JTO Clinical and Research Reports最新文献

The emergence of spontaneous nonmalignant chylous effusions during treatment with various tyrosine kinase inhibitors (TKIs) has been previously described; however, there have been no prior reports for alectinib. Herein, we report a case of symptomatic bilateral chylothorax during alectinib therapy in a patient with ALK-rearranged lung adenocarcinoma. Although immediate control of symptoms was achieved by placement of bilateral tunneled pleural catheters, the chylothorax ultimately resolved only after alectinib discontinuation and transition to an alternative TKI. This case adds alectinib to the growing list of TKIs that may be associated with the rare emergence of spontaneous, nonmalignant chylous effusions.

Introduction

Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of lung cancer associated with poor prognosis and resistance to conventional chemotherapy. Immune checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, were found to have clinical benefits in PSC in recent studies. Nevertheless, because these studies included a small number of patients owing to disease rarity, larger studies are needed to evaluate the effectiveness and safety of ICI-based therapy for PSC.

Methods

This multicenter retrospective study evaluated patients with ICI-naive advanced or metastatic PSC who were treated with ICI-based therapy at 25 hospitals in Japan.

Results

A total of 124 patients were evaluated. The overall response rate, median progression-free survival (PFS), and median overall survival (OS) were 59.0%, 10.5 months, and 32.8 months, respectively. The PFS and OS rates at 24 months were 35.3% and 51.5%, respectively. Programmed death-ligand 1 expression, concomitant chemotherapy, and the treatment line were not significantly associated with PFS or OS. Immune-related adverse events (irAEs) were observed in 70 patients (56.5%), including 30 (24.2%) with grade 3 to 5 events. Patients with mild irAEs (grades 1–2) had longer PFS and OS than did those with severe (grades 3–5) or no irAEs. In a multivariate analysis, any-grade irAEs and the absence of liver metastases were independently associated with PFS, whereas any-grade irAEs and Eastern Cooperative Oncology Group performance status less than or equal to 1 were independently associated with OS.

Conclusions

ICI-based therapy was found to have promising effectiveness in patients with advanced or metastatic PSC, regardless of programmed death-ligand 1 expression, concomitant chemotherapy, or treatment line.

Introduction

Mechanisms of resistance to EGFR exon 20 insertion mutation active inhibitors have not been extensively studied in either robust preclinical models or patient-derived rebiopsy specimens. We sought to characterize on-target resistance mutations identified in EGFR exon 20 insertion-mutated lung cancers treated with mobocertinib or poziotinib and evaluate whether these mutations would or would not have cross-resistance to next-generation inhibitors zipalertinib, furmonertinib, and sunvozertinib.

Methods

We identified mechanisms of resistance to EGFR exon 20 insertion mutation active inhibitors and then used preclinical models of EGFR exon 20 insertion mutations (A767_V769dupASV, D770_N771insSVD, V773_C774insH) plus common EGFR mutants to probe inhibitors in the absence/presence of EGFR-T790M or EGFR-C797S.

Results

Mobocertinib had a favorable therapeutic window in relation to EGFR wild type for EGFR exon 20 insertion mutants, but the addition of EGFR-T790M or EGFR-C797S negated the observed window. Zipalertinib had a favorable therapeutic window for cells driven by EGFR-A767_V769dupASV or EGFR-D770_N771insSVD in the presence or absence of EGFR-T790M. Furmonertinib and sunvozertinib had the most favorable therapeutic windows in the presence or absence of EGFR-T790M in all cells tested. EGFR-C797S in cis to all EGFR mutations evaluated generated dependent cells that were resistant to the covalent EGFR tyrosine kinase inhibitors mobocertinib, zipalertinib, furmonertinib, sunvozertinib, poziotinib, and osimertinib.

Conclusions

This report highlights that poziotinib and mobocertinib are susceptible to on-target resistance mediated by EGFR-T790M or -C797S in the background of the most prevalent EGFR exon 20 insertion mutations. Furmonertinib, sunvozertinib, and to a less extent zipalertinib can overcome EGFR-T790M compound mutants, whereas EGFR-C797S leads to covalent inhibitor cross-resistance—robust data that support the limitations of mobocertinib and should further spawn the development of next-generation covalent and reversible EGFR exon 20 insertion mutation active inhibitors with favorable therapeutic windows that are less vulnerable to on-target resistance.

