Examining crossover and postprotocol therapies in first-line immunotherapy trials in non-small cell lung cancer (NSCLC).

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy has led to significant improvement in outcomes for patients with nononcogene-driven advanced non-small cell lung cancer (NSCLC). The rate of crossover and receipt of postprotocol ICI in frontline trials for advanced NSCLC has not been systematically evaluated. METHODS: ClinicalTrials.gov was used to identify phase 3 studies evaluating the use of immunotherapy or combination chemoimmunotherapy against chemotherapy alone in the frontline management of advanced NSCLC. Data on outcomes, rate of crossover and/or subsequent post-protocol receipt of immunotherapy, and the start dates of these clinical trials were then extracted. RESULTS: Twenty-three frontline trials in nononcogene-driven advanced NSCLC were identified. Six trials with ICI monotherapy/dual ICI therapy and 17 trials evaluating chemotherapy/ICI in first-line advanced NSCLC were included in the analysis. The crossover rate ranged 0% to 54% in ICI monotherapy/dual ICI trials and 0% to 52% in chemotherapy/ICI trials. Nineteen of 23 trials provided information on subsequent postprotocol therapies. Among the trials not allowing crossover, postprotocol ICI was administered to 17% to 45.8% of patients. Information regarding the eventual receipt of ICI therapy was available for 22 of 23 trials. Of 6631 patients, 2507 (37.8%) randomized to the control arm eventually received ICI therapy. CONCLUSION: The rate of crossover and postprotocol ICI use was low in frontline trials for first-line NSCLC incorporating ICI. Given the proven survival overall survival of ICI in a broad population, there is a need to ensure availability of this life-prolonging therapy in future trials, either by crossover treatment or postprotocol administration.

ChatGPT-A promising generative AI tool and its implications for cancer care.

PLAIN LANGUAGE SUMMARY: Since its launch, ChatGPT has taken the internet by storm and has the potential to be used broadly in the health care system, particularly in a setting such as medical oncology. ChatGPT is well suited to review and extract key content from records of patients with cancer, interpret next-generation sequencing reports, and offer a list of potential clinical trial options.

Telemedicine in Cancer Care Beyond the COVID-19 Pandemic: Oncology 2.0?

PURPOSE OF REVIEW: This paper summarizes early experiences of telemedicine during the COVID-19 pandemic, the patient and physician experience, limitations in accessibility introduced by telemedicine, and the opportunities and anticipated sustained role of telemedicine for cancer care. RECENT FINDINGS: Research from a wide range of oncology facilities consistently demonstrates the feasibility of delivering telemedicine services over audio (telephone) and/or video platforms. Emerging work highlights that telemedicine is well suited for a subset of patients and clinical settings and that there are methods by which current disparities could potentially be ameliorated. Several current uncertainties limit the broad applicability of telemedicine longitudinally. Early responses to the pandemic that included rapid introduction of telemedicine demonstrated the feasibility of audio- and video-based platforms that achieved promising utility, while simultaneously demonstrating disparities based on patient characteristics and infrastructural support. Its long-term role will likely depend greatly on reimbursement and regulatory reform.

Nab-paclitaxel in older patients with non-small cell lung cancer who have developed disease progression after platinum-based doublet chemotherapy.

BACKGROUND: The selection of later-line treatment for older patients with AJCC (version 7) stage IV non-small cell lung cancer (NSCLC) remains controversial. Nanoparticle albumin-bound (nab)-paclitaxel is approved with carboplatin for the first-line treatment of patients with NSCLC and subgroup analysis of phase 3 data has suggested superior survival in older patients. METHODS: The authors conducted a phase 2 study of nab-paclitaxel in 42 patients aged ≥70 years who had been treated previously with a platinum doublet regimen; patients also could have received a PD-1 inhibitor. The primary endpoint of the current study was grade 3 to 5 toxicity (according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). In addition to response rate, progression-free survival (PFS), and overall survival (OS), geriatric assessments also were performed before and during treatment, associations between baseline sarcopenia and outcomes were explored, and changes in T lymphocyte p16 before and during treatment were measured. The authors also performed a retrospective subgroup analysis of 19 older patients who were treated with nab-paclitaxel as part of a larger, randomized, phase 2 study; data were not combined. RESULTS: The rate of grade 3 to 5 toxicities was 33.7%. The most common grade 3 to 5 toxicities were decreased white blood cell count (11.9%), neutropenia (9.5%), and fatigue (11.9%). The response rate was 34.2% (2.6% complete response rate and 31.6% partial response rate). The median PFS was 5.2 months and the median OS was 9.3 months. Adverse prognostic factors were common: 42% of patients were frail and 39% of patients were prefrail, whereas 21% had an Eastern Cooperative Oncology Group performance status of 2 and 27% were sarcopenic. Only frailty was found to be predictive of inferior survival. A subgroup analysis of 19 older patients treated with nab-paclitaxel alone in a prior trial demonstrated a response rate of 15.8%, a PFS of 4.2 months, and an OS of 13.6 months. CONCLUSIONS: Fit and prefrail older patients with stage IV NSCLC should be considered for treatment with nab-paclitaxel after disease progression with doublet chemotherapy.

