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.

Physician Awareness of Immune-Related Adverse Events of Immune Checkpoint Inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been proven to be very effective in the treatment of multiple cancers. They have a unique side-effect profile distinct from conventional chemotherapy that can manifest as immune-related adverse events (irAEs). With expanding ICI use, clinicians will increasingly encounter irAEs, and thus adequate physician knowledge on their recognition and management is crucial. METHODS: To assess physician knowledge of irAEs due to ICIs, an online survey was administered to resident physicians in internal medicine (IM), emergency medicine, and family medicine (FM), as well as to faculty physicians in IM and FM. RESULTS: We sent the survey to 413 physicians and received responses from 155 (38%), of which 110 were residents and 45 were faculty. Pembrolizumab was identified as an ICI by 79% of physicians, nivolumab by 64%, and ipilimumab by 55%. Twenty-five percent incorrectly thought infliximab and adalimumab were ICIs. Most physicians (93%) were able to identify the gastrointestinal tract as an irAE site, whereas only 57% and 67% were able to identify cardiovascular and renal systems as irAE sites, respectively. A total of 59% believed steroids negatively affect efficacy of ICIs and should be used with caution to treat irAEs, 65% incorrectly thought endocrinopathies due to irAEs are usually reversible, and 45% of FM residents considered antibiotics as the mainstay of treatment in ICI-mediated colitis. On a self-rated scale from 0 to 100, the median comfort level for all physicians in recognizing irAEs was 15 and for treatment of irAEs was 10. CONCLUSIONS: Significant knowledge gaps exist among residents and faculty physicians across multiple specialties regarding the recognition and treatment of irAEs due to ICIs. Given that these physicians are usually the first point of contact with patients, physician education on identification and treatment of irAEs is needed. Early detection of these toxicities is critical for their resolution.

Relations of perceived injustice to psycho-spiritual outcomes in advanced lung and prostate cancer: Examining the role of acceptance and meaning making.

OBJECTIVE: Many advanced cancer patients struggle with anxiety, depressive symptoms, and anger toward God and illness-related stressors. Patients may perceive their illness as an injustice (i.e., appraise their illness as unfair, severe, and irreparable or blame others for their illness), which may be a risk factor for poor psychological and spiritual outcomes. This study examined relations between cancer-related perceived injustice and psycho-spiritual outcomes as well as potential mediators of these relationships. METHODS: Advanced lung (n = 102) and prostate (n = 99) cancer patients completed a one-time survey. Using path analyses, we examined a parallel mediation model including the direct effects of perceived injustice on psycho-spiritual outcomes (i.e., anxiety, depressive symptoms, anger about cancer, anger towards God) and the indirect effects of perceived injustice on psycho-spiritual outcomes through two parallel mediators: meaning making and acceptance of cancer. We then explored whether these relations differed by cancer type. RESULTS: Path analyses indicated that perceived injustice was directly and indirectly-through acceptance of cancer but not meaning making-associated with psycho-spiritual outcomes. Results did not differ between lung and prostate cancer patients. CONCLUSIONS: Advanced cancer patients with greater perceived injustice are at higher risk for poor psycho-spiritual outcomes. Acceptance of cancer, but not meaning making, explained relationships between cancer-related perceived injustice and psycho-spiritual outcomes. Findings support testing acceptance-based interventions to address perceived injustice in advanced cancer patients.

Analysis of actionable genetic alterations in lung carcinoma from the VA National Precision Oncology Program.

