Phase I/II Trial of Carboplatin, Nab-paclitaxel, and Pembrolizumab for Advanced Non-Small Cell Lung Cancer: Hoosier Cancer Research Network LUN13-175.

BACKGROUND: Combination chemotherapy and immunotherapy regimens have significantly improved survival for patients with previously untreated advanced non-small cell lung cancer (NSCLC). Improvements in overall survival (OS) in two separate pembrolizumab trials have demonstrated survival improvements over chemotherapy alone, regardless of PD-L1 status. The optimal chemotherapy backbone for combination with immunotherapy is unknown. We hypothesized nab-paclitaxel may be a well-suited platinum partner to use in combination with checkpoint inhibitor therapy for both adenocarcinoma and squamous histology and conducted a phase I/II trial to assess the efficacy of this regimen in advanced NSCLC. METHODS: Adult patients with previously untreated, stage IIIB/IV NSCLC (any histology) with an Eastern Cooperative Oncology Group performance status of 0-1, any PD-L1 expression, and no EGFR mutations or ALK translocations, received carboplatin area under the curve (AUC) 6 day 1, nab-paclitaxel 100 mg/m2 days 1, 8, 15, and pembrolizumab 200 mg day 1 q21 days for 4 cycles followed by maintenance pembrolizumab q3w. Co-primary endpoints were progression-free survival (PFS) and overall response rate (ORR). RESULTS: Forty-six evaluable patients enrolled, 14 in phase I and 32 in phase II, from June 2015 to July 2018 with a median duration of follow-up of 35.4 months. Median time from enrollment to data lock was 42 months. In the ITT population, the ORR was 35%, median PFS was 5.6 months (95% CI, 4.6-8.2), and median OS was 15.4 months (CI, 12.4-28.1). There were no statistical differences in PFS or OS by PD-L1 status. The 2- and 3-year landmark OS rates were 33% and 24%, respectively. CONCLUSION: Carboplatin, nab-paclitaxel, and pembrolizumab are a safe and effective regimen for patients with both squamous and nonsquamous NSCLC. Although this study did not meet the prespecified endpoints, the median and landmark OS results are consistent with durable benefit of this regimen as seen in phase III trials for first-line treatment of advanced NSCLC.

Top advances in lung cancer, 2021.

Despite a global pandemic that continued to inflict chaos and confusion on the world, resulting in fewer cancer screenings and delayed surgeries, remarkable lung cancer treatment advancements were made in 2021. From immunotherapy in the adjuvant setting to the approval of the first-in-class, highly selective inhibitor of KRAS G12C, these treatment advances have significant clinical impact in patients with lung cancer. LAY SUMMARY: There has been tremendous innovation in the treatment of nonsmall cell lung cancer. The year 2021 was marked by new approaches to adjuvant therapy and the availability of agents to target new subsets of nonsmall cell lung cancer.

Management of Immunotherapy-Related Toxicities, Version 1.2022, NCCN Clinical Practice Guidelines in Oncology.

The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions, consisting of medical and hematologic oncologists with expertise across a wide range of disease sites, and experts from the areas of dermatology, gastroenterology, endocrinology, neurooncology, nephrology, cardio-oncology, ophthalmology, pulmonary medicine, and oncology nursing. The content featured in this issue is an excerpt of the recommendations for managing toxicities related to CAR T-cell therapies and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to immune checkpoint inhibitors, visit NCCN.org.

Metastatic Thymoma Harboring a Deleterious BRCA2 Mutation Derives Durable Clinical Benefit from Olaparib.

