Postoperative Chemotherapy Use and Outcomes From ADAURA: Osimertinib as Adjuvant Therapy for Resected EGFR-Mutated NSCLC

IntroductionAdjuvant chemotherapy is recommended in patients with resected stages II to IIIA (and select IB) NSCLC; however, recurrence rates are high. In the phase 3 ADAURA study (NCT02511106), osimertinib was found to have a clinically meaningful improvement in disease-free survival (DFS) in patients with resected stages IB to IIIA EGFR-mutated (EGFRm) NSCLC. Here, we report prespecified and exploratory analyses of adjuvant chemotherapy use and outcomes from ADAURA.MethodsPatients with resected stages IB to IIIA EGFRm NSCLC were randomized 1:1 to receive osimertinib or placebo for 3 years. Adjuvant chemotherapy before randomization was not mandatory, per physician and patient choice. DFS in the overall population (IB–IIIA), with and without adjuvant chemotherapy, was a prespecified analysis. Exploratory analyses included the following: adjuvant chemotherapy use by patient age, disease stage, and geographic location; DFS by adjuvant chemotherapy use and disease stage.ResultsOverall, 410 of 682 patients (60%) received adjuvant chemotherapy (osimertinib, n = 203; placebo, n = 207) for a median duration of 4.0 cycles. Adjuvant chemotherapy use was more frequent in patients: aged less than 70 years (338 of 509; 66%) versus more than or equal to 70 years (72 of 173; 42%); with stages II to IIIA (352 of 466; 76%) versus stage IB (57 of 216; 26%); and enrolled in Asia (268 of 414; 65%) versus outside of Asia (142 of 268; 53%). A DFS benefit favoring osimertinib versus placebo was observed in patients with (DFS hazard ratio = 0.16, 95% confidence interval: 0.10–0.26) and without adjuvant chemotherapy (hazard ratio = 0.23, 95% confidence interval: 0.13–0.40), regardless of disease stage.ConclusionsThese findings support adjuvant osimertinib as an effective treatment for patients with stages IB to IIIA EGFRm NSCLC after resection, with or without previous adjuvant chemotherapy.     

Impact of Patient Characteristics,Prior Therapy,and Sample Type on Tumor Cell Programmed Cell Death Ligand 1 Expression in Patients with Advanced NSCLC Screened for the ATLANTIC Study

IntroductionWe evaluated the impact of patient characteristics, sample types, and prior non-immunotherapy treatment on tumor cell (TC) programmed cell death ligand 1 (PD-L1) expression using samples from patients with advanced NSCLC.MethodsPatients (N = 1590) screened for the ATLANTIC study submitted a recently acquired (≤3 months) or archival (>3 months to >3 years old) tumor sample for PD-L1 assessment using the VENTANA PD-L1 (SP263) Assay with a cutoff of ≥25% of TCs expressing PD-L1 (TC ≥25%). Samples were acquired either before or after the two or more treatment regimens required for study entry and sample age varied among patients. A subset of patients (n = 123) provided both recent and archival samples.ResultsA total of 517 of 1590 (32.5%) patients had TC greater than or equal to 25%: prevalence was greater in smokers versus nonsmokers (p = 0.0005) and those with EGFR− versus EGFR+ tumors (p = 0.0002); these effects were independent. Prevalence of TC greater than or equal to 25% was increased in recent metastatic versus primary (p = 0.005) and recent versus archival (p = 0.039) samples. Chemotherapy or radiotherapy, but not tyrosine kinase inhibition, before sampling was associated with significantly increased PD-L1 prevalence. PD-L1 status (TC ≥25% cutoff) remained unchanged in 74.0% of patients with recent and archival samples; where PD-L1 status changed, it was more likely to increase than decrease over time or with intervening treatment.ConclusionsSeveral factors potentially impact PD-L1 TC greater than or equal to 25% prevalence in advanced NSCLC; however, no characteristic can be considered a surrogate for PD-L1 expression. Fresh biopsy may provide more accurate assessment of current tumoral PD-L1 expression where a low/negative result is seen in an archival sample, especially if the patient has received intervening therapy.     