Maintenance of Certification (MOC)-Benefit vs Burden.

This Viewpoint examines the demands of maintenance of certification (MOC) requirements from the ABIM on balance with the projected benefits to quality of patient care.

Managing multifocal bronchioloalveolar carcinoma/lepidic predominant adenocarcinoma: changing rules for an evolving clinical entity.

Although the clinical entity of bronchioloalveolar carcinoma (BAC) has been reclassified into adenocarcinoma in situ, lepidic predominant adenocarcinoma, and mucinous adenocarcinoma, it continues to merit special consideration based on its distinct natural history and response to therapy. The clinical behavior of multifocal BAC is highly variable, as is its response to various treatments. This characteristic should encourage latitude for individualized judgment rather than reliance on dogma about how advanced non-small cell lung cancer (NSCLC) should be managed. Specifically, it is worth first questioning whether any of the visible disease is progressing at a clinically significant pace. If clear progression is unlikely to occur over several months or longer, an appropriate option is attentive clinical and radiographic follow-up with no intervention. If significant progression is demonstrated in an isolated area, it is very reasonable to consider local therapy-whether surgery or radiation-in this area alone. If progression is clearly apparent, then optimal systemic therapy should be used based on molecular findings. This is the same approach that is generally recommended for other forms of advanced NSCLC, with the presence or absence of a driver mutation used to guide the selection of an epidermal growth factor receptor inhibitor, an anaplastic lymphoma kinase inhibitor, or conventional platinum-based chemotherapy (with the potential addition of bevacizumab).

Rapid Advances in Resectable Non-Small Cell Lung Cancer: A Narrative Review.

Importance: A series of high-profile clinical trials for patients with resectable early-stage non-small cell lung cancer (NSCLC) have recently changed the standard of care in this setting. Specifically, studies have demonstrated statistically and clinically significant improvements in efficacy with the targeted therapy for adjuvant osimertinib in patients with resected NSCLC harboring an epidermal growth factor receptor (EGFR) genomic abnormality (GA), whereas trials with chemotherapy combined with nivolumab in the neoadjuvant setting and others testing atezolizumab or pembrolizumab as adjuvant therapy have all demonstrated improvements in event-free survival (EFS) (for neoadjuvant therapy) or disease-free survival (DFS) (for adjuvant therapy). These trials introduce many open questions about how to apply these findings in clinical practice. Observations: Treatment with adjuvant osimertinib for 3 years was associated with significant improvement in both DFS and overall survival (OS), but the erosion of the DFS benefit after the duration of treatment ends suggests a potential value for more longitudinal treatment. The potential value of highly effective targeted therapies as adjuvant therapy for other GAs has a compelling rationale but no data at this time. Adjuvant atezolizumab or pembrolizumab, generally administered for 1 year after postoperative chemotherapy, are appropriate considerations, but only atezolizumab for patients with tumor programmed death-ligand 1 (PD-L1) levels of 50% has demonstrated a benefit in OS. Neoadjuvant chemotherapy with nivolumab offers a strong EFS benefit, a shorter interval of treatment, and radiographic and pathologic feedback for patients with resectable stage IB to IIIA NSCLC, although very recent randomized clinical trials of perioperative immunotherapy both combined with chemotherapy preoperatively and administered postoperatively highlight the debatable value of adjuvant immunotherapy after prior chemoimmunotherapy. Improved tumor shrinkage rates with neoadjuvant chemoimmunotherapy suggest the possibility that criteria for resectability may potentially be redefined in anticipation of a good response to neoadjuvant chemoimmunotherapy. Conclusions and Relevance: Developments in resectable NSCLC have arrived so rapidly that they have also created practical challenges of identifying optimal patients and prioritizing options among these new competing standards. In some cases, practical management requires clinical judgment and discussion with the patient to cover the gaps in prospective data. Caution should be exerted when extrapolating beyond the available data.

