Correlation of safety and efficacy of atezolizumab therapy across indications.

Background: The association between safety and efficacy of immune checkpoint inhibitors is known, but the correlation between severity and impact of specific organ involvement by immune-related adverse events (irAE) and cancer outcomes is poorly understood. Most irAEs are mild-to-moderate but severe irAEs may pose clinical management challenges and affect patient outcomes.

Methods: We assessed the association between irAE grade (G) and specific organ involvement with overall survival (OS) in 9,521 patients across 14 studies involving atezolizumab as mono (IO) or with chemo/targeted (C-IO) therapy as compared with chemo/targeted therapy (C) in advanced non-small cell lung, small-cell lung, renal cell, urothelial, and triple-negative breast cancers.

A phase I study to evaluate the safety, pharmacokinetics, and pharmacodynamics of PF-06939999 (PRMT5 inhibitor) in patients with selected advanced or metastatic tumors with high incidence of splicing factor gene mutations.

Background: Protein arginine methyltransferase 5 (PRMT5) methylates multiple substrates dysregulated in cancer, including spliceosome machinery components. PF-06939999 is a selective small-molecule PRMT5 inhibitor.

Patients And Methods: This phase I dose-escalation and -expansion trial (NCT03854227) enrolled patients with selected solid tumors.

A lack of association between BMI and chemoimmunotherapy efficacy in advanced non-small cell lung cancer: Secondary analysis of the IMpower150 and IMpower130 clinical trials.

Background: Multiple studies have indicated that patients with high body mass index (BMI) may have favourable survival outcomes following treatment with an immune checkpoint inhibitor (ICI). However, this evidence is limited by several factors, notably the minimal evidence from randomised controlled trials (RCTs), the use of categorised BMI with inconsistent cut point definitions, and minimal investigation of contemporary combination ICI therapy. Moreover, whether overweight and obese patients gain a larger benefit from contemporary frontline chemoimmunotherapy in non-small cell lung cancer (NSCLC) is unclear.

A phase II clinical trial evaluating the safety and efficacy of durvalumab as first line therapy in advanced and metastatic non-small cell lung cancer patients with Eastern Cooperative Oncology Group performance status of 2.

Background: Approximately 30-40% of patients with advanced and metastatic non-small cell lung cancer (NSCLC) present with an impaired performance status (PS). There are limited prospective data on the safety and efficacy of durvalumab in these patients.

Methods: In this single-arm phase II clinical trial (NCT02879617), patients with previously untreated Stage IIIB/IV NSCLC and ECOG PS of 2 received durvalumab 1500 mg every 28 days until progression or unacceptable toxicity.

Population Pharmacokinetics of MYL-1402O, a Proposed Biosimilar to Bevacizumab and Reference Product (Avastin) in Patients with Non-squamous Non-small Cell Lung Cancer.

Background And Objectives: MYL-1402O is a bevacizumab (Avastin) biosimilar. Pharmacokinetic and safety similarity of MYL-1402O and reference Avastin authorized in the European Union (EU-Avastin) and the US (US-Avastin) was demonstrated in healthy subjects (phase I, NCT02469987). The key objectives of this study were to establish a population pharmacokinetic (PopPK) model on pooled data from the phase I and phase III clinical studies to assess pharmacokinetic linearity of MYL-1402O and Avastin across dose ranges, to assess the pharmacokinetic similarity of MYL-1402O and Avastin in patients with non-squamous non-small cell lung cancer (nsNSCLC), and to explore potential covariates to account for systematic sources of variability in bevacizumab exposure.

Circulating Tumor DNA Monitoring on Chemo-immunotherapy for Risk Stratification in Advanced Non-Small Cell Lung Cancer.

Purpose: Chemoimmunotherapy (chemoIO) is a prevalent first-line treatment for advanced driver-negative non-small cell lung cancer (NSCLC), with maintenance therapy given after induction. However, there is significant clinical variability in the duration, dosing, and timing of maintenance therapy after induction chemoIO. We used circulating tumor DNA (ctDNA) monitoring to inform outcomes in patients with advanced NSCLC receiving chemoIO.

Impact of gender and mutational differences in hormone receptor expressing non-small cell lung cancer.

Background: The incidence of lung cancer in the US has been decreasing but a bigger decline has been observed in men despite similar declines in tobacco use between men and women. Multiple theories have been proposed, including exposure to exogenous estrogens. Our study seeks to understand the relationship between hormone receptors (HR), gender, and the genomic landscape of non-small lung cancer (NSCLC).

Combined use of CYFRA 21-1 and CA 125 predicts survival of patients with metastatic NSCLC and stable disease in IMpower150.