Phase 1 Expansion Cohort of Ramucirumab Plus Pembrolizumab in Advanced Treatment-Naive NSCLC

IntroductionData of first-line ramucirumab plus pembrolizumab treatment of programmed death-ligand 1 (PD-L1)–positive NSCLC (cohort E) are reported (NCT02443324).MethodsIn this multicenter, open-label phase 1a/b trial, patients received ramucirumab 10 mg/kg and pembrolizumab 200 mg every 21 days for up to 35 cycles. PD-L1 positivity was defined as tumor proportion score (TPS) greater than or equal to 1%. Exploratory NanoString biomarker analyses included three T-cell signatures (T-cell–inflamed, Gajewski, and effector T cells) and CD274 gene expression.ResultsCohort E included 26 patients. Treatment-related adverse events of any grade occurred in 22 patients (84.6%). Treatment-related adverse events of grade greater than or equal to 3 were reported in 11 patients (42.3%); the most frequent was hypertension (n = 4, 15.4%). Objective response rate was 42.3% in the treated population and 56.3% and 22.2% for patients with high (TPS ≥ 50%) and lower levels (TPS 1%–49%) of PD-L1 expression, respectively. Median progression-free survival (PFS) in the treated population was 9.3 months, and 12-month and 18-month PFS rates were 45% each. Median PFS was not reached in patients with PD-L1 TPS greater than or equal to 50% and was 4.2 months in patients with PD-L1 TPS 1% to 49%. Median overall survival was not reached in the treated population, and 12-month and 18-month overall survival rates were 73% and 64%, respectively. Biomarker data suggested a positive association among clinical response, three T-cell signatures, CD274 gene expression, and PD-L1 immunohistochemistry.ConclusionsFirst-line therapy with ramucirumab plus pembrolizumab has a manageable safety profile in patients with NSCLC, and the efficacy signal seems to be strongest in tumors with high PD-L1 expression.     

Updated Overall Survival Analysis From IMpower110: Atezolizumab Versus Platinum-Based Chemotherapy in Treatment-Naive Programmed Death-Ligand 1–Selected NSCLC

IntroductionIMpower110 previously revealed significant overall survival (OS) benefit with atezolizumab versus chemotherapy in patients with treatment-naive EGFR- and ALK-negative (wild type [WT]) metastatic NSCLC with high programmed death-ligand 1 (PD-L1) expression (≥50% on tumor cells [TCs] or ≥10% on tumor-infiltrating immune cells [ICs], per SP142 immunohistochemistry assay; p = 0.0106). We present primary OS analyses in lower PD-L1 expression groups and an updated, exploratory analysis in the high PD-L1 expression group.MethodsThis open-label, phase 3 trial randomized patients with PD-L1 expression on greater than or equal to 1% of TC or IC to receive atezolizumab or platinum-based chemotherapy. The primary end point was OS, hierarchically tested in PD-L1 expression WT subgroups: first the high PD-L1 expression subgroup, then the high-or-intermediate PD-L1 expression subgroup (≥5% on TC or IC), and then the any PD-L1 expression subgroup (≥1% on TC or IC).ResultsThe any PD-L1 expression WT population included 554 patients (excluded 18 EGFR- or ALK-positive patients). With 17 months’ additional follow-up, OS improvement in the atezolizumab versus chemotherapy arm was not statistically significant in high-or-intermediate PD-L1 expression WT patients (n = 328; hazard ratio = 0.87, 95% confidence interval: 0.66–1.14, p = 0.3091; median = 19.9 versus 16.1 mo), precluding formal OS testing in any PD-L1 expression WT patients. Exploratory analysis in high PD-L1 expression WT patients (n = 205) revealed maintained OS benefit in the atezolizumab arm (hazard ratio = 0.76, 95% confidence interval: 0.54–1.09; median = 20.2 versus 14.7 mo). Updated safety data continued to favor atezolizumab.ConclusionsStatistical significance for OS was not revealed in the high-or-intermediate expression WT group, and, as a result, OS in the any PD-L1 expression WT group was not formally tested. No new safety signals were found. This updated analysis of IMpower110 supports using atezolizumab in treatment-naive, metastatic WT NSCLC with high PD-L1 expression.     

Osimertinib Maintenance After Definitive Chemoradiation in Patients With Unresectable EGFR Mutation Positive Stage III Non–small-cell Lung Cancer: LAURA Trial in Progress

The LAURA trial (NCT03521154) will evaluate the efficacy and safety of osimertinib as maintenance therapy in patients with locally advanced, unresectable, epidermal growth factor receptor mutation-positive (EGFRm), stage III non–small-cell lung cancer (NSCLC) without disease progression during/following definitive platinum-based chemoradiation therapy (CRT). Eligible patients include adults aged ≥ 18 years (≥ 20 years in Japan) with locally advanced, unresectable, stage III NSCLC with local/central confirmation of an EGFR exon 19 deletion/L858R mutation. Patients must have received ≥ 2 cycles of concurrent/sequential platinum-based CRT, have no investigator-assessed progression, and have creatinine < 1.5 × upper limit of normal and creatinine clearance ≥ 30 mL/min. In this phase III trial, patients will be randomized 2:1 to once-daily osimertinib 80 mg or placebo, until objective radiological disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, confirmed by blinded independent central review (BICR). The primary objective is to assess the efficacy of osimertinib per BICR-confirmed progression-free survival (PFS). Secondary objectives include central nervous system PFS, overall survival, PFS by mutation status and safety. Patients with BICR-confirmed disease progression (or investigator-confirmed progression if after primary PFS analysis) may be unblinded and receive open-label osimertinib; all will have post-progression follow-up. Serious adverse events and adverse events of special interest will be collected throughout the trial and survival follow-up. The first patient was enrolled in July 2018, with results expected in late 2022.     

