Giving information strategically and transparently: A pilot trial of the Oncolo-GIST intervention to promote patients' prognostic understanding.

PURPOSE: Most patients with cancer lack the prognostic understanding necessary to make informed decisions. We tested the feasibility and acceptability of the Oncolo-GIST ("Giving Information Strategically and Transparently, GIST") intervention and explored its associations with patients' improved prognostic understanding. METHODS: The Oncolo-GIST intervention distills prognostic discussions into easy-to-understand talking points. Patients with metastatic cancers that progressed on ≥1 line of chemotherapy and not expected to survive 12 months (n = 31) were recruited from October 2020 through November 2022. We compared patients who discussed their progressive scans with an oncologist trained in the GIST technique or not (i.e., usual care). A primary outcome was prognostic understanding (e.g., patients reporting a life-expectancy of months) assessed within a week of the scan discussion visit. RESULTS: Oncologists (n = 4) appeared receptive to the Oncolo-GIST intervention and scored nearly perfectly on post-training tests of material mastery after a < 2-h tutorial. Post-scan discussion visit, 100% of patients who met with an Oncolo-GIST-trained clinician understood that their cancer was considered incurable (a 31% improvement from pre-visit) compared with 91% of patients meeting with usual care oncologists (an 18% improvement); 33% of patients who met with an Oncolo-GIST-trained oncologist understood that they likely had months, not years, compared to 18% in the usual care group. No statistically significant differences emerged for these changes, nor for therapeutic alliance, anxiety, or depression scores between groups. CONCLUSION: Oncolo-GIST appears to be an easily learned approach to improve prognostic understanding that neither undermines therapeutic alliances nor increases patients' anxiety or depressive symptoms. Efficacy testing in a larger trial is warranted.

Lung Cancer Stage Shift as a Result of COVID-19 Lockdowns in New York City, a Brief Report.

INTRODUCTION: The COVID-19 pandemic reached New York City in early March 2020 resulting in an 11-week lockdown period to mitigate further spread. It has been well documented that cancer care was drastically affected as a result. Given New York City's early involvement, we attempted to identify any stage shift that may have occurred in the diagnoses of non-small cell lung cancer (NSCLC) at our institution as a result of these lockdowns. PATIENTS AND METHODS: We conducted a retrospective review of a prospective database of lung cancer patients at our institution from July 1, 2019 until March 31, 2021. Patients were grouped by calendar year quarter in which they received care. Basic demographics and clinical staging were compared across quarters. RESULTS: Five hundred and fifty four patients were identified that underwent treatment during the time period of interest. During the lockdown period, there was a 50% reduction in the mean number of patients seen (15 ± 3 vs. 28 ± 7, P = .004). In the quarter following easing of restrictions, there was a significant trend towards earlier stage (cStage I/II) disease. In comparison to quarters preceding the pandemic lockdown, there was a significant increase in the proportion of patients with Stage IV disease in the quarters following phased reopening (P = .026). CONCLUSION: After a transient but significant increase in Stage I/II disease with easing of restrictions there was a significant increase in patients with Stage IV disease. Extended longitudinal studies must be conducted to determine whether COVID-19 lockdowns will lead to further increases in the proportion of patients with advanced NSCLC.

Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial.