Background: Patients with non-small cell lung cancer (NSCLC) and stable disease (SD) have an unmet clinical need to help guide early treatment adjustments.

Objective: To evaluate the potential of tumor biomarkers to inform on survival outcomes in NSCLC SD patients.

Methods: This post hoc analysis included 480 patients from the IMpower150 study with metastatic NSCLC, treated with chemotherapy, atezolizumab and bevacizumab combinations, who had SD at first CT scan (post-treatment initiation).

Pan-tumor survey of RET fusions as detected by next-generation RNA sequencing identified RET fusion positive colorectal carcinoma as a unique molecular subset.

Background: RET fusions are driver alterations in cancer and are most commonly found in non-small cell lung cancer and well-differentiated thyroid cancer. However, RET fusion have been reported in other solid tumors.

Material And Methods: A retrospective analysis of RET+ solid malignancies identified by targeted RNA sequencing and whole transcriptome sequencing of clinical tumor samples performed at Caris Life Science (Phoenix, AZ).

Emerging agents for the treatment of advanced or metastatic NSCLC without actionable genomic alterations with progression on first-line therapy.

Introduction: Lung cancer is the second most common cancer in the world and the leading cause of cancer-related mortality. Immune checkpoint inhibitors (ICIs), as monotherapy or in combination with platinum-based chemotherapy, have emerged as the standard of care first-line treatment option for patients with advanced non-small cell lung cancer (NSCLC) without actionable genomic alterations (AGAs). Despite significant improvements in patient outcomes with these regimens, primary or acquired resistance is common and most patients develop disease progression, resulting in poor survival.

Phase II Randomized Trial of Carboplatin, Pemetrexed, and Bevacizumab With and Without Atezolizumab in Stage IV Nonsquamous Non-Small-Cell Lung Cancer Patients Who Harbor a Sensitizing EGFR Mutation or Have Never Smoked.

Introduction: Patients with non-small-cell lung cancer (NSCLC) who have never smoked or have tumors with mutations in EGFR generally derive minimal benefit from single-agent PD-1/PD-L1 checkpoint inhibitors. Prior data indicate that adding PD-L1 inhibition to anti-VEGF and cytotoxic chemotherapy may be a promising approach to overcoming immunotherapy resistance in these patients, however prospective validation is needed. This trial in progress (NCT03786692) is evaluating patients with stage IV NSCLC who have never smoked or who have tumors with sensitizing EGFR alterations to determine if a 4-drug combination of atezolizumab, carboplatin, pemetrexed, and bevacizumab can improve outcomes compared to carboplatin, pemetrexed and bevacizumab without atezolizumab.

Safety, Tolerability, and Antitumor Activity of Zipalertinib Among Patients With Non-Small-Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Exon 20 Insertions.

Purpose: Although several agents targeting epidermal growth factor receptor () exon 20 insertions (ex20ins) have recently been approved by the US Food and Drug Administration, toxicities related to the inhibition of wild-type (WT) are common with these agents and affect overall tolerability. Zipalertinib (CLN-081, TAS6417) is an oral EGFR tyrosine kinase inhibitor (TKI) with a novel pyrrolopyrimidine scaffold leading to enhanced selectivity for ex20ins-mutant versus WT with potent inhibition of cell growth in ex20ins-positive cell lines.

Methods: This phase 1/2a study of zipalertinib enrolled patients with recurrent or metastatic ex20ins-mutant non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy.

Guidance for clinicians and patients with non-small cell lung cancer in the time of precision medicine.

Major advances in the diagnosis and treatment of non-small cell lung cancer (NSCLC) have resulted in a sharp decline in associated mortality rates, thereby propelling NSCLC to the forefront of precision medicine. Current guidelines recommend upfront comprehensive molecular testing for all known and actionable driver alterations/biomarkers (, , , , , , , , [], and PD-L1), especially in advanced disease stages, as they significantly influence response to therapy. In particular, hybrid capture-based next-generation sequencing (HC-NGS) with an RNA fusion panel to detect gene fusions is a veritable requirement at both diagnosis and progression (resistance) of any-stage non-squamous adenocarcinoma NSCLCs.

A longitudinal circulating tumor DNA-based model associated with survival in metastatic non-small-cell lung cancer.

One of the great challenges in therapeutic oncology is determining who might achieve survival benefits from a particular therapy. Studies on longitudinal circulating tumor DNA (ctDNA) dynamics for the prediction of survival have generally been small or nonrandomized. We assessed ctDNA across 5 time points in 466 non-small-cell lung cancer (NSCLC) patients from the randomized phase 3 IMpower150 study comparing chemotherapy-immune checkpoint inhibitor (chemo-ICI) combinations and used machine learning to jointly model multiple ctDNA metrics to predict overall survival (OS).