Lung cancer is the leading cause of cancer mortality in men and women. Genomic sequencing of non-small cell lung cancer (NSCLC) is critical for the optimal treatment of NSCLC. In this study we sought to describe the frequencies of highly actionable driver mutations in lung adenocarcinoma (LUAD), squamous cell (LUSQ) and other NSCLC histologies (LUOT) in Veterans tested through the VA's National Precision Oncology Program (NPOP) and compare these frequencies to other published datasets from highly specialized academic cancer centers. The NPOP cohort included 3,376 unique Veterans with a diagnosis of lung carcinoma tested between February 2019 and January 2021 including 1892 with LUAD, 940 with LUSQ, and 549 with LUOT. Among patients with LUAD, 27.5% had highly actionable genetic variants. The frequency of targetable mutations was as follows: ALK rearrangement 0.8%, BRAF V600E 2.1%, EGFR exon 20 insertion mutation 0.48%, EGFR sensitizing mutations 6.6%, ERBB2 small variants 1.2%, KRAS G12C 14.0%, MET exon 14 skipping mutation 1.5%, NTRK rearrangement 0.1%, RET rearrangement 0.4%, and ROS1 rearrangement 0.3%. The frequency of EGFR mutations, RET rearrangement, MET exon 14 and ERBB2 small variants frequencies were significantly lower in NPOP compared to other published reports while MET amplification was more common in NPOP. Combined rates of highly actionable genetic variants were 2.7% and 13.4% in LUSQ and LUOT, respectively. In this study, 27.5% of Veterans with lung adenocarcinoma have actionable genetic alterations eligible for FDA approved targeted therapies, a frequency only slightly lower than other published datasets despite higher smoking rates in Veterans. Genomic sequencing should be performed in all Veterans with advanced LUAD and LUOT.

In Vivo Targeting Replication Protein A for Cancer Therapy.

Replication protein A (RPA) plays essential roles in DNA replication, repair, recombination, and the DNA damage response (DDR). Retrospective analysis of lung cancer patient data demonstrates high RPA expression as a negative prognostic biomarker for overall survival in smoking-related lung cancers. Similarly, relative expression of RPA is a predictive marker for response to chemotherapy. These observations are consistent with the increase in RPA expression serving as an adaptive mechanism that allows tolerance of the genotoxic stress resulting from carcinogen exposure. We have developed second-generation RPA inhibitors (RPAis) that block the RPA-DNA interaction and optimized formulation for in vivo analyses. Data demonstrate that unlike first-generation RPAis, second-generation molecules show increased cellular permeability and induce cell death via apoptosis. Second-generation RPAis elicit single-agent in vitro anticancer activity across a broad spectrum of cancers, and the cellular response suggests existence of a threshold before chemical RPA exhaustion induces cell death. Chemical RPA inhibition potentiates the anticancer activity of a series of DDR inhibitors and traditional DNA-damaging cancer therapeutics. Consistent with chemical RPA exhaustion, we demonstrate that the effects of RPAi on replication fork dynamics are similar to other known DDR inhibitors. An optimized formulation of RPAi NERx 329 was developed that resulted in single-agent anticancer activity in two non-small cell lung cancer models. These data demonstrate a unique mechanism of action of RPAis eliciting a state of chemical RPA exhaustion and suggest they will provide an effective therapeutic option for difficult-to-treat lung cancers.

Immunotherapy in Lung Cancer: Current Landscape and Future Directions.

Over the past decade, lung cancer treatment has undergone a major paradigm shift. A greater understanding of lung cancer biology has led to the development of many effective targeted therapies as well as of immunotherapy. Immune checkpoint inhibitors (ICIs) have shown tremendous benefit in the treatment of non-small cell lung cancer (NSCLC) and are now being used as first-line therapies in metastatic disease, consolidation therapy following chemoradiation in unresectable locally advanced disease, and adjuvant therapy following surgical resection and chemotherapy in resectable disease. Despite these benefits, predicting who will respond to ICIs has proven to be difficult and there remains a need to discover new predictive immunotherapy biomarkers. Furthermore, resistance to ICIs in lung cancer is frequent either because of a lack of response or disease progression after an initial response. The utility of ICIs in the treatment of small cell lung cancer (SCLC) remains limited to first-line treatment of extensive stage disease in combination with chemotherapy with modest impact on overall survival. It is thus important to explore and exploit additional targets to reap the full benefits of immunotherapy in the treatment of lung cancer. Here, we will summarize the current state of immunotherapy in lung cancer, discuss novel targets, and explore the intersection between DNA repair defects and immunotherapy.

Role of surgery following neoadjuvant chemoradiation in patients with lymph node positive locally advanced esophageal adenocarcinoma: a national cancer database analysis.