Brief Report on Global Clinician Practices in the First-Line Management of Metastatic Non-Small Cell Lung Cancer.

INTRODUCTION: In the dynamic landscape of metastatic NSCLC (mNSCLC) management, marked by several frontline options and the integration of next generation sequencing (NGS) for informed decision-making, barriers persist despite advancements. This includes challenges in clinical trial recruitment. To gain global insights into clinicians' practices, we conducted a survey on their testing and management approaches for patients with mNSCLC. METHODS: The survey, conducted from July 12 to August 20, 2023, utilized multiple-choice questions and qualitative research questions, employing the Likert Scale for comprehensive insights. RESULTS: A total of 127 individuals responded, with 72% affiliated with academic health systems, and 55% practicing in the USA. Regarding testing practices, 93% consistently ordered NGS for non-squamous histology, while 54% did so for squamous cell histology. Concurrent tissue and liquid biopsies were routinely ordered by 28%, while 39% reported ordering both testing platforms concurrently for select cases only. Respondents cited logistical barriers, such as insufficient tissue and lack of infrastructure, as the most common hindrance to molecular testing (76%), followed by reimbursement challenges (56%) and concerns about delayed turnaround time (50%). While most respondents were confident in interpreting NGS results, 22% lacked confidence. Concerning treatment decisions, 72% preferred awaiting molecular testing results before initiating systemic therapy. Less than 50% routinely referred patients for clinical trials in the frontline setting for mNSCLC. For patients with disease expressing high PD-L1 levels, most oncologists preferred pembrolizumab monotherapy. For disease with low PD-L1 expression, a platinum doublet chemotherapy regimen combined with pembrolizumab was favored. In disease cases with negative PD-L1 expression, a platinum doublet chemotherapy regimen with pembrolizumab was preferred. Key factors influencing oncologists' preferred immune checkpoint inhibitor (ICI) included experience with one ICI over another, preferred status per national guidelines, availability of trial data with a significant follow-up period, and consideration of drug cost. CONCLUSION: Although this study demonstrates an improved awareness and adoption of ordering NGS for the management of mNSCLC, it underscores the persistence of various barriers that must be addressed to improve upon the quality of care for patients diagnosed with mNSCLC.

Frontline pembrolizumab monotherapy for metastatic non-small cell lung cancer with PD-L1 expression ≥50%: real-world outcomes in a US community oncology setting.

Background: This study investigated real-world time on treatment (rwToT) and overall survival (OS) for patients with metastatic non-small cell lung cancer (mNSCLC) who initiated first-line (1L) pembrolizumab monotherapy. We also explored discontinuation reasons and subsequent treatments, stratified by number of cycles among those who completed ≥17 cycles of 1L pembrolizumab. Methods: Patients with mNSCLC without actionable genetic aberrations, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2 and unknown, and PD-L1 TPS ≥ 50% starting 1L pembrolizumab monotherapy between 24-Oct-2016 and 31-Dec-2018 within The US Oncology Network were identified retrospectively and evaluated using structured data, with a data cutoff of 30-Sep-2021. Patient characteristics and disposition were summarized using descriptive statistics. OS and rwToT were evaluated using Kaplan-Meier method for all ECOG PS and PS 0-1. A subgroup of patients who completed ≥17 cycles were evaluated using supplemental chart review data to discern reasons for discontinuation. Results: Of the 505 patients with mNSCLC with PD-L1 TPS ≥50%, 61% had ECOG PS 0-1, 23% had ECOG PS 2, and 65% had nonsquamous histology. Median rwToT and OS of pembrolizumab were 7.0 (95% CI, 6.0-8.4) months and 24.5 (95% CI, 20.1-29.3) months, respectively. In the subgroup with ECOG PS 0-1, they were 7.6 months (95% CI, 6.2-9.2) and 28.8 months (95% CI, 22.4-37.5), respectively. Of the 103 patients who completed ≥17 cycles, 57 (55.3%) patients received 17 - 34 cycles and 46 (44.7%) patients received ≥35 cycles. Approximately 7.7% of the study population received pembrolizumab beyond 35 cycles. Most common reasons for discontinuation were disease progression (38.6%) and toxicity (19.3%) among patients who received 17-34 cycles of pembrolizumab, and disease progression (13.0%) and completion of therapy (10.9%) among patients who received ≥35 cycles. Conclusion: Consistent with findings from KEYNOTE-024 and other real-world studies, this study demonstrates the long-term effectiveness of pembrolizumab monotherapy as 1L treatment for mNSCLC with PD-L1 TPS ≥50%. Among patients who completed ≥17 cycles, nearly half completed ≥35 cycles. Disease progression and toxicity were the most common reasons for discontinuation among patients who received 17-34 cycles of pembrolizumab. Reasons for discontinuation beyond 35 cycles need further exploration.