A Phase II Study of Osimertinib for Radiotherapy-Naive Central Nervous System Metastasis From NSCLC: Results for the T790M Cohort of the OCEAN Study (LOGIK1603/WJOG9116L)

ObjectivesOsimertinib has been reported to be effective against central nervous system (CNS) metastasis from activating EGFR mutation-positive NSCLC. Nevertheless, the true antitumor effects of osimertinib alone for CNS metastasis are unclear because the aforementioned studies included previously irradiated cases, in which tumor shrinkage can occur later owing to the effects of radiotherapy (RT). This study aimed to evaluate the efficacy of osimertinib against RT-naive CNS metastasis from sensitizing EGFR mutation-positive NSCLC.MethodsThe OCEAN study was a two-cohort trial, involving 66 patients (T790M cohort [n = 40] and first-line cohort [n = 26]) with RT-naive CNS metastasis from sensitizing EGFR mutation-positive NSCLC. The patients were treated once daily with 80 mg osimertinib. The primary end point was brain metastasis response rate (BMRR) according to the PAREXEL criteria. In this report, we present the results for the T790M cohort with analysis of drug concentrations and plasma circulating tumor DNA.ResultsThe median age of the patients was 69 years, and 30% of them were males. Eight patients (20%) were symptomatic, and most had multiple CNS metastases (78%). Among the eligible 39 patients, the BMRR (PAREXEL criteria), median brain metastasis-related progression-free survival (PFS), median overall survival, overall response rate, and median PFS were 66.7% (90% confidence interval: 54.3%–79.1%), 25.2 months, 19.8 months, 40.5%, and 7.1 months, respectively. The BMRR according to the Response Evaluation Criteria in Solid Tumors criteria was 70.0% (n = 20). The brain metastasis-related PFS of patients with EGFR exon 19 deletion was significantly longer than that of exon 21 L858R (median = 31.8 versus 8.3 mo; log-rank p = 0.032). The treatment-related pneumonitis was observed in four patients (10%). On or after day 22, the median trough blood and cerebrospinal fluid concentrations of osimertinib were 568 nM and 4.10 nM, respectively, and those of its metabolite AZ5104 were 68.0 nM and 0.260 nM, respectively. The median blood to cerebrospinal fluid penetration rates of osimertinib and AZ5104 were 0.79% and 0.53%, respectively. The blood trough concentration at day 22 was not correlated with the efficacy of osimertinib against CNS metastasis. Plasma T790M and C797S mutations were detected in 83% and 3% of the patients before treatment, 11% and 3% of the patients on day 22, and 39% and 22% of the patients at the detection of progressive disease, respectively.ConclusionsThis study evaluated the efficacy of osimertinib against RT-naive CNS metastasis from T790M-positive NSCLC. The primary end point was met, and the results revealed the efficacy of osimertinib in patients with CNS metastasis harboring EGFR T790M mutations especially for EGFR-sensitizing mutation of exon 19 deletion.     

Avelumab Versus Docetaxel in Patients With Platinum-Treated Advanced NSCLC: 2-Year Follow-Up From the JAVELIN Lung 200 Phase 3 Trial

IntroductionIn the JAVELIN Lung 200 trial, avelumab (anti-programmed death-ligand 1 [PD-L1] antibody) did not significantly prolong overall survival (OS) versus docetaxel in patients with platinum-treated PD-L1+ NSCLC. We report greater than 2-year follow-up data.MethodsPatients with stage IIIB or IV or recurrent NSCLC with disease progression after platinum-doublet chemotherapy were randomized 1:1 to avelumab 10 mg/kg every 2 weeks or docetaxel 75 mg/m² every 3 weeks. The primary end point was OS in patients with PD-L1+ tumors (greater than or equal to 1% tumor cell expression; IHC 73-10 pharmDx assay).ResultsOf 792 patients, 529 had PD-L1+ tumors (264 versus 265 in the avelumab versus docetaxel arms, respectively). As of March 4, 2019, median duration of follow-up for OS in the PD-L1+ population was 35.4 months in the avelumab arm and 34.7 months in the docetaxel arm; study treatment was ongoing in 25 (9.5%) versus 0 patients, respectively. In the PD-L1+ population, 2-year OS rates (95% confidence interval [CI]) with avelumab versus docetaxel were 29.9% (24.5%–35.5%) versus 20.5% (15.6%–25.8%); in greater than or equal to 50% PD-L1+ subgroups, 2-year OS rates were 36.4% (29.1%–43.7%) versus 17.7% (11.8%–24.7%) and in the greater than or equal to 80% subgroup were 40.2% (31.3%–49.0%) versus 20.3% (12.9%–28.8%), respectively. Median duration of response (investigator assessed) was 19.1 months (95% CI: 10.8–34.8) versus 5.7 months (95% CI: 4.1–8.3). Safety profiles for both arms were consistent with the primary analysis.ConclusionsAlthough the JAVELIN Lung 200 primary analysis (reported previously) revealed that avelumab did not significantly prolong OS versus docetaxel in patients with platinum-treated PD-L1+ NSCLC, posthoc analyses at 2 years of follow-up revealed that 2-year OS rates were doubled with avelumab in subgroups with higher PD-L1 expression (greater than or equal to 50% and greater than or equal to 80%).     