Thymomas comprise a group of rare epithelial neoplasms of the anterior mediastinum. Whereas localized disease carries a favorable prognosis, the majority of patients with metastatic thymomas experience progression or recurrence over a 10-year period. Although targeted therapies have become standard of care in many malignancies, no clinically actionable mutations have consistently been identified in metastatic thymomas. Here, we describe a patient with an aggressive thymoma complicated by extensive pleural metastases. Over a 16-year period, she progressed on multiple treatment regimens. To identify additional treatment options, tissue from a pleural metastasis was sent for next-generation sequencing, revealing mutations in BRCA2, tyrosine kinase 2, and SET domain containing 2. Based on supporting evidence for poly (ADP-ribose) polymerase (PARP) inhibition in other BRCA-mutated tumors, the patient was started on the PARP inhibitor olaparib. She derived significant clinical benefit from treatment, with imaging showing overall stabilization of her disease. Here, we review the genotyping results of her tumor and discuss the functional and clinical significance of the mutations in her cancer as well as implications for managing patients with advanced BRCA-mutant thymomas. KEY POINTS: Targeted therapy has yet to enter the standard clinical management of metastatic thymomas. Patients with BRCA2-mutant thymomas may benefit from poly (ADP-ribose) polymerase inhibition.

NCCN Guidelines Insights: Management of Immunotherapy-Related Toxicities, Version 1.2020.

The NCCN Guidelines for Management of Immunotherapy-Related Toxicities provide interdisciplinary guidance on the management of immune-related adverse events (irAEs) resulting from cancer immunotherapy. These NCCN Guidelines Insights describe symptoms that may be caused by an irAE and should trigger further investigation, and summarize the NCCN Management of Immunotherapy-Related Toxicities Panel discussions for the 2020 update to the guidelines regarding immune checkpoint inhibitor-related diarrhea/colitis and cardiovascular irAEs.

Management of Immunotherapy-Related Toxicities, Version 1.2019.

The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions and ASCO, consisting of medical and hematologic oncologists with expertise in a wide array of disease sites, and experts from the fields of dermatology, gastroenterology, neuro-oncology, nephrology, emergency medicine, cardiology, oncology nursing, and patient advocacy. Several panel representatives are members of the Society for Immunotherapy of Cancer (SITC). The initial version of the NCCN Guidelines was designed in general alignment with recommendations published by ASCO and SITC. The content featured in this issue is an excerpt of the recommendations for managing toxicity related to immune checkpoint blockade and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to chimeric antigen receptor T-cell therapy, visit NCCN.org.

Intracranial Response to Anti-Programmed Death 1 Therapy in a Patient with Metastatic Non-Small Cell Lung Cancer with Leptomeningeal Carcinomatosis.

Central nervous system metastasis in non-small cell lung cancer remains a therapeutic challenge and confers a poor prognosis. Here we describe a patient with lung adenocarcinoma, parenchymal brain metastases, and leptomeningeal carcinomatosis who demonstrated a sustained response to programmed death 1 inhibition combined with stereotactic radiosurgery.

Implementing a Patient-Reported Outcome Dashboard in Oncology Telemedicine Encounters: Clinician and Patient Adoption and Acceptability.

PURPOSE: Telemedicine provides numerous benefits to patients, yet effective communication and symptom assessment remain a concern. The recent uptake of telemedicine provided an opportunity to use a newly developed dashboard with patient-reported outcome (PRO) information to enhance communication and shared decision making (SDM) during telemedicine appointments. The objective of this study was to identify barriers to using the dashboard during telemedicine, develop implementation strategies to address barriers, and pilot test use of this dashboard during telemedicine appointments in two practice settings to evaluate acceptability, adoption, fidelity, and effectiveness. METHODS: Patients and clinicians were interviewed to identify determinants to dashboard use in telemedicine. Implementation strategies were designed and refined through iterative feedback from stakeholders. A pilot study of dashboard use was conducted from March to September 2022. Acceptability, adoption, and fidelity were evaluated using mixed methods. SDM was evaluated using the collaboRATE measure. RESULTS: One hundred two patient encounters were evaluated. Most patients (62; 60%) had completed some PRO data at the time of their telemedicine encounter. Most (82; 80%) encounters had clinician confirmation that PRO data had been reviewed; however, collaborative review of the dashboard was documented in only 27%. Degree of SDM was high (mean collaboRATE score 3.40; SD, 0.11 [95% CI, 3.17 to 3.63] out of a maximum score of 4). Implementation strategies focused on patient engagement, education, and remote PRO completion. Clinician-facing strategies included education, practice facilitation, and small tests of change. CONCLUSION: This study demonstrated that implementation of a PRO-based dashboard into telemedicine appointments was feasible and had acceptable adoption and acceptability by patients and clinicians when several strategies were used to engage end users. Strategies targeting both patients and clinicians are needed to support routine and effective PRO integration in telemedicine.

