of these MPM cell lines failed to correctly execute AREG posttranslational processing by metalloprotease ADAM17/tumor necrosis factor-alpha-converting enzyme (TACE) and extracell secretion. The favorable prognostic value of high cytosolic AREG expression in MPM patients could therefore be sustained by default AREG posttranslational processing and release. Thus, the determination of mesothelioma cell AREG content could be further investigated as a prognostic marker for MPM patients and used as a stratification factor in future clinical trials.

Combination of Trastuzumab, Pertuzumab, and Docetaxel in Patients With Advanced Non-Small-Cell Lung Cancer Harboring HER2 Mutations: Results From the IFCT-1703 R2D2 Trial.

PURPOSE: HER2 exon 20 insertions and point mutations are oncogenic drivers found in 1%-2% of patients with non-small-cell lung cancer (NSCLC). No targeted therapy is approved for this subset of patients. We prospectively evaluated the effectiveness of the combination of two antibodies against human epidermal growth factor 2 (HER2 [HER2] trastuzumab and pertuzumab with docetaxel; trastuzumab and pertuzumab) and docetaxel. METHODS: The IFCT 1703-R2D2 trial is a multicenter, nonrandomized phase II study. Patients with HER2-mutated, advanced NSCLC who progressed after ≥ 1 platinum-based treatment were enrolled. Patients received pertuzumab at a loading dose of 840 mg and 420 mg thereafter; trastuzumab at an 8 mg/kg loading dose and 6 mg/kg thereafter; and docetaxel at a dose of 75 mg/m2 every 3 weeks. The primary outcome was the objective response rate (ORR). Other end points included the duration of response, progression-free survival, and safety (NCT03845270). RESULTS: Forty-five patients were enrolled and treated. The median age was 64.5 years (range, 31-84 years), 35% were smokers, 72% were females, 15% had an Eastern Cooperative Oncology Group performance status of 2, and 30% had brain metastases. The objective response rate was 29% (n = 13), and 58% had stable disease (n = 26). The median progression-free survival was 6.8 months (95% CI, 4.0 to 8.5). The median duration of response in patients with a confirmed response (n = 13) was 11 months (95% CI, 2.9 to 14.9). Grade 3/4 treatment-related adverse events were observed in 64% of the patients. No patient discontinued treatment because of toxicity. The most frequent grade ≥ 3 treatment-related adverse events were neutropenia (33%), diarrhea (13%), and anemia (9%). CONCLUSION: Triple therapy with trastuzumab, pertuzumab, and docetaxel is feasible and effective for HER2-mutated pretreated advanced NSCLC. These results highlight the effectiveness of the HER2 antibody-based strategy, which should be considered for these patients.

Tailoring maintenance chemotherapy upon response to induction chemotherapy as compared with pemetrexed continuation maintenance in advanced non-squamous NSCLC patients: Results of the IFCT-GFPC-1101 multicenter randomized phase III trial.

BACKGROUND: Benefit from maintenance in advanced non-squamous non-small cell lung cancer (NS-NSCLC) might favor switch maintenance after disease stabilization (SD) and continuation after objective response (OR). This trial assessed a maintenance strategy conditioned by response to cisplatin-gemcitabine (CG) with G continuation for patients with OR or switch to pemetrexed (P) for patients with SD as compared with a control arm based on the Paramount regimen. METHODS: Eligibility criteria: age 18-70 years, ECOG PS 0-1, untreated stage IV NS-NSCLC without EGFR or ALK alteration, ineligibility to bevacizumab. Patients were randomized 1:1 to receive either CG (4 cycles) followed by G maintenance in case of OR followed by P at progression, or switch to P for patients with SD, or 4 cycles of CP followed by P (control arm). Primary endpoint: overall Survival. RESULTS: Between 2012 and 2016, 932 patients were randomized (CG: 467, CP: 465) with well-balanced characteristics. 257 patients (56.7%) in the CG arm received maintenance (G: 142, P: 113) versus 277 patients (59.7%) in the CP arm. Median number of maintenance cycles was 5 for G and P (CG induction) and 4 for P (CP induction). OS adjusted HR was 0.97 (95% CI 0.84, 1.13; p = 0.71) with a median of 10.9 months (CG) versus 10.4 (CP). HR for PFS was 0.95 (95% CI 0.83, 1.09; p = 0.45) with a median of 4.8 months for CG versus 4.5 for CP. Safety profile was as expected. CONCLUSIONS: Adapting maintenance strategy according to response to induction chemotherapy does not improve patient outcome. CLINICAL TRIAL INFORMATION: NCT01631136.