Adjuvant Osimertinib vs. Placebo in Completely Resected Stage IA2–IA3 EGFR-Mutated NSCLC: ADAURA2

IntroductionOsimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M resistance mutations, with demonstrated efficacy in EGFR mutation-positive (EGFRm) non–small cell lung cancer (NSCLC), including central nervous system (CNS) metastases. Here we present the rationale and study design for ADAURA2 (NCT05120349), which will evaluate adjuvant osimertinib vs. placebo in patients with stage IA2–IA3 EGFRm NSCLC, following complete tumor resection.Patients and MethodsADAURA2 is a phase III, global, randomized, double-blind, placebo-controlled study. Patients will be adults aged ≥18 years with resected primary nonsquamous NSCLC stage IA2 or IA3 and central confirmation of an EGFR exon 19 deletion or L858R mutation. Patients will be stratified by pathologic risk of disease recurrence (high vs. low), EGFR mutation type (exon 19 deletion vs. L858R) and race (Chinese Asian vs. non-Chinese Asian vs. non-Asian), and randomized 1:1 to receive osimertinib 80 mg once daily (QD) or placebo QD until disease recurrence, treatment discontinuation, or a maximum treatment duration of 3 years. The primary endpoint of this study is disease-free survival (DFS) in the high-risk stratum. Secondary endpoints include DFS in the overall population, overall survival, CNS DFS, and safety. Health-related quality of life and pharmacokinetics will also be evaluated.ResultsStudy enrolment began in February 2022 and interim results of the primary endpoint are expected in August 2027.     

Programmed Death-Ligand 1 Immunohistochemistry Assay Comparison Studies in NSCLC: Characterization of the 73-10 Assay

IntroductionSeveral programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) assays have been developed independently within clinical programs for therapeutic anti–programmed cell death protein 1 (anti–PD-1) or PD-L1 antibodies, necessitating assessment of assay comparability. We characterized the Dako PD-L1 IHC 73-10 assay used in clinical trials of avelumab (anti–PD-L1) or bintrafusp alfa (M7824; bifunctional immunotherapy) and compared it with the Dako PD-L1 IHC 22C3 pharmDx assay, an approved companion diagnostic for pembrolizumab monotherapy in patients with advanced NSCLC.MethodsFormalin-fixed, paraffin-embedded NSCLC tumor samples from a commercial source and from the JAVELIN Solid Tumor phase 1 trial of avelumab (NCT01772004) were stained using the 73-10 and 22C3 IHC assays with a standard protocol.ResultsBoth assays displayed expected PD-L1 staining patterns. In 148 commercial NSCLC samples, the 73-10 assay stained greater than or equal to 1%, greater than or equal to 50%, and greater than or equal to 80% of tumor cells as PD-L1+ in 64.2%, 36.5%, and 23.6% of the samples, respectively, whereas the 22C3 assay stained 20.3% of the samples as greater than or equal to 50% PD-L1+. In 83 NSCLC clinical trial samples, the 73-10 assay stained 79.5% and 31.3% of the samples as greater than or equal to 1% and greater than or equal to 80% PD-L1+, respectively, whereas the 22C3 assay stained 59.0% and 21.7% as greater than or equal to 1% and greater than or equal to 50% PD-L1+, respectively. Efficacy of avelumab was similar in the subgroups classified with the 73-10 and 22C3 assays using greater than or equal to 80% and greater than or equal to 50% PD-L1+ cutoffs, with objective response rates of 26.9% and 33.3%, respectively.ConclusionsThe 73-10 assay demonstrated high sensitivity for PD-L1 staining, and staining was comparable between the greater than or equal to 80% cutoff of the 73-10 assay and greater than or equal to 50% cutoff of the 22C3 assay.     