BACKGROUND: Previous phase 2 trials of neoadjuvant anti-PD-1 or anti-PD-L1 monotherapy in patients with early-stage non-small-cell lung cancer have reported major pathological response rates in the range of 15-45%. Evidence suggests that stereotactic body radiotherapy might be a potent immunomodulator in advanced non-small-cell lung cancer (NSCLC). In this trial, we aimed to evaluate the use of stereotactic body radiotherapy in patients with early-stage NSCLC as an immunomodulator to enhance the anti-tumour immune response associated with the anti-PD-L1 antibody durvalumab. METHODS: We did a single-centre, open-label, randomised, controlled, phase 2 trial, comparing neoadjuvant durvalumab alone with neoadjuvant durvalumab plus stereotactic radiotherapy in patients with early-stage NSCLC, at NewYork-Presbyterian and Weill Cornell Medical Center (New York, NY, USA). We enrolled patients with potentially resectable early-stage NSCLC (clinical stages I-IIIA as per the 7th edition of the American Joint Committee on Cancer) who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients were randomly assigned (1:1) to either neoadjuvant durvalumab monotherapy or neoadjuvant durvalumab plus stereotactic body radiotherapy (8 Gy × 3 fractions), using permuted blocks with varied sizes and no stratification for clinical or molecular variables. Patients, treating physicians, and all study personnel were unmasked to treatment assignment after all patients were randomly assigned. All patients received two cycles of durvalumab 3 weeks apart at a dose of 1·12 g by intravenous infusion over 60 min. Those in the durvalumab plus radiotherapy group also received three consecutive daily fractions of 8 Gy stereotactic body radiotherapy delivered to the primary tumour immediately before the first cycle of durvalumab. Patients without systemic disease progression proceeded to surgical resection. The primary endpoint was major pathological response in the primary tumour. All analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrial.gov, NCT02904954, and is ongoing but closed to accrual. FINDINGS: Between Jan 25, 2017, and Sept 15, 2020, 96 patients were screened and 60 were enrolled and randomly assigned to either the durvalumab monotherapy group (n=30) or the durvalumab plus radiotherapy group (n=30). 26 (87%) of 30 patients in each group had their tumours surgically resected. Major pathological response was observed in two (6·7% [95% CI 0·8-22·1]) of 30 patients in the durvalumab monotherapy group and 16 (53·3% [34·3-71·7]) of 30 patients in the durvalumab plus radiotherapy group. The difference in the major pathological response rates between both groups was significant (crude odds ratio 16·0 [95% CI 3·2-79·6]; p<0·0001). In the 16 patients in the dual therapy group with a major pathological response, eight (50%) had a complete pathological response. The second cycle of durvalumab was withheld in three (10%) of 30 patients in the dual therapy group due to immune-related adverse events (grade 3 hepatitis, grade 2 pancreatitis, and grade 3 fatigue and thrombocytopaenia). Grade 3-4 adverse events occurred in five (17%) of 30 patients in the durvalumab monotherapy group and six (20%) of 30 patients in the durvalumab plus radiotherapy group. The most frequent grade 3-4 events were hyponatraemia (three [10%] patients in the durvalumab monotherapy group) and hyperlipasaemia (three [10%] patients in the durvalumab plus radiotherapy group). Two patients in each group had serious adverse events (pulmonary embolism [n=1] and stroke [n=1] in the durvalumab monotherapy group, and pancreatitis [n=1] and fatigue [n=1] in the durvalumab plus radiotherapy group). No treatment-related deaths or deaths within 30 days of surgery were reported. INTERPRETATION: Neoadjuvant durvalumab combined with stereotactic body radiotherapy is well tolerated, safe, and associated with a high major pathological response rate. This neoadjuvant strategy should be validated in a larger trial. FUNDING: AstraZeneca.

Hematology and oncology clinical care during the coronavirus disease 2019 pandemic.

New York City has been at the epicenter of the coronavirus disease 2019 (COVID-19) pandemic that has already infected over a million people and resulted in more than 70,000 deaths as of early May 2020 in the United States alone. This rapid and enormous influx of patients into the health care system has had profound effects on all aspects of health care, including the care of patients with cancer. In this report, the authors highlight the transformation they underwent within the Division of Hematology and Medical Oncology as they prepared for the COVID-19 crisis in New York City. Under stressful and uncertain conditions, some of the many changes they enacted within their division included developing a regular line of communication among division leaders to ensure the development and implementation of a restructuring strategy, completely reconfiguring the inpatient and outpatient units, rapidly developing the ability to perform telemedicine video visits, and creating new COVID-rule-out and COVID-positive clinics for their patients. These changes allowed them to manage the storm while minimizing the disruption of important continuity of care to their patients with cancer. The authors hope that their experiences will be helpful to other oncology practices about to experience their own individual COVID-19 crises.