Assessment of nivolumab in HIV-Infected patients with advanced non-small cell lung cancer after prior chemotherapy. The IFCT-1602 CHIVA2 phase 2 clinical trial.

IMPORTANCE: Therapies targeting immune checkpoints, such as the programmed cell death 1 (PD-1) receptor, have become the standard-of-care for patients with non-small cell lung cancer (NSCLC), but people living with HIV (PLWH) were excluded from these studies. OBJECTIVE: To evaluate the efficacy and tolerability of nivolumab in PLWH with advanced NSCLC. DESIGN: The CHIVA2 study was a nonrandomized, open-label, phase 2 clinical trial in PLWH with previously treated advanced NSCLC. SETTING: National multicenter prospective study. PARTICIPANTS: patients had viral load of <200 copies/mL, regardless of their CD4+ T-cell count. INTERVENTION: Nivolumab was administered in second or third line, as monotherapy intravenously at 3 mg/kg every 2 weeks, until disease progression or limiting toxicity. MAIN OUTCOMES AND MEASURES: The primary endpoint was disease control rate, evaluated using the Response Evaluation Criteria in Solid Tumors, version 1.1. Adverse events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Sixteen patients with advanced NSCLC were enrolled: 14 (88 %) were men, median age was 58 years (range: 44-71), and all were smokers. The median duration of nivolumab treatment was 3.5 months (range: 0.5-26.5). The median follow-up was 23.6 months. Disease control rate was 62.5 % for 15 evaluable patients at 8 weeks (2 with partial response, 8 with stable disease, and 5 with disease progression). Twelve (75 %) patients had treatment-related adverse events, which were mild or moderate, except for one patient experiencing severe pruritus, onycholysis, and pemphigoid. There were no opportunistic infections or unexpected immune-related events. HIV viral load was stable during treatment. An increase in proliferating CD8+ and CD4+ T-cells was observed after 3 nivolumab cycles in a subgroup of 9 patients. CONCLUSIONS AND RELEVANCE: Second/third-line nivolumab treatment was well-tolerated and beneficial in PLWH with NSCLC. Future trials should investigate immune checkpoint inhibitors in first-line settings. TRIAL REGISTRATION: EudraCT.ema.europa.eu registration number: 2016-003796-22.

First-Line Afatinib plus Cetuximab for EGFR-Mutant Non-Small Cell Lung Cancer: Results from the Randomized Phase II IFCT-1503 ACE-Lung Study.

PURPOSE: Double inhibition of epidermal growth factor receptor (EGFR) using a tyrosine kinase inhibitor plus a monoclonal antibody may be a novel treatment strategy for non-small cell lung cancer (NSCLC). We assessed the efficacy and toxicity of afatinib + cetuximab versus afatinib alone in the first-line treatment of advanced EGFR-mutant NSCLC. PATIENTS AND METHODS: In this phase II, randomized, open-label study, patients with stage III/IV EGFR-positive NSCLC were randomly assigned (1:1) to receive afatinib (group A) or afatinib + cetuximab (group A + C). Oral afatinib 40 mg was given once daily; cetuximab 250 mg/m² was administered intravenously on day 15 of cycle 1, then every 2 weeks at 500 mg/m² for 6 months. The primary endpoint was time to treatment failure (TTF) rate at 9 months. Exploratory analysis of EGFR circulating tumor DNA in plasma was performed. RESULTS: Between June 2016 and November 2018, 59 patients were included in group A and 58 in group A + C. The study was ended early after a futility analysis was performed. The percentage of patients without treatment failure at 9 months was similar for both groups (59.3% for group A vs. 64.9% for group A + C), and median TTF was 11.1 (95% CI, 8.5-14.1) and 12.9 (9.2-14.5) months, respectively. Other endpoints, including progression-free survival and overall survival, also showed no improvement with the combination versus afatinib alone. There was a slight numerical increase in grade ≥3 adverse events in group A + C. Allele frequency of the EGFR gene mutation in circulating tumor DNA at baseline was associated with shorter PFS, regardless of the treatment received. CONCLUSIONS: These results suggest that addition of cetuximab to afatinib does not warrant further investigation in treatment-naïve advanced EGFR-mutant NSCLC.