Perioperative Therapy for Resectable Non-Small-Cell Lung Cancer: Weighing Options for the Present and Future.

Anatomic surgical resection followed by cisplatin-based platinum-doublet adjuvant chemotherapy has been a long-standing standard of care for patients with early-stage, resectable non-small-cell lung cancer (NSCLC). More recently, incorporating of immunotherapy and targeted therapy in the perioperative setting has demonstrated improved disease-free or event-free survival in biomarker-defined subsets of patients. This article summarizes the results of major trials that led to approvals beyond chemotherapy in the perioperative setting. Alongside adjuvant osimertinib as a favored strategy for patients with EGFR mutation-positive NSCLC, there are competing potential standards of care for integrating immunotherapy in the neoadjuvant versus adjuvant setting, with advantages and disadvantages for each strategy. Emerging data in the coming years will provide further insight that may potentially lead to a combination of neoadjuvant and adjuvant treatment for many patients. Future trials should focus on clarifying the benefit of each component of treatment, defining an optimal treatment duration, and incorporating minimal residual disease to optimize treatment decisions.

Perioperative Immune Checkpoint Inhibition in Early-Stage Non-Small Cell Lung Cancer: A Review.

Importance: Although cancer-related mortality continues to decline, lung cancer remains the No. 1 cause of cancer deaths in the US. Almost half of the patients with non-small cell lung cancer (NSCLC) are diagnosed with early-stage, local or regional disease and are at high risk of recurrence within 5 years of diagnosis. Observations: Immune checkpoint inhibitors (ICIs) have improved outcomes for patients with metastatic NSCLC and have recently been tested in multiple clinical trials to determine their efficacy in the neoadjuvant or adjuvant setting for patients with local or regional disease. The landscape for perioperative ICIs in lung cancer is evolving rapidly, with recently reported and soon to mature clinical trials; however, the recent data highlight the potential of ICIs to increase response rates and decrease rates of relapse in early stages of lung cancer. Concurrently, novel applications of cell-free DNA may guide perioperative management strategies. Conclusions and Relevance: This article reviews the various approaches of incorporating perioperative use of immunotherapeutic agents for the treatment of early stages of NSCLC.

Novel Program Offering Remote, Asynchronous Subspecialist Input in Thoracic Oncology: Early Experience and Insights Gained During the COVID-19 Pandemic.

