Safety, tolerability, and clinical activity of selinexor in combination with pembrolizumab in treatment of metastatic non-small cell lung cancer.

BACKGROUND: In lung cancer, overexpression of nuclear export proteins can result in inactivation of critical tumor suppressor proteins and cell-cycle regulators. Selective suppression of nuclear export proteins has immunomodulatory activities. Here, clinical safety and early efficacy data are presented on the combination of pembrolizumab and an oral selective nuclear export inhibitor, selinexor, for the treatment of metastatic non-small cell lung cancer (mNSCLC). METHODS: The primary objective of this prospective investigator-initiated study was to determine the safety and tolerability of selinexor in combination with pembrolizumab in patients with mNSCLC. Secondary objectives included determination of objective tumor response rate, disease control rate, and progression-free survival duration. RESULTS: A total of 17 patients were included in the final analysis. Fifteen (88%) received more than two lines of prior systemic therapy and 10 (59%) had prior exposure to anti-PD-1/programmed death-ligand 1 (PD-L1) therapy. The median age was 67.5 years. Ten patients had grade ≥3 adverse events related to selinexor treatment. Responses to treatment occurred in patients who did and did not undergo previous anti-PD-1/PD-L1 therapy and in patients with activating driver mutations. The median overall survival and progression-free survival were 11.4 months (95% CI, 3.4-19.8 months) and 3.0 months (95% CI, 1.7-5.7 months), respectively. The overall response rate was 18% and the 6-month disease control rate was 24%. CONCLUSIONS: Selinexor in combination with pembrolizumab demonstrated promising antitumor activity in patients with mNSCLC, including those who had previously received anti-PD-1/PD-L1 therapy. The therapy-related toxic effects were consistent with the prior safety data for both drugs, and no overlapping toxic effects were observed. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02419495. PLAIN LANGUAGE SUMMARY: New strategies to prevent or reverse resistance to immune checkpoint inhibitors are under investigation. Selective inhibitors of nuclear export proteins, such as selinexor, can induce restoration of tumor-suppressing pathways and induce potent immunomodulatory activities. This article contains the clinical safety and early efficacy data on the combination of pembrolizumab and selinexor in treatment of metastatic non-small cell lung cancer.

Lung Cancer Screening in Head and Neck Cancer Patients: An Untapped Opportunity.

BACKGROUND: Despite evidence demonstrating that lung cancer screening (LCS) decreases mortality, widespread implementation is lagging. Efforts to identify and recruit patients for LCS are in need. Candidacy for LCS is based on identifiable risk factors, many of which overlap with those of head and neck malignancies. Thus, we aimed to evaluate the prevalence of candidacy for LCS in the head and neck cancer patient population. METHODS: We performed a review of anonymous surveys collected from patients who presented to a head and neck cancer clinic. Variables collected from these surveys included age, biologic sex, smoking history, and head and neck cancer history. Patients' candidacy for screening was determined, and descriptive analyses were performed. RESULTS: A total of 321 patient surveys were reviewed. Mean age was 63.7 years, and 195 (60.7%) were men. In this sample, 19 (5.91%) were current smokers, and 112 (34.9%) were former smokers, having quit an average of 19.4 years prior to completing the survey. Average pack-years was 29.3. Of the 321 patients surveyed, 60 (18.7%) would qualify for LCS using current guidelines. However, among those 60 patients who qualified for LCS, only 15 (25%) patients had been offered screening and only 14 (23.3%) had been screened. CONCLUSIONS: We have importantly demonstrated both a substantial prevalence of candidacy for LCS in the head and neck cancer population as well as disappointingly low levels of screening utilization in this group of patients. We have identified this setting as a key patient population that ought to be targeted for information about and access to LCS.

Real-World Efficacy and Safety of Amivantamab for EGFR-Mutant NSCLC.