Biomarker-Directed Phase II Platform Study in Patients With EGFR Sensitizing Mutation-Positive Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy (ORCHARD)

IntroductionOsimertinib, a third-generation, irreversible, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), selectively inhibits both EGFR-TKI sensitizing (EGFRm) and EGFR T790M resistance mutations and has demonstrated efficacy in non-small cell lung cancer (NSCLC) CNS metastases. Most patients with EGFRm NSCLC treated with osimertinib will eventually develop resistance. ORCHARD (NCT03944772) is a phase II study aiming to characterize first-line osimertinib resistance and identify post-progression treatments.MethodsAdults aged ≥ 18 years (Japan ≥ 20 years), with EGFRm locally advanced/metastatic NSCLC will be allocated to one of three groups after first-line osimertinib progression, based on molecular profiling from a post-progression tumor biopsy. Group A will evaluate patients with protocol-determined biomarkers of resistance treated with novel osimertinib combination therapies, Group B will evaluate patients without a detectable protocol-determined biomarker treated with non-biomarker selected therapies that are chemotherapy- or EGFR-TKI-based, and Group C (observational) includes patients with histologically transformed disease, and/or a biomarker with an available therapy not investigated in ORCHARD. Group C patients will be treated as per local practice and followed to assess overall survival. The study's platform design allows for adaptability to include emerging treatments related to novel resistance mechanisms. The primary endpoint is confirmed objective response rate (investigator assessed). Other endpoints are progression-free survival, duration of response, overall survival, pharmacokinetics and safety.ConclusionsORCHARD aims to characterize mechanisms of resistance to first-line osimertinib and explore treatments to overcome acquired resistance. The modular design allows for additional biomarker-directed cohorts and treatment options as understanding of osimertinib resistance mechanisms evolves.     

Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment

BackgroundThe efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR.Patients and methodsWe identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B).ResultsIn cohort A, median progression-free survival (PFS) was 2.1 and 1.3 months for T790M-negative and T790M-positive patients, respectively (P = 0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20–1.24). Median PFS was 2.1 and 1.3 months for patients with a PD-L1 expression level of ≥1% or <1%, respectively (P = 0.084; hazard ratio of 0.37, 95% confidence interval of 0.10–1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of ≥10% and ≥50%. The proportion of tumors with a PD-L1 level of ≥10% or ≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8⁺ TIL density and nonsynonymous mutation burden.ConclusionT790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.     

Efficacy and Safety of First-Line Immunotherapy Combinations for Advanced NSCLC: A Systematic Review and Network Meta-Analysis

IntroductionA series of randomized controlled trials have investigated different first-line immunotherapy combinations, but the optimal combination strategy is yet to be established.MethodsWe performed a systematic review and Bayesian network meta-analysis by retrieving relevant literature from PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and major international conferences. We included published and gray sources of randomized clinical trials comparing immunotherapy combinations with other treatments as first-line treatments for patients with advanced NSCLC. This study was registered in the Prospective Register of Systematic Reviews (CRD42020210501) to ensure transparency.ResultsWe analyzed a total of 16 studies involving 8278 patients and including 10 immunotherapy combinations. For patients without programmed death-ligand 1 (PD-L1) selection, pembrolizumab plus chemotherapy was found to be comparable with sintilimab plus chemotherapy in providing the best overall survival (OS) benefit (hazard ratio = 0.96, 95% confidence interval [CI]: 0.72–1.29). Furthermore, atezolizumab plus bevacizumab plus chemotherapy seemed to provide the best progression-free survival (hazard ratio = 0.45, 95% CI: 0.36–0.55) and the best objective response rate (OR = 0.23, 95% CI: 0.12–0.42). Subgroup analysis by PD-L1 suggested that nivolumab plus ipilimumab plus chemotherapy was associated with the best OS in patients with PD-L1 less than 1% and that pembrolizumab plus chemotherapy was associated with the best OS in patients with PD-L1 greater than or equal to 1%. Pembrolizumab and sintilimab were associated with relatively fewer grade greater than or equal to 3 adverse events when compared with other immunotherapies combined with chemotherapy.ConclusionsOur results suggest that antiprogrammed death-1 combinations are associated with potentially higher survival outcomes than anti–PD-L1 combinations with comparable safety profiles. Moreover, pem-chemo and nivo-ipi-chemo seem to be superior first-line immunotherapy combinations for patients with advanced NSCLC with positive and negative PD-L1 expression, respectively. Although atezo-beva-chemo treatment provided the best progression-free survival and objective response rate, the addition of chemotherapy to immunotherapy would increase the toxicity, especially when antiangiogenesis drugs are simultaneously added.     