Circulating Tumor DNA as a Prognostic Determinant in Small Cell Lung Cancer Patients Receiving Atezolizumab.

BACKGROUND: The IFCT-1603 trial evaluated atezolizumab in small cell lung cancer (SCLC). The purpose of the present study was to determine whether circulating tumor DNA (ctDNA), prospectively collected at treatment initiation, was associated with the prognosis of SCLC, and whether it identified patients who benefited from atezolizumab. METHODS: 68 patients were included in this study: 46 patients were treated with atezolizumab and 22 with conventional chemotherapy. Circulating DNA was extracted from plasma and NGS (Next Generation Sequencing) looked for mutations in the TP53, RB1, NOTCH1, NOTCH2, and NOTCH3 genes. ctDNA was detectable when at least one somatic mutation was identified, and its relative abundance was quantified by the variant allele fraction (VAF) of the most represented mutation. RESULTS: We found that 49/68 patients (70.6%) had detectable baseline ctDNA. The most frequently identified mutations were TP53 (32/49; 65.3%) and RB1 (25/49; 51.0%). Patients with detectable ctDNA had a significantly lower disease control rate at week 6 compared with patients with no detectable ctDNA, regardless of the nature of the treatment. Detection of ctDNA was associated with a poor OS prognosis. The detection of ctDNA at a relative abundance greater than the median value was significantly associated with poor overall survival (OS) and progression free survival (PFS). Interestingly, the benefit in overall survival (OS) associated with low ctDNA was more pronounced in patients treated with atezolizumab than in patients receiving chemotherapy. Among patients whose relative ctDNA abundance was below the median, those treated with atezolizumab tended to have higher OS than those in the chemotherapy arm. CONCLUSION: ctDNA is strongly associated with the prognosis of SCLC patients treated with second-line immunotherapy. Its analysis seems justified for future SCLC clinical trials.

Switch maintenance chemotherapy versus observation after carboplatin and weekly paclitaxel doublet chemotherapy in elderly patients with advanced non-small cell lung cancer: IFCT-1201 MODEL trial.

PURPOSE: Maintenance chemotherapy is a reasonable choice for patients with metastatic non-small cell lung carcinoma (NSCLC) not progressing after induction therapy with a platinum-based doublet. Nevertheless, there have been no studies dedicated to elderly patients. PATIENTS AND METHODS: We conducted a randomised trial in patients aged 70-89 years, with advanced NSCLC (with neither EGFR mutation nor ALK rearrangement), who had not progressed after four cycles of monthly carboplatin and weekly paclitaxel in order to compare maintenance with either pemetrexed (500 mg/m2 d1, 22) in patients with non-squamous cell carcinoma or gemcitabine (1,150 mg/m2 d1, 8, 22) in squamous cell carcinoma to simple observation. The patients were required to have a performance status (PS) 0-2, mini-mental score >23, and creatinine clearance ≥45 mL/min. The primary end-point was overall survival (OS). RESULTS: 632 patients were enrolled from May 2013 to October 2016. Of the 328 (52.3%) patients randomised after induction therapy, 166 patients were assigned to the observation arm, versus 162 to the switch maintenance arm, 119 of whom received pemetrexed and 43 gemcitabine. The median OS from randomisation was 14.1 months (95% confidence interval [CI]: 12.0-17.0) in the observation arm and 14 months (95% CI: 10.9-16.9) in the maintenance arm (p = 0.72). The median progression-free survival (PFS) from randomisation was 2.7 months (95% CI: 2.6-3.1) in the observation arm versus 5.7 months (95% CI: 4.8-7.1) in the maintenance arm (p < 0.001). CONCLUSION: Switch maintenance therapy significantly prolonged PFS but not OS and, thus, should not be proposed to elderly patients with advanced NSCLC.

First-line carboplatin plus pemetrexed with pemetrexed maintenance in HIV-positive patients with advanced non-squamous non-small cell lung cancer: the phase II IFCT-1001 CHIVA trial.