INTRODUCTION: Amivantamab-vmjw (amivantamab) is a bispecific EGFR/MET antibody approved for patients with advanced NSCLC with EGFR exon 20 insertion mutations, after prior therapy. Nevertheless, the benefits and safety of amivantamab in other EGFR-mutant lung cancer, with or without osimertinib, and with concurrent radiation therapy, are less known. METHODS: We queried the MD Anderson Lung Cancer GEMINI, Fred Hutchinson Cancer Research Center, University of California Davis Comprehensive Cancer Center, and Stanford Cancer Center's database for patients with EGFR-mutant NSCLC treated with amivantamab, not on a clinical trial. The data analyzed included initial response, duration of treatment, and concomitant radiation safety in overall population and prespecified subgroups. RESULTS: A total of 61 patients received amivantamab. Median age was 65 (31-81) years old; 72.1% were female; and 77% were patients with never smoking history. Median number of prior lines of therapies was four. On the basis of tumor's EGFR mutation, 39 patients were in the classical mutation cohort, 15 patients in the exon 20 cohort, and seven patients in the atypical cohort. There were 37 patients (58.7%) who received amivantamab concomitantly with osimertinib and 25 patients (39.1%) who received concomitant radiation. Furthermore, 54 patients were assessable for response in the overall population; 19 patients (45.2%) had clinical response and disease control rate (DCR) was 64.3%. In the classical mutation cohort of the 33 assessable patients, 12 (36.4%) had clinical response and DCR was 48.5%. In the atypical mutation cohort, six of the seven patients (85.7%) had clinical response and DCR was 100%. Of the 13 assessable patients in the exon 20 cohort, five patients (35.7%) had clinical response and DCR was 64.3%. Adverse events reported with amivantamab use were similar as previously described in product labeling. No additional toxicities were noted when amivantamab was given with radiation with or without osimertinib. CONCLUSIONS: Our real-world multicenter analysis revealed that amivantamab is a potentially effective treatment option for patients with EGFR mutations outside of exon 20 insertion mutations. The combination of osimertinib with amivantamab is safe and feasible. Radiation therapy also seems safe when administered sequentially or concurrently with amivantamab.

Identifying MAGE-A4-positive tumors for TCR T cell therapies in HLA-A∗02-eligible patients.

T cell receptor (TCR) T cell therapies target tumor antigens in a human leukocyte antigen (HLA)-restricted manner. Biomarker-defined therapies require validation of assays suitable for determination of patient eligibility. For clinical trials evaluating TCR T cell therapies targeting melanoma-associated antigen A4 (MAGE-A4), screening in studies NCT02636855 and NCT04044768 assesses patient eligibility based on: (1) high-resolution HLA typing and (2) tumor MAGE-A4 testing via an immunohistochemical assay in HLA-eligible patients. The HLA/MAGE-A4 assays validation, biomarker data, and their relationship to covariates (demographics, cancer type, histopathology, tissue location) are reported here. HLA-A∗02 eligibility was 44.8% (2,959/6,606) in patients from 43 sites across North America and Europe. While HLA-A∗02:01 was the most frequent HLA-A∗02 allele, others (A∗02:02, A∗02:03, A∗02:06) considerably increased HLA eligibility in Hispanic, Black, and Asian populations. Overall, MAGE-A4 prevalence based on clinical trial enrollment was 26% (447/1,750) across 10 solid tumor types, and was highest in synovial sarcoma (70%) and lowest in gastric cancer (9%). The covariates were generally not associated with MAGE-A4 expression, except for patient age in ovarian cancer and histology in non-small cell lung cancer. This report shows the eligibility rate from biomarker screening for TCR T cell therapies and provides epidemiological data for future clinical development of MAGE-A4-targeted therapies.

Severe Radiation-Induced Lymphopenia Attenuates the Benefit of Durvalumab After Concurrent Chemoradiotherapy for NSCLC.

Introduction: Durvalumab after concurrent chemoradiation (CCRT) for NSCLC improves survival, but only in a subset of patients. We investigated the effect of severe radiation-induced lymphopenia (sRIL) on survival in these patients. Methods: Outcomes after CCRT (2010-2019) or CCRT followed by durvalumab (2018-2019) were reviewed. RIL was defined by absolute lymphocyte count (ALC) nadir in samples collected at end of CCRT; sRIL was defined as nadir ALC less than 0.23 × 109/L (the lowest tertile). Progression-free survival (PFS) and overall survival (OS) were calculated by the Kaplan-Meier method. Cox proportional hazard modeling evaluated associations between clinical variables and survival. Results: Of 309 patients, 192 (62%) received CCRT only and 117 (38%) CCRT plus durvalumab. Multivariable logistic regression analysis indicated that sRIL was associated with planning target volume (OR = 1.002, p = 0.001), stage IIIB disease (OR = 2.77, p = 0.04), and baseline ALC (OR = 0.36, p < 0.01). Durvalumab extended median PFS (23.3 versus 14.1 mo, p = 0.003) and OS (not reached versus 30.8 mo, p < 0.01). sRIL predicted poorer PFS and OS in both treatment groups. Among patients with sRIL, durvalumab did not improve survival (median = 24.6 mo versus 18.1 mo CCRT only, p = 0.079). On multivariable analyses, sRIL (OR = 1.81, p < 0.01) independently predicted poor survival. Conclusions: Severe RIL compromises survival benefits from durvalumab after CCRT for NSCLC. Measures to mitigate RIL after CCRT may be warranted to enhance the benefit of consolidation durvalumab.