Real-World Pattern of Treatment and Clinical Outcomes of EGFR-Mutant Non-Small Cell Lung Cancer in a Single Academic Centre in Quebec

The discovery of EGFR tyrosine kinase inhibitors (TKI) for the treatment of EGFR mutant (EGFRm) metastatic NSCLC is regarded as a landmark in lung cancer. EGFR-TKIs have now become a standard first-line treatment for EGFRm NSCLC. The aim of this retrospective cohort study is to describe real-world patterns of treatment and treatment outcomes in patients with EGFRm metastatic NSCLC who received EGFR-TKI therapy outside of clinical trials. One hundred and seventy EGFRm metastatic NSCLC patients were diagnosed and initiated on first-line TKI therapy between 2004 and 2018 at the Peter Brojde Lung Cancer Centre in Montreal. Following progression of the disease, 137 (80%) patients discontinued first-line treatment. Moreover, 80/137 (58%) patients received second-line treatment, which included: EGFR-TKIs, platinum-based, or single-agent chemotherapy. At the time of progression on first-line treatment, 73 patients were tested for the T790M mutation. Moreover, 30/73 (41%) patients were found to be positive for the T790M mutation; 62/80 patients progressed to second-line treatment and 20/62 were started on third-line treatment. The median duration of treatment was 11.5 (95% CI; 9.62–13.44) months for first-line treatment, and 4.4 (95% CI: 1.47–7.39) months for second-line treatment. Median OS from the time of diagnosis of metastatic disease was 23.5 months (95% CI: 16.9–30.1) and median OS from the initiation of EGFR-TKI was 20.6 months (95% CI: 13.5–27.6). We identified that ECOG PS ≤ 2, presence of exon 19 deletion mutation, and absence of brain metastases were associated with better OS. A significant OS benefit was observed in patients treated with osimertinib in second-line treatment compared to those who never received osimertinib. Overall, our retrospective observational study suggests that treatment outcomes in EGFRm NSCLC in real-world practice, such as OS and PFS, reflect the result of RCTs. However, given the few observational studies on real-world treatment patterns of EGFR-mutant NSCLC, this study is important for understanding the potential impact of EGFR-TKIs on survival outside of clinical trials. Further real-world studies are needed to characterize patient outcomes for emerging therapies, including first-line osimertinib use and combination of osimertinib with chemotherapy and potential future combination of osimertinib and novel anticancer drug, outside of a clinical trial setting.     

Efficacy and safety of osimertinib in treating EGFR-mutated advanced NSCLC: A meta-analysis

Osimertinib is the only Food and Drug Administration-approved third-generation epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI). A meta-analysis was performed to aggregate the mixed results of published clinical trials to assess the efficacy and safety of osimertinib. A systematic search of the PubMed, Web of Science, and Cochrane Library electronic databases was performed to identify eligible literature. The primary endpoints were overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and adverse events (AEs). A total of 3,086 advanced nonsmall cell lung cancer (NSCLC) patients from 11 studies have been identified. The aggregate efficacy parameters for treatment-naïve patients with EGFR-TKI-sensitizing mutations are as follows: ORR 79% (95% CI 75–84%), DCR 97% (95% CI 95–99%), 6-month PFS 83% (95% CI 80–87%), and 12-month PFS 64% (95% CI 59–69%). The aggregate efficacy parameters for advanced NSCLC harboring T790M mutations after earlier-generation EGFR-TKI therapy are as follows: ORR 58% (95% CI 46–71%), DCR 80% (95% CI 63–98%), 6-month PFS 63% (95% CI 58–69%), and 12-month PFS 32% (95% CI 17–47%). EGFR-TKI-naïve patients with EGFR-positive mutations tend to have longer median PFS than EGFR-TKI-pretreated counterparts (19.17 vs. 10.58 months). The most common AEs were diarrhea and rash, of which the pooled incidences were 44 and 42%, respectively. Generally, osimertinib is a favorable treatment option for previously treated T790M mutation-positive advanced NSCLC as well as a preferable therapy for untreated EGFR mutation-positive advanced NSCLC. Additionally, osimertinib is well tolerated by most patients.     

Classification of Tumor Immune Microenvironment According to Programmed Death-Ligand 1 Expression and Immune Infiltration Predicts Response to Immunotherapy Plus Chemotherapy in Advanced Patients With NSCLC