HIV infection is an exclusion criterion in lung cancer trials. This multicentre phase II trial aimed to assess feasibility, efficacy and safety of first-line carboplatin plus pemetrexed (CaP) followed by pemetrexed (P) maintenance in people living with HIV (PLHIV) with advanced non-squamous non-small cell lung cancer (NS-NSCLC).Four cycles of CaP were followed by P-maintenance therapy in patients with Eastern Cooperative Oncology Group performance status ≤2. The primary objective was a disease control rate (DCR) ≥30% after 12 weeks.Of the 61 PLHIV enrolled, 49 (80%) had a performance status of 0-1, and 19 (31%) had brain metastases. Median CD4 lymphocyte count was 418 cells·µL-1 (range 18-1230), median CD4 lymphocyte nadir was 169.5 cells·µL-1 (1-822); 48 (80%) patients were virologically controlled. Four-cycle inductions were achieved by 38 (62%) patients, and 31 (51%) started P-maintenance (median of 4.1 cycles (range 1-19)). The 12-week DCR was 50.8% (95% CI 38.3-63.4) and partial response rate 21.3%. Median progression-free survival and overall survival were 3.5 (95% CI 2.7-4.4) and 7.6 months (5.7-12.8), respectively. Patients with a performance status of 0-1 had the longest median progression-free survival (4.3 months, 95% CI 3.1-5.2) and overall survival (11.9 months, 95% CI 6.4-14.3). During induction, CaP doublet was well tolerated apart from grade 3-4 haematological toxicities (neutropenia 53.8%; thrombocytopenia 35.0%; anaemia 30.0%). Two fatal treatment-related sepses were reported. No opportunistic infections were experienced.In PLHIV with advanced NS-NSCLC, first-line four-cycle CaP induction followed by P-maintenance was effective and reasonably well-tolerated. Further studies should evaluate combination strategies of CaP with immunotherapy in PLHIV.

Weekly paclitaxel plus bevacizumab versus docetaxel as second- or third-line treatment in advanced non-squamous non-small-cell lung cancer: Results of the IFCT-1103 ULTIMATE study.

PURPOSE: Second-line chemotherapy regimens have demonstrated poor benefit after failure of platinum-based chemotherapy in advanced non-squamous non-small-cell lung cancer (nsNSCLC). METHODS: In this multicentre, open-label phase III trial, patients with advanced nsNSCLC treated with one or two prior lines, including one platinum-based doublet, were centrally randomised to receive 90 mg/m2 of paclitaxel (D1, D8, D15) plus 10 mg/kg of bevacizumab (D1, D15) every 28 days or docetaxel (75 mg/m2) every 21 days; crossover was allowed after disease progression. Primary end-point was progression-free survival (PFS). ClinicalTrials.gov registration number: NCT01763671. RESULTS: One hundred sixty six patients were randomised (paclitaxel plus bevacizumab: 111, docetaxel: 55). The median PFS was longer in patients receiving paclitaxel plus bevacizumab than in patients receveing docetaxel [5·4 months versus 3·9 months, adjusted hazard ratio (HR) 0·61 (95% confidence interval [CI]: 0·44-0·86); p = 0·005]. Objective response rates (ORRs) were 22·5% (95% CI: 14·8-30·3) and 5·5% (95% CI: 0·0-11·5) (p = 0·006), respectively. Median overall survivals were similar (adjusted HR 1·17; p = 0·50). Crossover occurred in 21 of 55 (38·2%) docetaxel-treated patients. Grade III-IV adverse events (AEs) were reported in 45·9% and 54·5% of patients treated with paclitaxel and bevacizumab or docetaxel, respectively (p = NS), including neutropenia (19·3% versus 45·4%), neuropathy (8·3% versus 0·0%) and hypertension (7·3% versus 0·0%). Three patients died due to treatment-related AEs (1·8% in each group). CONCLUSION: Weekly paclitaxel plus bevacizumab as second- or third-line improves PFS and ORR compared with docetaxel in patients with nsNSCLC, with an acceptable safety profile. These results place weekly paclitaxel plus bevacizumab as a valid option in this population. CLINICAL TRIALS REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01763671.

Randomized Phase II Trial Evaluating Treatment with EGFR-TKI Associated with Antiestrogen in Women with Nonsquamous Advanced-Stage NSCLC: IFCT-1003 LADIE Trial.