HIP1-ALK is a relatively rare fusion pattern in ALK-rearranged NSCLC. Existing studies on the efficacy of ALK tyrosine kinase inhibitor (TKI) resistance mechanisms and treatment strategies in HIP1-ALK–rearranged lung cancer are limited. Here, we report the case of an 18-year-old man with HIP1-ALK–rearranged adenocarcinoma who developed BRAF V600E and V1180L mutations after ALK TKI therapy, in whom the administration of BRAF and MEK inhibitors was ineffective. Brigatinib was effective after chemotherapy with cytotoxic drugs. Development of effective treatments is desirable for rare variants of ALK-rearranged lung cancer after acquiring resistance to ALK TKIs.

Introduction

Stigma thwarts progress in lung cancer risk reduction and control and adversely affects patients across the entire lung cancer care continuum. In developing and disseminating patient and public-facing interventions to increase lung screening, we must be cognizant of how communications have the potential for further stigmatization of at-risk populations. Creation of the Lung Cancer Stigma Communications Assessment Tool (LCS-CAT) version 1 was supported by the American Cancer Society’s National Lung Cancer Roundtable to help content developers identify, remove, and replace potentially stigmatizing language and imagery from materials designed to engage individuals across the lung cancer continuum.

Methods

The LCS-CAT considers language, imagery, and context and was used to audit a public-facing health communication and decision support tool called LungTalk.

Results

The audit performed by two behavioral scientists revealed multiple issues in all three areas, and specific feedback and alternatives were identified.

Conclusions

Applying the LCS-CAT to LungTalk was a productive process that helped remove potentially stigmatizing language and imagery from this tool designed to engage individuals in the process of making an informed decision about lung screening. To support destigmatization of lung cancer, communication creators should consider a stigma biopsy on all public-facing campaigns for lung screening to help identify, eliminate, and replace messages that could compromise engagement with the lung cancer screening opportunity.

Introduction

A literature review was undertaken to identify clinical trials and real-world studies of patients with stage IV NSCLC who had progressed on or after treatment with platinum-based chemotherapy.

Methods

The EMBASE and MEDLINE databases were used to search for English-language studies published between September 28, 2017, and September 28, 2021. Studies were included in the review if they (1) were clinical trials or real-world analyses of one or more treatment regimens for patients with stage IV NSCLC who had progressed on or after treatment with platinum-based chemotherapy, (2) contained an end point including efficacy, effectiveness, or safety, and (3) included 45 or more patients.

Results

In total, there were 15 publications (nine unique trials and three real-world studies) included. Sample size ranged from 49 to 1253 patients. At least one treatment arm in eight of the nine clinical trials reported an overall response rate of ≥15%. Median progression-free survival (PFS) and overall survival ranged from 1.9 to 5.2 months and 5.4 to 15.4 months in clinical trials and 4.4 to 6.8 months and 8.3 to 18.0 months in real-world studies, respectively. Within studies reporting median PFS, a median PFS of more than or equal to 3 months was reported in eight of 11 clinical trials and both real-world studies. Discontinuation due to adverse events ranged from 1.9% to 18% across all included studies.

Conclusions

Patients with stage IV NSCLC had limited response and a high burden of adverse events during treatment after progression on platinum-containing chemotherapy. There remains a pressing unmet need for additional, effective, and tolerable treatment options in this setting.

ROS1 tyrosine kinase inhibitors (TKIs) were found to provide a substantial clinical benefit for patients with advanced ROS1-positive (ROS1+) NSCLC. Nevertheless, TKI resistance inevitably develops with different mechanisms, preventing prolonged responses. For this reason, next-generation compounds are under clinical development. ROS1 F2004 substitutions have been previously detected on circulating tumor DNA of patients progressing to entrectinib. Hereby, we report the case of a patient with ROS1+ NSCLC in which F2004V-acquired mutation was detected on a site of disease progression, after entrectinib and crizotinib failure. A subsequent treatment with next-generation TKI repotrectinib led to disease response, providing the first clinical evidence of activity of repotrectinib against F2004V resistance mutation.