BACKGROUND: Concurrent chemoradiation (CRT) followed by surgery is a standard of care for locally advanced esophageal adenocarcinoma. It remains unclear if surgery following CRT offers any meaningful survival benefit compared to CRT alone in patients with clinical N3 disease who are at the highest risk of developing distant disease relapse. METHODS: We conducted analysis of the National Cancer Database (NCDB) to compare overall survival (OS) of patients with locally advanced esophageal adenocarcinoma (cTanyN1-3M0 based on AJCC 7th staging system) who underwent CRT with or without surgery and analyzed outcomes based on the cN stage. RESULTS: 7,520 patients were included in the analysis-74.7% had cN1 disease, 21.1% had cN2 disease, and 4.3% had cN3 disease. The median OS advantage offered by CRT followed by surgery was 22, 15.8, and 9.6 months compared to CRT alone in cN1, cN2, and cN3 patients, respectively. The 5-year OS estimates in the surgical group were 36.9%, 31.6% and 15.9% in cN1, cN2 and cN3 groups, respectively. CONCLUSIONS: Surgery following CRT in patients with locally advanced esophageal adenocarcinoma leads to improvement in OS, with the largest benefit noted in patients with cN1 and cN2 disease. Surgery following CRT also confers meaningful long-term survival advantage for a subset of cN3 patients.

A Phase II Trial of Adjuvant Durvalumab Following Trimodality Therapy for Locally Advanced Esophageal and Gastroesophageal Junction Adenocarcinoma: A Big Ten Cancer Research Consortium Study.

BACKGROUND: Most patients with resectable locally advanced esophageal and gastroesophageal junction (GEJ) adenocarcinoma (AC) receive concurrent chemoradiation (CRT) followed by esophagectomy. The majority of patients do not achieve pathologic complete response (pCR) with neoadjuvant CRT, and the relapse rate is high among these patients. METHODS: We conducted a phase II study (ClinicalTrials.gov Identifier: NCT02639065) evaluating the efficacy and safety of PD-L1 inhibitor durvalumab in patients with locally advanced esophageal and GEJ AC who have undergone neoadjuvant CRT followed by R0 resection with evidence of persistent residual disease in the surgical specimen. Patients received durvalumab 1500 mg IV every 4 weeks for up to 1 year. The primary endpoint was 1-year relapse free survival (RFS). Secondary endpoint was safety and tolerability of durvalumab following trimodality therapy. Exploratory endpoints included correlation of RFS with PD-L1 expression, HER-2 expression, and tumor immune cell population. RESULTS: Thirty-seven patients were enrolled. The majority (64.9%) had pathologically positive lymph nodes. The most common treatment related adverse events were fatigue (27%), diarrhea (18.9%), arthralgia (16.2%), nausea (16.2%), pruritus (16.2%), cough (10.8%), and increase in AST/ALT/bilirubin (10.8%). Three (8.1%) patients developed grade 3 immune mediated adverse events. One-year RFS was 73% (95% CI, 56-84%) with median RFS of 21 months (95% CI, 14-40.4 months). Patients with GEJ AC had a trend toward superior 1-year RFS compared to those with esophageal AC (83% vs. 63%, p = 0.1534). There was a numerical trend toward superior 1-year RFS among patients with PD-L1 positive disease compared to those with PD-L1 negative disease, using CPS of ≥10 (100% vs. 66.7%, p = 0.1551) and ≥1 (84.2% vs. 61.1%, p = 0.1510) cutoffs. A higher relative proportion of M2 macrophages and CD4 memory activated T cells was associated with improved RFS (HR = 0.16; 95% CI, 0.05-0.59; p = 0.0053; and HR = 0.37; 95% CI, 0.15-0.93, p = 0.0351, respectively). CONCLUSIONS: Adjuvant durvalumab in patients with residual disease in the surgical specimen following trimodality therapy for locally advanced esophageal and GEJ AC led to clinically meaningful improvement in 1-year RFS compared to historical control rate. Higher PD-L1 expression may have a correlation with the efficacy of durvalumab in this setting. Higher proportion of M2 macrophages and CD4 memory activated T cells was associated with superior RFS.