PURPOSE: The incidence of lung cancer has dramatically increased in women. Preclinical data have suggested that combining EGFR-tyrosine kinase inhibitor (TKI) with an antiestrogen may overcome resistance to EGFR-TKI. PATIENTS AND METHODS: The IFCT-1003 LADIE trial was a 2 × 2 arms parallel open-label randomized phase II trial. EGFR-TKI-naïve postmenopausal women with advanced lung cancer were treated with gefitinib (G) versus gefitinib + fulvestrant (G+F) in the EGFR-mutated group (EGFR+) or with erlotinib (E) versus erlotinib + fulvestrant (E+F) in the EGFR wild-type group (EGFR-WT). The primary objective was progression-free survival (PFS) at 3 and 9 months for EGFR-WT and EGFR+ patients. RESULTS: Overall, 204 patients (gefitinib 104 and G+F 100) and 175 patients (erlotinib 87 and E+F 88) were enrolled in the EGFR+ and EGFR-WT cohorts. In the EGFR+ cohort, the primary endpoint was reached, with 58% of the G+F group patients being nonprogressive at 9 months. Adding fulvestrant to gefitinib was not associated with improved PFS (9.9 vs 9.4 months) or overall survival (OS; 22.1 vs 28.6 months). In the EGFR-WT cohort, the primary endpoint was also achieved (33.7% of the patients were nonprogressive at 3 months). Adding fulvestrant to erlotinib was not associated with improved outcome (PFS 1.8 vs 2.0 and OS 10.3 vs 7.3 months). No PFS difference was observed regarding estrogen receptor alpha expression. The tolerance was as expected with no treatment-related death. CONCLUSIONS: Adding fulvestrant to EGFR-TKI is feasible, but not associated with prolonged PFS regardless of EGFR status. The lack of benefits while combining fulvestrant to EGFR-TKI does not support its future development in an unselected population.

Development and Validation of a Simplified Prognostic Score in SCLC.

INTRODUCTION: This study aimed at generating a new simplified prognostic score (SPS) using common clinical and biological variables to discriminate a limited number of subgroups of patients with SCLC differing by their overall survival (OS). METHODS: The SPS was developed exploring the Montpellier University Hospital retrospective database of 401 patients over a 16-year period. All patients had received etoposide - platinum-based chemotherapy as first-line treatment. The SPS development took into account significant determinants of OS in the Cox model, weighted by their regression ß coefficients. Validation of the consequent SPS has been done separately in a combined population of 213 patients accrued from two different published trials (NCT03059667 and NCT00930891). RESULTS: The significant independent determinants of OS included the following: (1) American Joint Committee on Cancer TNM stage IV (hazard ratio [HR]: 2.52; 95% confidence interval [CI]: 1.91-3.33); (2) Eastern Cooperative Oncology Group performance status greater than 1 (HR: 2.27; 95% CI: 1.79-2.87); (3) the presence of liver metastases (HR: 1.66; 95% CI: 1.29-2.15); and (4) neutrophil-to-lymphocyte ratio greater than 4 (HR: 1.39; 95% CI: 1.11-1.92). The SPS generated with these four variables, segregated three groups (good, intermediate, and poor prognosis) with respective median OS of 26.9 months (95% CI: 20.1-38.9), 11.5 months (95% CI: 9.8-13.0), and 6.8 months (95% CI: 5.8-8.3; log-rank p < 10-4). Harrell's C statistic estimate was 0.68 ± 0.012, suggesting goodness of calibration. In the validation cohort, the SPS segregated the aforementioned three subgroups in a nearly similar manner, with respective median OS: 27.2, 12.3, and 8.6 months (log-rank p < 10-3; Harrell's C statistic: 0.58 ± 0.02). CONCLUSIONS: The SPS is easy to calculate in real-life practice and efficiently discriminates three populations with different prognoses. This study deserves further validation of this score in patients with SCLC receiving immunochemotherapy.

Outcomes of Patients With Advanced NSCLC From the Intergroupe Francophone de Cancérologie Thoracique Biomarkers France Study by KRAS Mutation Subtypes.