Cancer Surveillance in Solid Organ Transplant Recipients With a Pretransplant History of Malignancy: Multidisciplinary Collaborative Expert Opinion.

With improved medical treatments, the prognosis for many malignancies has improved, and more patients are presenting for transplant evaluation with a history of treated cancer. Solid organ transplant (SOT) recipients with a prior malignancy are at higher risk of posttransplant recurrence or de novo malignancy, and they may require a cancer surveillance program that is individualized to their specific needs. There is a dearth of literature on optimal surveillance strategies specific to SOT recipients. A working group of transplant physicians and cancer-specific specialists met to provide expert opinion recommendations on optimal cancer surveillance after transplantation for patients with a history of malignancy. Surveillance strategies provided are mainly based on general population recurrence risk data, immunosuppression effects, and limited transplant-specific data and should be considered expert opinion based on current knowledge. Prospective studies of cancer-specific surveillance models in SOT recipients should be supported to inform posttransplant management of this high-risk population.

General population reference values for the Functional Assessment of Cancer Therapy-Lung and PROMIS-29.

BACKGROUND: Therapeutic advances in lung cancer have turned attention toward patient-reported outcome measures (PROMs) as important clinical outcomes. The Functional Assessment of Cancer Therapy-Lung (FACT-L) is a common endpoint in lung cancer trials. This study calculated FACT-L reference values for the United States (US) general population. METHODS: Adults from the US general population (N = 2001) were surveyed between September 2020 and November 2020. Surveys contained 126 questions, including the FACT-L [36 items; FACT-G and four subscales (Physical Well-Being [PWB], Social Well-Being [SWB], Emotional Well-Being [EWB], and Functional Well-Being [FWB]) and the Lung Cancer Subscale (LCS), and a Trial Outcome Index (TOI)]. Reference values for each FACT-L scale were calculated with means for the total sample and separately for participants with: no comorbidities, COVID-19 as only comorbidity, no COVID-19. RESULTS: In the total sample, the reference scores were as follows: PWB = 23.1; SWB = 16.8; EWB = 18.5; FWB = 17.6; FACT-G = 76.0; LCS = 23.0, TOI = 63.7, and FACT-L Total = 99.0. Scores were lower for those reporting a prior diagnosis of COVID-19, especially for SWB (15.7) and FWB (15.3). SWB scores were lower than previous references values. CONCLUSIONS: These data provide US general adult population reference value set for FACT-L. While some of the subscale results were lower than those found in the reference data for other PROMs, these data were obtained in a more contemporaneous time frame juxtaposed with the COVID-19 pandemic and may represent a new peri-pandemic norm. Thus, these reference values will be useful for future clinical research.

Regulatory T-Cells as an Emerging Barrier to Immune Checkpoint Inhibition in Lung Cancer.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigm for lung cancer in recent years. These strategies consist of neutralizing antibodies against negative regulators of immune function, most notably cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and PD-1 ligand 1 (PD-L1), thereby impeding the ability of tumor cells to escape immune surveillance. Though ICIs have proven a significant advance in lung cancer therapy, overall survival rates remain low, and lung cancer continues to be the leading cause of cancer-related death in the United States. It is therefore imperative to better understand the barriers to the efficacy of ICIs, particularly additional mechanisms of immunosuppression within the lung cancer microenvironment. Recent evidence suggests that regulatory T-lymphocytes (Tregs) serve as a central mediator of immune function in lung cancer, suppressing sterilizing immunity and contributing to the clinical failure of ICIs. Here, we provide a comprehensive summary of the roles of Tregs in lung cancer pathobiology and therapy, as well as the potential means through which these immunosuppressive mechanisms can be overcome.

The Impact of Beta Blockers on Survival Outcomes in Patients With Non-small-cell Lung Cancer Treated With Immune Checkpoint Inhibitors.