Impact of smoke-free ordinance strength on smoking prevalence and lung cancer incidence.

BACKGROUND: Smoke-free ordinances (SFO) have been shown to be effective public health interventions, but there is limited data on the impact SFO on lung cancer outcomes. We explored the effect of county-level SFO strength with smoking prevalence and lung cancer incidence in Indiana. METHODS: We obtained county-level lung cancer incidence from the Indiana State Cancer Registry and county-level characteristics from the Indiana Tobacco Prevention and Cessation Commission's policy database between 1995 and 2016. Using generalized estimating equations, we performed multivariable analyses of smoking prevalence and age-adjusted lung cancer rates with respect to the strength of smoke-free ordinances at the county level over time. RESULTS: Of Indiana's 92 counties, 24 had a SFO by 2011. In 2012, Indiana enacted a state-wide SFO enforcing at least moderate level SFO protection. Mean age-adjusted lung cancer incidence per year was 76.8 per 100,000 population and mean smoking prevalence per year was 25% during the study period. Counties with comprehensive or moderate SFO had a smoking prevalence 1.2% (95% CI [-1.88, -0.52]) lower compared with counties with weak or no SFO. Counties that had comprehensive or moderate SFO also had an 8.4 (95% CI [-11.5, -5.3]) decrease in new lung cancer diagnosis per 100,000 population per year compared with counties that had weak or no SFO. CONCLUSION: Counties with stronger smoke-free air ordinances were associated with decreased smoking prevalence and fewer new lung cancer cases per year. Strengthening SFO is paramount to decreasing lung cancer incidence.

Where to Start and What to Do Next: The Sequencing of Treatments in Metastatic Esophagogastric Cancer.

Esophagogastric cancer is associated with rising incidence and high mortality. Nearly 40% of patients have metastatic disease at the time of diagnosis with poor 5-year overall survival. The treatment of squamous cell carcinoma of the esophagus and gastroesophageal adenocarcinoma has started to bifurcate in recent years, owing to the evolving understanding of the biologic and genomic characteristics of these tumors. Incorporation of HER2-directed therapy in the form of monoclonal antibody and antibody-drug conjugate is now standard of care for patients with HER2-positive disease. The addition of immune checkpoint inhibitors to the therapeutic landscape of metastatic esophagogastric cancer is associated with modest improvement in overall survival, and definition of predictive biomarkers of response to checkpoint inhibition remains imprecise. A number of therapeutic targets including FGFR2b, Claudin 18.2, DKK-1, and DNA repair defects are being explored in clinical trials. Similarly, combination immunotherapy and novel HER2-targeting agents, such as bispecific antibody and small-molecule inhibitors, are at various stages of clinical development. Despite the progress made in the field of targeted therapies and checkpoint inhibition, chemotherapy remains an integral part of treatment of metastatic esophagogastric cancer but is associated with considerable toxicity. Clinical trials focusing on minimizing toxicity of currently available therapeutic agents, development of novel biomarker-driven treatment strategies, and overcoming resistance to immune checkpoint inhibition will define the future of this traditionally indelible disease.

Long-Term Overall Survival From KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin With or Without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC.