IntroductionAccording to mechanisms of adaptive immune resistance, tumor immune microenvironment (TIME) is classified into four types: (1) programmed death-ligand 1 (PD-L1)–negative and tumor-infiltrating lymphocyte (TIL)–negative (type I); (2) PD-L1–positive and TIL-positive (type II); (3) PD-L1–negative and TIL-positive (type III); and (4) PD-L1–positive and TIL-negative (type IV). However, the relationship between the TIME classification model and immunotherapy efficacy has not been validated by any large-scale randomized controlled clinical trial among patients with advanced NSCLC.MethodsOn the basis of RNA-sequencing and immunohistochemistry data from the ORIENT-11 study, we optimized the TIME classification model and evaluated its predictive value for the efficacy of immunotherapy plus chemotherapy.ResultsPD-L1 mRNA expression and immune score calculated by the ESTIMATE method were the strongest predictors for the efficacy of immunotherapy plus chemotherapy. Therefore, they were determined as the optimized definition of the TIME classification system. When compared between combination therapy and chemotherapy alone, only the type II subpopulation with high immune score and high PD-L1 mRNA expression was significantly associated with improved progression-free survival (PFS) (hazard ratio = 0.12, 95% confidence interval: 0.06–0.25, p < 0.001) and overall survival (hazard ratio = 0.27, 95% confidence interval: 0.13–0.55, p < 0.001). In the combination group, the type II subpopulation had a much longer survival time, not even reaching the median PFS or overall survival, but the other three subpopulations were susceptible to having similar PFS. In the chemotherapy group, there was no marked association between survival outcomes and TIME subtypes.ConclusionsOnly patients with both high PD-L1 expression and high immune infiltration could benefit from chemotherapy plus immunotherapy in first-line treatment of advanced NSCLC. For patients lacking either PD-L1 expression or immune infiltration, chemotherapy alone might be a better treatment option to avoid unnecessary toxicities and financial burdens.     

Systemic and Intracranial Outcomes With First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC and Baseline Brain Metastases From CheckMate 227 Part 1

IntroductionIn CheckMate 227 Part 1, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with metastatic NSCLC, regardless of tumor programmed death-ligand 1 (PD-L1) expression. Here, we report post hoc exploratory systemic and intracranial efficacy outcomes and safety by baseline brain metastasis status at 5 years’ minimum follow-up.MethodsTreatment-naive adults with stage IV or recurrent NSCLC without EGFR or ALK alterations, including asymptomatic patients with treated brain metastases, were enrolled. Patients with tumor PD-L1 greater than or equal to 1% were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy; patients with tumor PD-L1 less than 1% were randomized to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy groups. Assessments included OS, systemic and intracranial progression-free survival per blinded independent central review, new brain lesion development, and safety. Brain imaging was performed at baseline (all randomized patients) and approximately every 12 weeks thereafter (patients with baseline brain metastases only).ResultsOverall, 202 of 1739 randomized patients had baseline brain metastases (nivolumab plus ipilimumab: 68; chemotherapy: 66). At 61.3 months’ minimum follow-up, nivolumab plus ipilimumab prolonged OS versus chemotherapy in patients with baseline brain metastases (hazard ratio = 0.63; 95% confidence interval: 0.43–0.92) and in those without (hazard ratio = 0.76; 95% confidence interval: 0.66–0.87). In patients with baseline brain metastases, 5-year systemic and intracranial progression-free survival rates were higher with nivolumab plus ipilimumab (12% and 16%, respectively) than chemotherapy (0% and 6%). Fewer patients with baseline brain metastases developed new brain lesions with nivolumab plus ipilimumab (4%) versus chemotherapy (20%). No new safety signals were observed.ConclusionsWith all patients off immunotherapy for more than or equal to 3 years, nivolumab plus ipilimumab continued to provide a long-term, durable survival benefit in patients with or without brain metastases. Intracranial efficacy outcomes favored nivolumab plus ipilimumab versus chemotherapy. These results further support nivolumab plus ipilimumab as an efficacious first-line treatment for patients with metastatic NSCLC, regardless of baseline brain metastasis status.     

Relationship Between Programmed Death Receptor-Ligand 1 Expression and Response to Checkpoint Inhibitor Immunotherapy in Pulmonary Sarcomatoid Carcinoma: A Pooled Analysis

BackgroundPulmonary sarcomatoid carcinoma (PSC) or pleomorphic carcinoma is a rare subtype of non-small cell lung cancer. Some reports have suggested the efficacy of checkpoint inhibitor immunotherapy for PSC. However, owing to the small number of patients in each report, it remains unclear whether programmed death receptor-ligand 1 (PD-L1) expression is predictive of tumor response or survival.Patients and MethodsThe English literature was systematically searched for articles published from 2015 to 2019 and reported on tumor response or progression-free survival (PFS) after immunotherapy for advanced PSC. In addition, our institutional electronic medical records were searched for eligible cases to be included. Pooled analyses were performed.ResultsAnalyses included 90 patients. Best tumor response was partial or complete response in 54.5%, stable disease 15.9%, and progressive disease in 29.6%. The median PFS was 7.0 months. Among 66 patients with reported PD-L1 expression, the level was <1% in 7 patients (10.6%), 1%-49% in 10 patients (15.2%), and ≥50% in 49 patients (74.2%). A positive relationship between PD-L1 level and tumor response was observed. Among 47 patients with a PD-L1 of ≥50%, 33 patients (70.2%) achieved response, compared with 5 of 10 patients (50%) with a PD-L1 of 1%-49% and 2 of 7 patients (28.6%) with a PD-L1 of <1% (P = .026). PFS was superior among patients with a PD-L1 of ≥1% compared with those with a PD-L1 of <1% (14.4 months vs. 2.7 months respectively; P = .04).ConclusionsAmong patients with advanced PSC, PD-L1 expression is significantly associated with increased tumor responses and improved PFS after checkpoint inhibitor immunotherapy.     