INTRODUCTION: KRAS mutations are detected in 20% to 30% of NSCLC. However, KRAS mutation subtypes may differently influence the outcome of patients with advanced NSCLC. METHODS: In the Biomarkers France study, 4894 KRAS mutations (26.2%) were detected in 4634 patients from the 17,664 enrolled patients with NSCLC. Survival and treatment data on noncurative stage III to IV NSCLC were available for 901 patients. First- and second-line treatment effects on progression-free survival and overall survival were analyzed according to the KRAS mutations subtype. RESULTS: Over 95% of patients with KRAS mutation were smokers or former smokers who were white (99.5%), presenting with adenocarcinoma (82.5%). The most common KRAS mutation subtype was G12C (374 patients; 41.5%), followed by G12V (168; 18.6%), G12D (131; 14.5%), G12A (62; 6.9%), G13C (45; 5.0%), G13D (31; 3.4%), and others (10; 1%). Approximately 21% of patients had transition mutation and 68.2% had a transversion mutation. G12D and transition mutations were predominant in never-smokers. The median overall survival for patients with KRAS-mutated NSCLC was 8.1 months (95% confidence interval [CI]: 7.5-9.5), without any differences according to the different KRAS subtypes mutations. The median progression-free survival was 4.6 months (95% CI: 4.2-5.1) for first-line treatment and 4.8 months (95% CI: 4.3-6.8) for second-line treatment, without any differences according to the different KRAS subtypes mutations. CONCLUSIONS: KRAS mutation subtypes influenced neither treatment responses nor outcomes. The KRAS G12C mutation was detected in 41.5% of patients, who are now eligible for potent and specific G12C inhibitors.

Independent prognostic value of ultra-sensitive quantification of tumor pre-treatment T790M subclones in EGFR mutated non-small cell lung cancer (NSCLC) treated by first/second generation TKI, depends on variant allele frequency (VAF): Results of the French cooperative thoracic intergroup (IFCT) biomarkers France project.

OBJECTIVES: T790M mutations inEGFR-mutated non-small cell lung cancer (NSCLC) account for nearly 50% of acquired resistance mechanisms to EGFR-TKIs. Earlier studies suggested that tumor T790M could also be detected in TKI-naïve EGFR-mutated NSCLC. The aim of the study is to assess the prevalence and clinical significance of quantification of tumor pre-treatment T790M subclones. MATERIALS AND METHODS: We analyzed 366 EGFR-mutated NSCLC patients of the real-life IFCT Biomarkers France study with available pre-treatment formalin-fixed paraffin-embedded (FFPE) tumor DNA before treatment by first/second-generation EGFR-TKI. We used ultra-sensitive Droplet Digital Polymerase Chain Reaction (ddPCR) QX200 (BIO-RAD®, Hercules, CA, USA). All samples were tested in duplicate. RESULTS: ddPCR identified T790M in 19/240 specimens (8%). T790M-positive and T790M-negative populations were not different for clinical baseline characteristics. T790M Variant Allele Frequency (VAF) was > 0.01% <0.1%, > 0.1% <1%, > 1% <10%, and >10% in five (26.3%), six (31.6%), six (31.6%), and two (10.5%) patients, respectively. T790M VAF was >0.1% in 11/13 (84%) patients with rapid (<3 months) or usual progression (3-20 months) compared to 0/3 with low progression (>20 months) (p = 0.02). In a Cox model, T790M mutation positivity was correlated with overall survival (OS) and progression-free survival (PFS) for 10% > VAF >1% (hazard ratio [HR] = 2.83, 95% confidence interval [CI] 1.13-7.07, p = 0.03; HR=3.62, 95%CI 1.43-4.92, p = 0.007, respectively) and for VAF >10% (HR = 19.14, 95%CI 4.35-84.26, p < 0.001; HR = 17.89, 95%CI 2.21-144.86, p = 0.007, respectively). CONCLUSION: Ultra-sensitive detection of tumor T790M mutation concerned 8% of EGFR-mutated TKI-naïve NSCLC patients and has a negative prognostic value only for T790M VAF over 1%.

Role of the YAP-1 Transcriptional Target cIAP2 in the Differential Susceptibility to Chemotherapy of Non-Small-Cell Lung Cancer (NSCLC) Patients with Tumor RASSF1A Gene Methylation from the Phase 3 IFCT-0002 Trial.