INTRODUCTION: In cohort G of KEYNOTE-021 (NCT02039674), first-line pembrolizumab plus pemetrexed-carboplatin significantly improved the objective response rate and progression-free survival versus chemotherapy alone with manageable toxicity in advanced nonsquamous NSCLC. We report the long-term outcomes from this study. METHODS: Patients with previously untreated advanced nonsquamous NSCLC without sensitizing EGFR or ALK alterations were randomly assigned 1:1 to receive open-label pemetrexed 500 mg/m2 plus carboplatin at area under the concentration-time curve of 5 mg/mL/min (four cycles) with or without pembrolizumab 200 mg (up to 2 years), with optional pemetrexed maintenance, each administered every 3 weeks. Eligible patients could crossover from the chemotherapy arm to pembrolizumab monotherapy after progression. Responses were assessed per the Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: After the median time of 49.4 months from randomization to data cutoff, objective response rate (58% versus 33%) and progression-free survival (median: 24.5 versus 9.9 mo; hazard ratio: 0.54; 95% confidence interval: 0.35‒0.83) remained improved with pembrolizumab combination (n = 60) versus chemotherapy (n = 63), regardless of programmed death ligand 1 status. Median overall survival was 34.5 versus 21.1 months (hazard ratio: 0.71; 95% confidence interval: 0.45‒1.12), despite a 70% crossover rate from chemotherapy alone to anti‒programmed death (ligand) 1 therapy. Among the 12 patients who completed 2 years of pembrolizumab, 92% were alive at data cutoff; the estimated 3-year duration of response rate was 100%. Grade 3 to 5 treatment-related adverse events occurred in 39% of patients receiving pembrolizumab combination and 31% receiving chemotherapy. CONCLUSIONS: First-line pembrolizumab plus pemetrexed-carboplatin continued to show improved response and survival versus chemotherapy alone in advanced nonsquamous NSCLC, with durable clinical benefit in patients who completed 2 years of therapy. No new safety signals were observed with longer follow-up.

Histone Deacetylase Inhibition in Non-small Cell Lung Cancer: Hype or Hope?

Epigenetic modulation, including acetylation, methylation, phosphorylation, and ubiquitination, plays a pivotal role in regulation of gene expression. Histone acetylation-a balance between the activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs)-is one of the key epigenetic events. Our understanding of the role of HDACs in cancer is evolving. A number of HDAC isoenzymes are overexpressed in a variety of malignancies. Aberrant histone acetylation is associated with dysregulation of tumor suppressor genes leading to development of several solid tumors and hematologic malignancies. Pre-clinical studies have demonstrated that HDAC-1 gene expression is associated with lung cancer progression. Histone hypoacetylation is associated with more aggressive phenotype in adenocarcinoma of the lung. HDAC inhibitors (HDACi) have pleiotropic cellular effects and induce the expression of pro-apoptotic genes/proteins, cause cellular differentiation and/or cell cycle arrest, inhibit angiogenesis, and inhibit transition to a mesenchymal phenotype. Consequently, treatment with HDACi has shown anti-proliferative activity in non-small cell lung cancer (NSCLC) cell lines. Despite promising results in pre-clinical studies, HDACi have shown only modest single agent activity in lung cancer clinical trials. HDAC activation has been implicated as one of the mechanisms causing resistance to chemotherapy, molecularly targeted therapy, and immune checkpoint inhibition. Therefore, there is a growing interest in combining HDACi with these agents to enhance their efficacy or reverse resistance. In this paper, we review the available preclinical and clinical evidence for the use of HDACi in NSCLC. We also review the challenges precluding widespread clinical utility of HDACi as a cancer therapy and future directions.

A phase 2 trial of consolidation pembrolizumab following concurrent chemoradiation for patients with unresectable stage III non-small cell lung cancer: Hoosier Cancer Research Network LUN 14-179.

BACKGROUND: Five-year overall survival (OS) for patients with unresectable stage III non-small cell lung cancer (NSCLC) is poor. Until recently, a standard of care was concurrent chemoradiation alone. Patients with metastatic NSCLC treated with anti-programmed death 1 antibodies have demonstrated improved OS. This trial evaluated pembrolizumab as consolidation therapy after concurrent chemoradiation in patients with unresectable stage III disease. METHODS: Patients with unresectable stage III NSCLC received concurrent chemoradiation with cisplatin and etoposide, cisplatin and pemetrexed, or carboplatin and paclitaxel and 59.4 to 66.6 Gy of radiation. Patients with nonprogression of disease were enrolled and received pembrolizumab (200 mg intravenously every 3 weeks for up to 12 months). The primary endpoint was the time to metastatic disease or death (TMDD). Secondary endpoints included progression-free survival (PFS) and OS. RESULTS: The median follow-up for 93 patients (92 for efficacy) was 32.2 months (range, 1.2-46.6 months). The median TMDD was 30.7 months (95% confidence interval [CI], 18.7 months to not reached), which was significantly longer than the historical control of 12 months (P < .0001). The median PFS was 18.7 months (95% CI, 12.4-33.8 months), and the median OS was 35.8 months (95% CI, 24.2 months to not reached). The 1-, 2-, and 3-year OS estimates were 81.2%, 62.0%, and 48.5%, respectively. Forty patients (43.5%) completed 12 months of treatment (median number of cycles, 13.5). Symptomatic pneumonitis (grade 2 or higher) was noted in 16 patients (17.2%); these cases included 4 grade 3 events (4.3%), 1 grade 4 event (1.1%), and 1 grade 5 event (1.1%). CONCLUSIONS: Consolidation pembrolizumab after concurrent chemoradiation improves TMDD, PFS, and OS in comparison with historical controls of chemoradiation alone. Rates of grade 3 to 5 pneumonitis were similar to those reported with chemoradiation alone.