Distinct molecular and immune hallmarks of inflammatory arthritis induced by immune checkpoint inhibitors for cancer therapy.

Immune checkpoint inhibitors are associated with immune-related adverse events (irAEs), including arthritis (arthritis-irAE). Management of arthritis-irAE is challenging because immunomodulatory therapy for arthritis should not impede antitumor immunity. Understanding of the mechanisms of arthritis-irAE is critical to overcome this challenge, but the pathophysiology remains unknown. Here, we comprehensively analyze peripheral blood and/or synovial fluid samples from 20 patients with arthritis-irAE, and unmask a prominent Th1-CD8+ T cell axis in both blood and inflamed joints. CX3CR1hi CD8+ T cells in blood and CXCR3hi CD8+ T cells in synovial fluid, the most clonally expanded T cells, significantly share TCR repertoires. The migration of blood CX3CR1hi CD8+ T cells into joints is possibly mediated by CXCL9/10/11/16 expressed by myeloid cells. Furthermore, arthritis after combined CTLA-4 and PD-1 inhibitor therapy preferentially has enhanced Th17 and transient Th1/Th17 cell signatures. Our data provide insights into the mechanisms, predictive biomarkers, and therapeutic targets for arthritis-irAE.

Dose-modified gemcitabine plus nab-paclitaxel front-line in advanced pancreatic ductal adenocarcinoma with baseline hyperbilirubinemia.

BACKGROUND: Von Hoff et al. demonstrated survival improvement with gemcitabine (GEM) + nab-paclitaxel (NabP) for metastatic pancreatic ductal adenocarcinoma (PDAC) compared to GEM alone. GEM + NabP resulted in a median overall survival (OS) and progression-free survival (PFS) of 8.5 and 5.5 months, respectively. Patients with baseline hyperbilirubinemia were excluded. Primary objective was OS. Secondary objectives included time on treatment (TOT), disease control rate, dosing practices, delays/admissions, and adverse effects. METHODS: Patients with borderline resectable, locally advanced, or metastatic PDAC who initiated front-line GEM-NabP during July 01, 2013-July 01, 2017 were reviewed. Patients with a baseline total bilirubin ≥2 mg/dL were included. RESULTS: Twelve patients total were included. Median age was 71 years old. Median baseline total bilirubin was 2.4 mg/dL (range, 2.1-5.2 mg/dL). 58% had metastatic disease. Median doses were NabP 100 mg/m2 + GEM 600 mg/m2 IV with a fixed-dose rate infusion (10 mg/m2/min). GEM-NabP was given biweekly or 3 weeks on 1 week off. Median OS, TOT, and disease control rate were 13.9, 5.2 months, and 58%, respectively. Fifty percent of patients required a dose delay. Metastatic patients only (n=7) had median OS and TOT of 6.9 and 2.1 months, respectively. No admissions related to toxicity were found. CONCLUSIONS: Our analysis revealed safety with NabP (median dose =100 mg/m2) + GEM (median dose =600 mg/m2 at fixed-dose rate) given predominately biweekly in patients with a baseline elevated total bilirubin (≥2 mg/dL).

Lung Cancer Patient Perceptions of the Value of an Outreach Thoracic Surgical Clinic.