PURPOSE: AccessHope is a program developed initially by City of Hope to provide remote subspecialist input on cancer care for patients as a supplemental benefit for specific payers or employers. The leading platform for this work has been an asynchronous model of review of medical records followed by a detailed assessment of past and current management along with discussion of potential future options in a report sent to the local oncologist. This summary describes an early period of development and growth of this service, focusing on cases of lung cancer, particularly during the COVID-19 pandemic. METHODS: Cases were primarily identified by a trigger list of cancer diagnoses that included non-small-cell lung cancer and small-cell lung cancer. After medical records were obtained, a summary narrative was provided to a thoracic oncology specialist who wrote a case review sent to the local physician, followed by a direct discussion with the recipient. We focused on feasibility as measured by case volumes, the rates of concordance between the subspecialist reviewer with the local team, and cost savings from recommended changes, using descriptive statistics. RESULTS: From April 2019 to November 2020, 110 cases were reviewed: 55% male, median age 62.5 years (range, 33-92 years); 82% non-small-cell lung cancer (12% stage I or II, 16% stage III, and 57% stage IV), and 17% small-cell lung cancer (4% limited and 14% extensive). Median turnaround time for report send-out was 5.0 days. The review agreed with local management in 79 (72%) cases and disagreed in 31 (28%) cases; notably, specific additional recommendations were associated with evidence-based anticipated improvements in efficacy in 76 cases (69%) and improvement in potential for cure in 14 cases (13%). Recommendations leading to cost savings were identified in 14 cases (13%), translating to a projected cost savings of $19,062 (USD) per patient for the entire cohort of patient cases reviewed. CONCLUSION: We demonstrate the feasibility of completing a rapid turnaround of cases of lung cancer either patient-initiated for review or prospectively triggered by diagnosis and stage. This program of asynchronous second opinions identified evidence-based management changes affecting current treatment in 28% and potential improvements to improve care in 92% of patients, along with cost savings realized by eliminating low-value interventions.

Beyond Crizotinib: A Systematic Review and Meta-Analysis of the Next-Generation ALK Inhibitors as First-Line Treatment for ALK-Translocated Lung Cancer.

Background: Second and third-generation ALK inhibitors (ALKIs) have been recently approved for ALK-translocated lung cancer treatment, improving - and expanding - the first-line scenario. Methods: In this systematic review and metanalysis, we investigated the efficacy and safety of next-generation ALKIs in untreated advanced ALK-translocated lung cancer patients, searching for randomized phase III controlled trials through databases (PubMed, EMBASE, and the Cochrane Library). Inclusion and exclusion of studies, quality assessment, data extraction, and synthesis were independently accomplished by two reviewers, with discrepancies adjudicated by a third reviewer. Stata (StataCorp., v.16) software was used for the metanalysis. Results: In total, seven randomized controlled trials met our inclusion criteria. Comparing the results of next-generation ALKIs and control therapy (crizotinib or chemotherapy), next-generation ALKIs significantly improved progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), any lesion (aCNSRR) and measurable lesions of central nervous system response rate (mCNSRR). Safety results were similar between the experimental and control groups. Conclusion: Our analysis confirmed that next-generation ALKIs are the preferred first-line treatment option for ALK-translocated lung cancer. They are superior to crizotinib or chemotherapy in several clinical endpoints, including OS, PFS, ORR and CNS disease control, without increased toxicity. In the absence of head-to-head data, the choice between these molecules should be guided by physician experience and preference, drug-specific safety profile and schedule.

Clinical efficacy of atezolizumab plus bevacizumab and chemotherapy in KRAS-mutated non-small cell lung cancer with STK11, KEAP1, or TP53 comutations: subgroup results from the phase III IMpower150 trial.