The significance of EGFR targeted therapy in the lung adenocarcinoma is paramount. Several controlled clinical trials have reported considerable survival of EGFR mutation positive patients on receiving the EGFR tyrosine kinase inhibitor (TKI). However, the real-world evidence of benefits of EGFR TKI would be further useful to understand how the designated therapeutic regimen benefits the patients. In this study, we report a decade long real-world evidence of EGFR molecular testing in lung cancer at Tata Memorial Hospital (Mumbai, India). Laboratory and hospital records containing basic demographic details, clinical characteristics, treatment regimen, survival outcome were collected retrospectively. Statistical association and survival analysis were performed using the R programming. The cohort includes 9,053 lung cancer patients tested for EGFR mutations during 2011 to 2019. Baseline T790M and compound mutations were the only mutations observed co-occurring while all other EGFR mutations were mutually exclusive. Furthermore, the baseline T790M were also observed to be associated with TTF1 positivity, smoking and local metastasis. Overall survival of the patients harboring co-occurring compound mutations was significantly lesser than the other EGFR positive patients. Overall, our study suggests that EGFR TKI may provide real-world benefit to the lung cancer patients harboring mutually exclusive EGFR mutations. On the other hand, further systematic study is essential to develop better therapeutic regimen for co-occurring baseline EGFR T790M and other compound mutations.

Introduction

Durvalumab consolidation therapy is the standard of care after concurrent chemoradiotherapy (CRT) for stage III NSCLC. Immune-related pneumonitis during durvalumab treatment is potentially fatal; however, information is lacking regarding the impact of pneumonitis on patient survival. This study investigates the effect of pulmonary and nonpulmonary immune-related adverse events (irAEs) on the efficacy of durvalumab treatment in patients with stage III NSCLC.

Methods

We retrospectively assessed 158 patients who received durvalumab after CRT at nine Japanese institutions between July 2018 and March 2020. Survival outcomes were compared between patients who developed pneumonitis with those who developed irAEs other than pneumonitis. Patients who survived for less than 3 months were excluded to reduce immortal time bias.

Results

Among 158 evaluated patients, 76 (48%) experienced grade less than or equal to one irAEs, whereas 82 (52%) experienced grade greater than or equal to two irAEs. Among the patients with grade greater than or equal to two irAEs, those with grade greater than or equal to two pneumonitis (n = 55) were compared with those with grade greater than or equal to two irAEs other than pneumonitis (n = 27). Patients with grade greater than or equal to two pneumonitis exhibited a significantly worse overall survival than those with grade greater than or equal to two irAEs that excluded pneumonitis. Multivariate analysis revealed that grade greater than or equal to two pneumonitis (hazard ratio = 3.71; 95% confidence interval, 1.85–7.45; p < 0.001) and squamous histology (hazard ratio = 2.64; 95% confidence interval, 1.29–5.42; p = 0.008) were independently associated with worse overall survival.

Conclusions

After minimizing immortal time bias, pneumonitis grade two or greater and squamous histology were poor prognostic factors in patients who received consolidation durvalumab after CRT.

Introduction

In the phase 3 KEYNOTE-604 study (NCT03066778), pembrolizumab plus etoposide and platinum chemotherapy (EP) significantly (p = 0.0023) improved progression-free survival versus placebo plus EP in previously untreated extensive-stage SCLC (ES-SCLC). We present health-related quality of life (HRQoL) results from KEYNOTE-604.

Methods

Patients with stage IV SCLC were randomized 1:1 to pembrolizumab 200 mg or placebo every 3 weeks for 35 cycles plus four cycles of EP. Secondary end points included mean change from baseline to week 18 in the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire—Core 30 (QLQ-C30) global health status/quality of life (GHS/QoL) scale and time to deterioration in the composite outcome of cough, chest pain, or dyspnea from QLQ-C30 and QLQ—Lung Cancer Module 13. Two-sided, nominal p values are reported.

Results

A total of 439 patients completed at least one QLQ-C30 and QLQ—Lung Cancer Module 13 assessment (pembrolizumab + EP, n = 221; placebo + EP, n = 218). GHS/QoL scores improved from baseline to week 18: least squares mean (95% confidence interval [CI]) changes were 8.7 (5.3–12.1) for pembrolizumab plus EP and 4.2 (0.9–7.5) for placebo plus EP. Between-group differences in least squares mean scores were improved for pembrolizumab plus EP (4.4 [95% CI: 0.2–8.7], p = 0.040]). Median time to deterioration for the composite end point was not reached and 8.7 (95% CI: 5.9–not reached) months, respectively (hazard ratio = 0.80 [95% CI: 0.56–1.14], p = 0.208).

Conclusions

First-line pembrolizumab plus EP therapy maintained HRQoL in patients with ES-SCLC and may be associated with greater improvement than placebo plus EP. Together with the efficacy and safety findings in KEYNOTE-604, HRQoL data support the benefit of pembrolizumab in ES-SCLC.