BACKGROUND: Beta blockers have been associated with anti-tumorigenic effects, potentially by reducing adrenergic-mediated stress responses. Preclinical studies have additionally shown that beta blockade may enhance the efficacy of cancer immunotherapy. We investigated patients with lung cancer who concomitantly used beta blockers and immune checkpoint inhibitors (ICIs), with the hypothesis that beta blockade would positively impact clinical outcomes. PATIENTS AND METHODS: We retrospectively reviewed the health records of 109 patients who were treated at Northwestern University from January 2014 through August 2018 with ICIs for non-small-cell lung cancer (NSCLC). Comparisons of overall survival and progression-free survival (PFS) were performed using Kaplan-Meier analysis with log-rank test, and a univariate regression analysis was performed with a Cox proportional hazards model. RESULTS: Among 109 patients treated with ICIs for NSCLC, 28 of them were concomitantly prescribed beta blockers. Use of beta blockers was associated with increased PFS, with a hazard ratio of 0.58 and 95% confidence interval of 0.36 to 0.93. There was not a significant increase in overall survival among patients who took beta blockers (hazard ratio, 0.66; 95% confidence interval, 0.38-1.17). In a regression model, beta blockers were identified as predictive of PFS, as were non-squamous histology, tumor programmed death-ligand 1 positivity, and lower line of treatment. CONCLUSIONS: Our data suggests beta blocker use may be associated with improved PFS among patients treated with ICIs for NSCLC. This was a small study, and these findings should be further validated in prospective clinical studies.

Patient-reported tolerability of veliparib combined with cisplatin and etoposide for treatment of extensive stage small cell lung cancer: Neurotoxicity and adherence data from the ECOG ACRIN cancer research group E2511 phase II randomized trial.

OBJECTIVES: The ECOG-ACRIN Cancer Research Group trial E2511 recently demonstrated a potential benefit for the addition of veliparib to cisplatin-etoposide (CE) in patients with extensive stage small cell lung cancer (ES-SCLC) in a phase II randomized controlled trial. Secondary trial endpoints included comparison of the incidence and severity of neurotoxicity, hypothesized to be lower in the veliparib arm, and tolerability of the addition of veliparib to CE. Physician-rated and patient-reported neurotoxicity was also compared. MATERIALS AND METHODS: Patients randomized to veliparib plus CE (n = 64) or placebo plus CE (n = 64) completed the 11-item Functional Assessment of Cancer Therapy Gynecologic Oncology Group Neurotoxicity (questionnaire pre-treatment, end of cycle 4 [ie 3 months after randomization] and 3 months post-treatment [ie 6-months]). Adherence analysis was based on treatment forms. RESULTS AND CONCLUSION: No significant differences in mean or magnitude of change in neurotoxicity scores were observed between treatment arms at any time point. However, patients in the placebo arm reported worsening neurotoxicity from baseline to 3-months (M difference = -1.5, P = .045), compared to stable neurotoxicity in the veliparib arm (M difference = -0.2, P = .778). Weakness was the most common treatment-emergent (>50%) and moderate to severe (>16%) symptom reported, but did not differ between treatment arms. The proportion of adherence to oral therapy in the overall sample was 75%. Three percent of patients reported clinically significant neurotoxicity that was not captured by physician assessment. Neurotoxicity scores were not different between treatment arms. The addition of veliparib to CE appeared tolerable, though weakness should be monitored. CLINICALTRIALS. GOV IDENTIFIER: NCT01642251.

Eating patterns and overweight status in young adults: the Bogalusa Heart Study.

Several studies have focused on the association between eating patterns and obesity. However, the findings have not been consistent. The goal of the present study was to identify the eating patterns associated with overweight among young adults aged 19-28 years (n=504) in Bogalusa, Louisiana. Food intake was determined using a single 24-h dietary recall, and height and weights were measured to determine the body mass index. The association between eating patterns and overweight status was evaluated using logistic regression and analysis of covariance. Twenty-four percent of young adults were overweight and 18% were obese; with the highest prevalence of obesity seen among black females. The percentage gram consumption of fruit/fruit juices (P < 0.01) was negatively associated with overweight status, and diet beverage consumption (P < 0.05) was positively associated with obesity. Eating patterns are associated with overweight status in young adults; however, the amount of variance explained in the body mass index was very small.

Alveolar soft part sarcoma mimics prostate cancer metastasis.