BACKGROUND: The efficacy of atezolizumab (A) and/or bevacizumab (B) with carboplatin/paclitaxel (CP) chemotherapy was explored in the phase III, randomized IMpower150 study in patients with non-squamous non-small cell lung cancer (NSCLC) according to KRAS mutations (mKRAS) and co-occurring STK11, KEAP1, or TP53 mutations. METHODS: Mutation status was determined by circulating tumor DNA next-generation sequencing. Overall survival (OS) and progression-free survival (PFS) were analyzed in a mutation-evaluable intention-to-treat population (MEP; n=920) and SP263 (programmed cell death ligand 1 (PD-L1)) biomarker-evaluable population (n=774). RESULTS: Within the mKRAS population (24.5% of MEP), ABCP showed numerical improvements vs BCP in median OS (19.8 vs 9.9 months; HR 0.50; 95% CI 0.34 to 0.72) and PFS (8.1 vs 5.8 months; HR 0.42; 95% CI 0.29 to 0.61)-greater than with ACP (OS: 11.7 vs 9.9 months; HR 0.63; 95% CI 0.43 to 0.91; PFS: 4.8 vs 5.8 months; HR 0.80; 95% CI 0.56 to 1.13) vs BCP. Across PD-L1 subgroups in mKRAS patients, OS and PFS were longer with ABCP vs BCP, but OS with ACP was similar to BCP in PD-L1-low and PD-L1-negative subgroups. Conversely, in KRAS-WT patients, OS was longer with ACP than with ABCP or BCP across PD-L1 subgroups. KRAS was frequently comutated with STK11, KEAP1, and TP53; these subgroups conferred different prognostic outcomes. Within the mKRAS population, STK11 and/or KEAP1 mutations were associated with inferior OS and PFS across treatments compared with STK11-WT and/or KEAP1-WT. In mKRAS patients with co-occurring mSTK11 and/or mKEAP1 (44.9%) or mTP53 (49.3%), survival was longer with ABCP than with ACP or BCP. CONCLUSIONS: These analyses support previous findings of mutation of STK11 and/or KEAP1 as poor prognostic indicators. While clinical efficacy favored ABCP and ACP vs BCP in these mutational subgroups, survival benefits were greater in the mKRAS and KEAP1-WT and STK11-WT population vs mKRAS and mKEAP1 and mSTK11 population, suggesting both prognostic and predictive effects. Overall, these results suggest that atezolizumab combined with bevacizumab and chemotherapy is an efficacious first-line treatment in metastatic NSCLC subgroups with mKRAS and co-occurring STK11 and/or KEAP1 or TP53 mutations and/or high PD-L1 expression.

Telemedicine in Oncology: Delivering on an Overdue Promise in the COVID-19 Era.

Telemedicine has historically been underutilized in medicine broadly, and specifically in oncology, despite the general availability of the needed infrastructure to offer it as a platform for remote care. The COVID-19 pandemic posed new risks of infection exposure and potentially life-threatening complications, particularly in patients with cancer, created a new setting for cancer care ideally suited for the rapid roll-out of telemedicine for patients with cancer who need regular follow up but in whom live visits may not be critical. In the months since the upheaval of our health care system and wider society in the United States, as well as other countries, our early experience with telemedicine has demonstrated the feasibility of telemedicine for a subset of patients with cancer, facilitated by a removal of regulatory hurdles and payment parity, at least temporarily. At the same time, however, many patients still need to return to the clinic for routine infusions of anti-cancer therapy that obviate much of the value of remote clinic visits, and many patients remain limited by access to hardware, fast and reliable internet, and technical expertise. While we need to address these shortcomings and ensure training of health care professionals in "webside manner" with patients, as well as to work to develop ways to incorporate remote care in the conduct of clinical trials, telemedicine is poised to emerge not merely as an interim solution to a transient challenge but as a valuable tool ideally suited to deliver cancer care efficiently for a subset of patients well suited to adopt this platform.

Novel targeted agents for lung cancer.

It has been quite challenging to demonstrate significant improvements in survival for patients with non-small-cell lung cancer (NSCLC) over the past decade, but targeted therapies such as epidermal growth factor receptor (EGFR) inhibitors and angiogenesis inhibitors have been associated with benefits sufficient to alter our treatment standards. In addition to variations within these classes and combinations of such agents, several novel targeted therapy strategies have been introduced and are now emerging with encouraging results in early clinical trials for patients with advanced NSCLC. Immunotherapies targeting the MUC1 protein, MAGE-A3, and EGFR have shown early evidence of clinical benefits. Belagenpumatucel-L is a nonspecific allogeneic vaccine derived from multiple lung cancer cell lines, and the agent talactoferrin alfa might improve clinical outcomes based on broad immune system activation and stimulation. Other approaches that inhibit insulin-like growth factor receptor or heat-shock protein, both involved with multiple pathways involved with cell growth and survival, have shown activity in early trials and are moving forward in trials that specifically focus on patients with advanced NSCLC. This article reviews current data and future directions for each of these approaches.

Malignant Pericardial Effusion, or Fluid Around the Heart Due to Cancer.

This JAMA Oncology Patient Page describes the accumulation of excess fluid around the heart caused by cancer, known as malignant pericardial effusion.

Cancer Care in the Era of Artificial Intelligence.

This JAMA Oncology Patient Page explains artifical intelligence and what patients should know about how it can be used in oncology.