Low Risk of Hyperprogression with First-Line Chemoimmunotherapy for Advanced Non-Small Cell Lung Cancer: Pooled Analysis of 7 Clinical Trials.

Background: Monotherapy immune checkpoint inhibitor (ICI) used in second- or later-line settings has been reported to induce hyperprogression. This study evaluated hyperprogression risk with ICI (atezolizumab) in the first-, second-, or later-line treatment of advanced non-small cell lung cancer (NSCLC), and provides insights into hyperprogression risk with contemporary first-line ICI treatment.

Methods: Hyperprogression was identified using Response Evaluation Criteria in Solid Tumours (RECIST)-based criteria in a dataset of pooled individual-participant level data from BIRCH, FIR, IMpower130, IMpower131, IMpower150, OAK, and POPLAR trials.

Association of Immune-Related Adverse Events With Efficacy of Atezolizumab in Patients With Non-Small Cell Lung Cancer: Pooled Analyses of the Phase 3 IMpower130, IMpower132, and IMpower150 Randomized Clinical Trials.

Importance: Immune-related adverse events (irAEs) arising from immune checkpoint inhibitor (ICI) cancer therapy may potentially predict improved outcomes.

Objective: To evaluate the association between irAEs and atezolizumab efficacy in patients with advanced non-small cell lung cancer (NSCLC) using pooled data from 3 phase 3 ICI studies.

Design, Setting, And Participants: IMpower130, IMpower132, and IMpower150 were phase 3, multicenter, open-label, randomized clinical trials to evaluate the efficacy and safety of chemoimmunotherapy combinations involving atezolizumab.

Tumor Dynamic Model-Based Decision Support for Phase Ib/II Combination Studies: A Retrospective Assessment Based on Resampling of the Phase III Study IMpower150.

Purpose: Model-based tumor growth inhibition (TGI) metrics are increasingly incorporated into go/no-go decisions in early clinical studies. To apply this methodology to new investigational combinations requires independent evaluation of TGI metrics in recently completed Phase III trials of effective immunotherapy.

Patients And Methods: Data were extracted from IMpower150, a positive, randomized, Phase III study of first-line therapy in 1,202 patients with non-small cell lung cancer.

A Single Center Retrospective Study of the Impact of COVID-19 Infection on Immune-related Adverse Events in Cancer Patients Receiving Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) can cause a variety of immune-related adverse events (irAEs). The coronavirus disease 2019 (COVID-19) is associated with increased amounts of pro-inflammatory cytokines, which may affect the outcome of irAEs. Data are limited regarding the impact of COVID-19 on irAEs in ICI-treated cancer patients.

COVID-19 Outcomes in Stage IV Cancer Patients Receiving Immune Checkpoint Inhibitors.

Cancer patients are a vulnerable population in the current coronavirus disease 2019 (COVID-19) outbreak. The impact of immune checkpoint inhibitors (ICIs) on the outcomes of COVID-19 infection in cancer patients remains largely unclear. We retrospectively investigated all solid cancer patients who received at least one cycle of ICIs at a single institution between August 2020 and August 2021.

The Applicability of the Results in the Asian Population of ORIENT-11 to a Western Population According to the ICH-E5 Framework.

Sintilimab combined with pemetrexed and platinum met the primary endpoint of improving progression-free survival (PFS) as a first-line therapy for nonsquamous non-small cell lung cancer (NSCLC) in the phase 3 trial ORIENT-11 (NCT03607539). As seen in similar trials, the addition of sintilimab, a PD-1 inhibitor, to chemotherapy improved the PFS without significantly worsening the toxicity, with improvements in response rate and duration of response. In contrast to previous trials, the ORIENT-11 trial was conducted completely in China.

A phase 1b/2 study of PF-06747775 as monotherapy or in combination with Palbociclib in patients with epidermal growth factor receptor mutant advanced non-small cell lung cancer.

Introduction: This Phase 1/2 study (NCT02349633) explored the safety and antitumor activity of PF-06747775 (oral, third-generation epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor) in patients with advanced non-small cell lung cancer after progression on an EGFR inhibitor.

Methods: Phase 1 was a dose-escalation study of PF-06747775 monotherapy (starting dose: 25 mg once daily [QD]). Phase 1b/2 evaluated PF-06747775 monotherapy at recommended Phase 2 dose (RP2D; Cohort 1); PF-06747775 200 mg QD plus palbociclib (starting dose: 100 mg QD orally; Cohort 2A); and PF-06747775 monotherapy at RP2D in a Japanese lead-in cohort.