A 61-year-old man presented to the oncology clinic with Gleason 9 (4 + 5) prostate cancer. Staging CT showed multiple nodules in both lungs. Since the lung lesions were too small for biopsy, he was started on anti-androgen therapy for suspected metastatic, hormone-sensitive prostate cancer. While his prostate-specific antigen decreased from 32 to <0.1 ng/ml, the multiple lung lesions showed no response on subsequent imaging. The patient presented during follow-up with severe right leg pain, at which time magnetic resonance imaging revealed a large, hyperintense mass in the femur. The mass was resected along with two lung nodules, with pathology demonstrating metastatic alveolar soft part sarcoma. This serves as an important reminder that lesions suspicious for metastases may be due to cancers of multiple primary origins, particularly if the pattern of metastasis is atypical or there is varied response to therapy.

Use of Low-Frequency Driver Mutations Detected by Cell-Free Circulating Tumor DNA to Guide Targeted Therapy in Non-Small-Cell Lung Cancer: A Multicenter Case Series.

PURPOSE: To evaluate the clinical outcome of patients with non-small-cell lung cancer treated by targeting low variant allelic frequency (VAF) driver mutations identified through cell-free DNA (cfDNA) next-generation sequencing (NGS). Detection of driver mutations in cancer is critically important in the age of targeted therapy, where both tumor-based as well as cfDNA sequencing methods have been used for therapeutic decision making. We hypothesized that VAF should not be predictive of response and that low VAF alterations detected by cfDNA NGS can respond to targeted therapy. PATIENTS AND METHODS: A multicenter retrospective case review was performed to identify patients with non-small-cell lung cancer who received targeted molecular therapy on the basis of findings of low VAF alterations in cfDNA NGS. Mutations at low VAF were defined as < 0.2% mutated cfDNA molecules in a background of wild-type cfDNA. RESULTS: One hundred seventy-two patients underwent cfDNA NGS testing. Of the 172 patients, 12 were identified as having low VAF driver alterations and were considered for targeted therapy. The median progression-free survival (PFS) for all patients was 52 weeks (range, 17 to 88 weeks). For patients with EGFR exon 19 deletion (n = 7), the median PFS was 52 weeks (range, 17 to 60.5 weeks). For patients with EML4-ALK fusions (n = 3), the median PFS was 60 weeks (range, 18 to 88 weeks). The median overall survival for all patients after diagnosis was 57.6 weeks. CONCLUSION: Targeted treatment response for driver mutations detected by cfDNA may be independent of VAF, even in relation to other higher VAF aberrations in plasma, and directly dependent on the underlying disease biology and ability to treat the patient with appropriate targeted therapy.

Biomarkers for PD-1/PD-L1 Blockade Therapy in Non-Small-cell Lung Cancer: Is PD-L1 Expression a Good Marker for Patient Selection?

Immunotherapy has emerged as a promising treatment modality in cancer therapy. With improved understanding of how to tip the balance of immune homeostasis, novel therapeutics targeting immune checkpoints have been developed, with durable responses observed in multiple solid tumors, including melanoma, renal cell carcinoma, and non-small-cell lung cancer. Clinical trials have reported favorable responses using programmed cell death-1 protein receptor (PD-1)/programmed cell death-1 protein ligand (PD-L1) blockade as monotherapy and most impressively in combinatorial trials with cytotoxic T-lymphocyte antigen-4 protein blockade. Nonetheless, a clinical benefit has not been observed in all patients. Therefore, identifying the ideal biomarkers for patient selection would be of great value in optimizing and personalizing immunotherapy. The utility of PD-L1 expression as a biomarker has varied in different clinical trials and immunohistochemistry assays. In addition, the response to immune checkpoint inhibition has been complicated by PD-L1 expression as a marker influenced by the dynamic tumor microenvironment. No consensus has yet been reached on whether PD-L1 expression is an ideal marker for patient selection. Recent research has shown promise for alternative markers, including T-cell immunohistochemistry, other immunologic markers, T-cell receptor clonality, and somatic mutational burden. However, additional studies are needed to assess the value of these as practical predictive biomarkers for patient selection and treatment response.