An Ivor Lewis Esophagectomy Designed to Minimize Anastomotic Complications and Optimize Conduit Function.

We describe a novel esophagogastric anastomotic technique ("side-to-side: staple line-on-staple line", STS) for intrathoracic anastomoses designed to create a large diameter anastomosis while simultaneously maintaining conduit blood supply. This technique aims to minimize the incidence of anastomotic leaks and strictures, which is a frequent source of morbidity and occasional mortality after esophagectomy. We analyze the results of this STS technique on 368 patients and compared outcomes to 112 patients who underwent esophagogastric anastomoses using an end-to-end stapler (EEA) over an 8-year time interval at our institution. The STS technique involves aligning the remaining intrathoracic esophagus over the tip of the lesser curve staple line of a stomach tube, created as a replacement conduit for the esophagus. A linear stapling device cuts through and restaples the conduit staple line to the lateral wall of the esophagus in a side-to-side fashion. The open common lumen is then closed in two layers of sutures. There was a total of 12 (3.8%) anastomotic leaks in patients who underwent STS esophagogastric anastomosis. Two of eight patients (25%) had anastomotic leaks after esophagectomy for end-stage achalasia as compared to a 2.8% leak rate (10/336) after esophagectomy for other conditions. Eighteen (5.2%) patients required a median of 2 dilatations for anastomotic stricture after STS anastomosis. Supplemental jejunostomy feedings were required in only 11.1% of patients undergoing STS anastomoses following hospital discharge. In contrast, patients undergoing EEA anastomoses demonstrated anastomotic leak and stricture rates of 16.1% and 14.3% respectively (p<0.01). Time analysis of postoperative contrast studies following the STS technique typically demonstrated a straight/uniform diameter conduit with essentially complete contrast emptying into the small bowel within 3 minutes in 88.4% of patients. The incidence of esophagogastric anastomotic leaks and strictures were extremely low using this novel anastomotic technique. Additionally we believe that based on time and qualitative analyses of postoperative contrast studies, this technique appears to optimize postoperative upper gastrointestinal tract function; however, further comparative studies are needed.

Pembrolizumab After Two or More Lines of Previous Therapy in Patients With Recurrent or Metastatic SCLC: Results From the KEYNOTE-028 and KEYNOTE-158 Studies.