Efficacy and Safety of Anti–PD-1 Immunotherapy in Patients With Advanced NSCLC With BRAF,HER2, or MET Mutations or RET Translocation: GFPC 01-2018

IntroductionImmune-checkpoint inhibitor (ICI) efficacy in patients with NSCLC harboring molecular alterations remains poorly elucidated. This study was undertaken to determine ICI efficacy against BRAF-, HER2-, MET-, and RET-NSCLC in a real-world setting.MethodsIn this retrospective, multicenter study in ICI-treated BRAF-, HER2-, MET- or RET-NSCLCs, we analyzed clinical characteristics and outcomes: ICI-treatment duration, progression-free survival (PFS), objective response rate, duration of response, and overall survival (OS).ResultsThere were 107 patients with NSCLC (mean age, 65.5 y) included from 21 centers: 37% were never-smokers, 54% were men, and 93% had adenocarcinoma. Among them, 44 had BRAF mutation (V600: 26), 23 had HER2 mutation, 30 had MET mutation, and nine had RET translocation. Programmed cell death ligand 1 (PD-L1) status was known for 70 patients and was greater than or equal to 1% in 34 patients. Before ICI, patients had received a median of one treatment line. Median duration of response, PFS, and OS were 15.4 (95% confidence interval [CI]: 12.6–not reached [NR]) months, 4.7 (95% CI: 2.3–7.4) months, and 16.2 (95% CI: 12.0–24.0) months, respectively, for the entire cohort. The response rates for BRAF-V600, BRAF–non-V600, HER2, MET, and RET-altered NSCLC were 26%, 35%, 27%, 36%, and 38%, respectively. For patients who were PD-L1 negative and those who were PD-L1 positive, PFS was 3.0 (95% CI: 1.2–NR) and 4.3 (95% CI: 2.1–8.5) months, respectively, and OS was 11.7 (95% CI: 4.1–NR) and 35.8 (95% CI: 9.0–35.2) months, respectively. Toxicities were reported in 28 patients (26%), including 11 patients (10%) with a grade greater than or equal to three.ConclusionsIn this real-world setting, ICI efficacy against patients with BRAF-, HER2-, MET-, or RET-NSCLC seemed close to that observed in unselected patients with NSCLC. Large prospective studies on these subsets of patients are needed.     

Clinical Activity,Tolerability, and Long-Term Follow-Up of Durvalumab in Patients With Advanced NSCLC

IntroductionDurvalumab is a selective, high-affinity human immunoglobulin G1 monoclonal antibody that blocks programmed cell death ligand 1 (PD-L1) binding to programmed death 1. Here we report safety and clinical activity in the NSCLC cohort of a phase I/II trial that included multiple tumor types (Study 1108; NCT01693562).MethodsPatients with stage IIIB–IV NSCLC (squamous or nonsquamous) received durvalumab 10 mg/kg every 2 weeks for 12 months or until confirmed progressive disease or unacceptable toxicity. Primary objectives were safety and antitumor activity. Tumoral PD-L1 expression was assessed using the VENTANA SP263 Assay. Responses were assessed by blinded independent central review (Response Evaluation Criteria in Solid Tumors v1.1). Adverse events were graded according to National Cancer Institute’s Common Terminology Criteria for Adverse Events (v4.03).ResultsOf 304 patients, 79.0% were previously treated. Confirmed objective response rate was 21.8% in patients with greater than or equal to 25% PD-L1 expression and 6.4% in those with less than 25%; 25.9% in first-line patients and 12.7% in previously treated patients; and 14.0% in squamous and 16.7% in nonsquamous disease. Median overall survival was 12.4 months and median progression-free survival was 1.7 months; both were numerically longer in the PD-L1 greater than or equal to 25% group than in the PD-L1 less than 25% group (overall survival 16.4 versus 7.6 months, respectively; progression-free survival 2.6 versus 1.4 months, respectively). Treatment-related adverse events occurred in 57.2%, were grade 3/4 in 10.2%, and led to discontinuation in 5.6%. One patient (0.3%) died of treatment-related pneumonia with underlying pneumonitis.ConclusionsDurvalumab was clinically active irrespective of histology in this mostly pretreated population, with a manageable safety profile. Response rates and survival appeared to be enhanced in patients with greater tumoral PD-L1 expression.