RASSF1 gene methylation predicts longer disease-free survival (DFS) and overall survival (OS) in patients with early-stage non-small-cell lung cancer treated using paclitaxel-based neo-adjuvant chemotherapy compared to patients receiving a gemcitabine-based regimen, according to the randomized Phase 3 IFCT (Intergroupe Francophone de Cancérologie Thoracique)-0002 trial. To better understand these results, this study used four human bronchial epithelial cell (HBEC) models (HBEC-3, HBEC-3-RasV12, A549, and H1299) and modulated the expression of RASSF1A or YAP-1. Wound-healing, invasion, proliferation and apoptosis assays were then carried out and the expression of YAP-1 transcriptional targets was quantified using a quantitative polymerase chain reaction. This study reports herein that gemcitabine synergizes with RASSF1A, silencing to increase the IAP-2 expression, which in turn not only interferes with cell proliferation but also promotes cell migration. This contributes to the aggressive behavior of RASSF1A-depleted cells, as confirmed by a combined knockdown of IAP-2 and RASSF1A. Conversely, paclitaxel does not increase the IAP-2 expression but limits the invasiveness of RASSF1A-depleted cells, presumably by rescuing microtubule stabilization. Overall, these data provide a functional insight that supports the prognostic value of RASSF1 gene methylation on survival of early-stage lung cancer patients receiving perioperative paclitaxel-based treatment compared to gemcitabine-based treatment, identifying IAP-2 as a novel biomarker indicative of YAP-1-mediated modulation of chemo-sensitivity in lung cancer.

Shorter Survival in Malignant Pleural Mesothelioma Patients With High PD-L1 Expression Associated With Sarcomatoid or Biphasic Histology Subtype: A Series of 214 Cases From the Bio-MAPS Cohort.

BACKGROUND: Anticancer immune responses are negatively regulated by programmed cell death 1 (PD-1) T-cell membrane protein interaction with its ligand, programmed death ligand 1 (PD-L1), on cancer cells. We sought to assess the prognostic role of PD-L1 expression in tumor samples from patients enrolled onto the IFCT-0701 MAPS randomized phase 3 trial (NCT00651456). PATIENTS AND METHODS: Tumor samples were analyzed by immunohistochemistry for percentages of PD-L1 membrane-stained tumor cells using the E1L3N clone, and data were correlated to survival by multivariate Cox models including stratification variables. RESULTS: PD-L1 staining was assessed in 214 (47.75%) of 448 patients. Epithelioid subtype represented 83.7% (179/214). Absence of PD-L1 staining occurred in 137 (64.1%) of 214 malignant pleural mesothelioma (MPM) samples, while 77 (35.9%) of 214 were PD-L1 positive, with 50 (64.9%) of 77 showing < 50% PD-L1-expressing tumor cells. Sarcomatoid/biphasic subtypes were more commonly PD-L1 positive than epithelioid subtype (P < .001). In patients with 1% or more PD-L1-stained tumor cells, median overall survival (OS) was 12.3 months versus 22.2 months for other patients (hazard ratio [HR] = 1.25; 95% confidence interval [CI], 0.93-1.67; P = .14). OS did not differ according to PD-L1 positivity in multivariate analyses (adjusted HR = 1.10; 95% CI, 0.81-1.49; P = .55). With a 50% cutoff, PD-L1-positive patients displayed a 10.5 months median OS versus 19.3 months for patients with lower PD-L1 expression (HR = 1.93; 95% CI, 1.27-2.93; P = .002). OS did not significantly differ in adjusted Cox models (adjusted HR = 1.20; 95% CI, 0.74-1.94; P = .47). In the 179 epithelioid MPM patients, high PD-L1 staining (≥ 50% of tumor cells) negatively affected OS, although not significantly, showing a 12.3-month median OS (95% CI, 4.3-21.6) versus 23-month (95% CI, 18.5-25.2) for patients with tumor PD-L1 staining in < 50% cells (P = .071). The progression-free survival (PFS) differences were statistically significant, with a longer 9.9-month median PFS in patients with low PD-L1 staining (< 50% cells) compared to 6.7 months of median PFS in patients with high PD-L1 expression (≥ 50% cells) (P = .0047). CONCLUSION: Although high PD-L1 tumor cell expression was associated with poorer OS in MPM patients from the MAPS trial, its prognostic influence was lost in multivariate analyses in the whole cohort, while PD-L1 expression was strongly associated with the sarcomatoid/biphasic subtypes. In the epithelioid MPM subset of patients, high PD-L1 tumor expression (≥ 50%) negatively affected OS and PFS, with this prognostic influence remaining statistically significant for PFS after adjustment in multivariate Cox model.