INTRODUCTION: Pembrolizumab has shown clinical benefit in patients with previously treated recurrent or metastatic SCLC in the phase 1b multicohort study KEYNOTE-028 (NCT02054806) and the phase 2 multicohort study KEYNOTE-158 (NCT02628067). We present a pooled analysis of patients from KEYNOTE-028 and KEYNOTE-158 who had received two or more lines of previous therapy for SCLC. METHODS: Eligible patients were aged 18 years and above, had histologically or cytologically confirmed incurable recurrent or metastatic SCLC, had an Eastern Cooperative Oncology Group performance status of 1 and below, and had received two or more lines of previous therapy. Patients in KEYNOTE-028 were required to have a programmed death ligand 1 (PD-L1)-positive tumor. Patients received pembrolizumab (10 mg/kg every 2 weeks in KEYNOTE-028 or 200 mg every 3 weeks in KEYNOTE-158) for up to 2 years. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1, which is presented here per independent review. RESULTS: Eighty-three patients who had received two or more lines of previous therapy (KEYNOTE-028, n = 19; KEYNOTE-158, n = 64) were included. Median follow-up duration was 7.7 (range, 0.5-48.7) months. Objective response rate was 19.3% (95% confidence interval: 11.4-29.4); two patients had complete response (one with a PD-L1-positive tumor), and 14 patients had partial response (13 with PD-L1-positive tumors). The median duration of response was not reached (range, 4.1‒35.8+ mo; plus sign indicates ongoing response); 61% of responders had responses lasting 18 months or longer. Fifty-one patients (61.4%) experienced any-grade treatment-related adverse events; eight patients (9.6%) had grade 3 or higher events. CONCLUSIONS: Pembrolizumab exhibited durable antitumor activity in a subset of patients with recurrent or metastatic SCLC who had undergone two or more previous lines of therapy, regardless of PD-L1 expression. Pembrolizumab was well tolerated.

Acceptance and Commitment Therapy for Symptom Interference in Advanced Lung Cancer and Caregiver Distress: A Pilot Randomized Trial.

CONTEXT: Advanced lung cancer patients typically have a poor prognosis and many symptoms that interfere with functioning, contributing to high rates of emotional distress in both patients and family caregivers. There remains a need for evidence-based interventions to improve functional outcomes and distress in this population. OBJECTIVES: This pilot trial examined the feasibility and preliminary efficacy of telephone-based Acceptance and Commitment Therapy (ACT) for symptomatic, advanced lung cancer patients and their distressed family caregivers. Primary outcomes were patient symptom interference with functioning and patient and caregiver distress. METHODS: Symptomatic, advanced lung cancer patients and distressed caregivers (n = 50 dyads) were randomly assigned to six sessions of ACT or an education/support condition. Patients completed measures of symptom interference and measures assessing the severity of fatigue, pain, sleep disturbance, and breathlessness. Patients and caregivers completed measures of distress and illness acceptance and struggle. RESULTS: The eligibility screening rate (51%) and retention rate (76% at six weeks postintervention) demonstrated feasibility. No group differences were found with respect to patient and caregiver outcomes. Both groups showed a small, significant decrease in struggle with the illness over the study period, but did not show meaningful change in other outcomes. CONCLUSION: Findings suggest that telephone-based ACT is feasible for many advanced lung cancer patients and caregivers, but may not substantially reduce symptom interference and distress. Low baseline levels of certain symptoms may have contributed to null findings. Next steps include applying ACT to specific, clinically meaningful symptom interference and varying intervention dose and modality.

A phase 2, open-label study of brentuximab vedotin in patients with CD30-expressing solid tumors.

Purpose Brentuximab vedotin (BV) is an anti-CD30 antibody-drug conjugate used in the treatment of several types of lymphomas. Expression of the target antigen has also been reported on a variety of malignant tumors of nonlymphoid origin. This phase 2, open-label study evaluated the safety and antitumor activity of BV in patients with CD30-expressing nonlymphomatous malignancies. Methods Patients were dosed with 1.8 or 2.4 mg/kg BV once every three weeks. Antitumor activity was assessed at Cycles 2, 4, and every 4 cycles thereafter. Patients with stable disease or better were eligible to continue treatment until disease progression, unacceptable toxicity, or study closure. Results Of the 2693 patients screened, 3.8% had solid tumors with CD30 expression and 63 eligible patients with solid tumors enrolled in this study. The most common CD30 positive solid tumors were testicular cancer and mesothelioma. Both subtypes had more than one patient with an objective response. The median duration of BV exposure was 6.1 weeks. The disease control rate, defined as achieving stable disease or better at any point during the study, was 55%. The objective response rate was 11%, with a median duration of response of 2.92 months. The most common adverse events reported were fatigue (57%), nausea (33%), and decreased appetite (32%). Conclusion The safety profile of BV in patients with solid tumors was similar to the known safety profile of BV. In solid tumors, BV had modest activity as a single agent, which was similar to other second-line treatments already available to patients.