BACKGROUND: Although specialty outreach clinics have been associated with improved outcomes and access to care, their role for patients with non-small cell lung cancer (NSCLC) has not been described. We sought to characterize perceptions of the utility of a specialty outreach clinic among patients with suspected NSCLC. METHODS: Surveys were administered to patients who were suspected to have NSCLC and were seen at an outreach thoracic surgery clinic (2016 to 2017). The clinic was located approximately 20 miles from the academic cancer center. RESULTS: Sixty-nine patients completed surveys. The median distance traveled to the clinic was 43.5 miles (interquartile range: 5.0 to 111.3 miles). Among patients traveling 50 miles or more, the overwhelming majority (27 of 32 patients, 84.4%) cited physician expertise as the primary benefit of treatment at the clinic. Moreover, compared with patients living in closer proximity, they were more willing to travel 100 miles or more to have surgery (71.0% versus 26.7%, p = 0.001) or to consult with a surgeon (71.0% versus 25.8%, p < 0.001). Patients for whom it was very important to receive care close to home (33 of 68 patients, 48.5%) were less willing to travel 100 miles or more for consultation (surgeon: 33.3% versus 65.6%, p = 0.011; medical oncologist: 33.3% versus 65.6%, p = 0.011; radiation oncologist: 33.3% versus 64.5%, p = 0.015) and for treatment (surgery: 33.3% versus 65.6%, p = 0.011; chemotherapy: 36.7% versus 60.7%, p = 0.067; radiotherapy: 33.3% versus 64.3%, p = 0.018). CONCLUSIONS: Many patients value receiving oncologic care close to home and are sensitive to distance required to travel for care. Thoracic surgical outreach clinics may provide a benefit for patients with lung cancer in the settings of initial consultation, preoperative care, and postoperative care.

Evaluation and Improvement of Bottlenecking in a Multidisciplinary Oncology Clinic: An Electronic Medical Record Intervention.

PURPOSE: Clinic members reported slower patient flow in the mornings at a multidisciplinary oncology clinic. This study identified the causes of clinic bottlenecking via analysis of patient schedules and transit times, then corrected discrepancies through a quality improvement program. METHODS: Transit times were measured using tracking cards handed out at check-in, marked by each clinic member throughout the encounter, and collected upon discharge. Data were analyzed for differences between morning and afternoon patients, and a Pareto chart was formulated to assess for discrepancies in distribution. Repeat plan-do-study-act (PDSA) cycles were conducted, implementing two changes to redistribute appointments to optimize clinic workflow. RESULTS:  A total of 2951 patient appointments were analyzed: 589 at baseline, 277 following an initial intervention, and 2085 following a subsequent intervention. Analysis of patient transit times revealed no significant differences between morning and afternoon patient groups (t-test, p=.13-.99), with no transit interval markedly longer than others (t-test, p=.32-.83). However, upon evaluation of appointment times, a maldistribution was noted with 57% of patients concentrated between 9:00 am to 12:00 pm, accounting for the perception of bottlenecking. An initial intervention offering patients afternoon appointments on a voluntary basis was insufficient for rebalancing distribution (chi-square test, p=.299); however, an electronic medical record (EMR) intervention with rigid appointment templates was successful (chi-square test, p<.001). CONCLUSION: An imbalance of appointment times contributed to the perception of slow clinic throughput. This study emphasizes the importance of systematically investigating even consensus observations for validity prior to costly interventions. Furthermore, these results support the utility of information technology in optimizing clinic workflow.

Cervical and Breast Cancer Screening After CARES: A Community Program for Immigrant and Marginalized Women.

INTRODUCTION: Marginalized populations such as immigrants and refugees are less likely to receive cancer screening. Cancer Awareness: Ready for Education and Screening (CARES), a multifaceted community-based program in Toronto, Canada, aimed to improve breast and cervical screening among marginalized women. This matched cohort study assessed the impact of CARES on cervical and mammography screening among under-screened/never screened (UNS) attendees. METHODS: Provincial administrative data collected from 1998 to 2014 and provided in 2015 were used to match CARES participants who were age eligible for screening to three controls matched for age, geography, and pre-education screening status. Dates of post-education Pap and mammography screening up to June 30, 2014 were determined. Analysis in 2016 compared screening uptake and time to screening for UNS participants and controls. RESULTS: From May 15, 2012 to October 31, 2013, a total of 1,993 women attended 145 educational sessions provided in 20 languages. Thirty-five percent (118/331) and 48% (99/206) of CARES participants who were age eligible for Pap and mammography, respectively, were UNS on the education date. Subsequently, 26% and 36% had Pap and mammography, respectively, versus 9% and 14% of UNS controls. ORs for screening within 8 months of follow-up among UNS CARES participants versus their matched controls were 5.1 (95% CI=2.4, 10.9) for Pap and 4.2 (95%=CI 2.3, 7.8) for mammography. Hazard ratios for Pap and mammography were 3.6 (95% CI=2.1, 6.1) and 3.2 (95% CI=2.0, 5.3), respectively. CONCLUSIONS: CARES' multifaceted intervention was successful in increasing Pap and mammography screening in this multiethnic under-screened population.