Afatinib With Pembrolizumab for Treatment of Patients With Locally Advanced/Metastatic Squamous Cell Carcinoma of the Lung: The LUX-Lung IO/KEYNOTE 497 Study Protocol.

BACKGROUND: Afatinib is a selective, irreversible ErbB family blocker that has shown survival benefit in lung squamous-cell carcinoma (SCC) patients. Pembrolizumab, a humanized immunoglobulin G4 monoclonal antibody to the programmed cell death 1 (PD-1) receptor, has also shown survival benefit in lung SCC. Concurrent inhibition of the PD-1 and epidermal growth factor receptor (EGFR) pathways represents a rational approach to improve responses and delay the onset of treatment resistance in lung SCC. TRIAL DESIGN: This phase II, open-label, single-arm study (NCT03157089) is designed to assess the efficacy and safety of afatinib in combination with pembrolizumab in patients with stage IIIB/IV lung SCC that has progressed during/after first-line platinum-based chemotherapy. Eligible patients must have ≥1 target lesion (as per Response Evaluation Criteria in Solid Tumors version 1.1) and must have not received previous immune checkpoint inhibitor/EGFR-targeted therapy. The recommended phase II dose (RP2D) and safety profile will be determined during a safety run-in with oral afatinib (starting dose, 40 mg/d) with intravenous pembrolizumab (200 mg every 3 weeks). In the main study, all patients will receive afatinib at the RP2D with pembrolizumab until disease progression, unacceptable toxicity, or for up to 35 cycles. The primary end point is objective response (complete + partial response). Other end points include disease control, duration of objective response, progression-free survival, overall survival, tumor shrinkage, RP2D, and pharmacokinetics. Exploratory biomarker analysis will be performed. This study is being conducted in the United States, Spain, France, South Korea, and Turkey. Enrollment commenced in September 2017, with a target of 50 to 62 patients.

Therapy of Small Cell Lung Cancer (SCLC) with a Topoisomerase-I-inhibiting Antibody-Drug Conjugate (ADC) Targeting Trop-2, Sacituzumab Govitecan.

Purpose: We evaluated a Trop-2-targeting antibody conjugated with SN-38 in metastatic small cell lung cancer (mSCLC) patients.Experimental Design: Sacituzumab govitecan was studied in patients with pretreated (median, 2; range, 1-7) mSCLC who received either 8 or 10 mg/kg i.v. on days 1 and 8 of 21-day cycles. The primary endpoints were safety and objective response rate (ORR); duration of response, progression-free survival (PFS), and overall survival (OS) were secondary endpoints.Results: Sixty percent of patients showed tumor shrinkage from baseline CTs. On an intention-to-treat basis (N = 50), the ORR was 14% (17% for the 10-mg/kg group); the median response duration, 5.7 months; the clinical benefit rate (CBR ≥4 months), 34%; median PFS, 3.7 months; and median OS, 7.5 months. There was a suggested improvement in PR, CBR, and PFS with sacituzumab govitecan in second-line patients who were sensitive to first-line therapy, but no difference between first-line chemosensitive versus chemoresistant patients in the overall population. There was a statistically significant higher OS in those patients who received prior topotecan versus no topotecan therapy in a small subgroup. Grade ≥3 adverse events included neutropenia (34%), fatigue (13%), diarrhea (9%), and anemia (6%). Trop-2 tumor staining was not required for patient selection. No antibodies to the drug conjugate or its components were detected on serial blood collections.Conclusions: Sacituzumab govitecan appears to have a safe and effective therapeutic profile in heavily pretreated mSCLC patients, including those who are chemosensitive or chemoresistant to first-line chemotherapy. Additional studies as a monotherapy or combination therapy are warranted. Clin Cancer Res; 23(19); 5711-9. ©2017 AACR.

Therapy of Advanced Non-Small-Cell Lung Cancer With an SN-38-Anti-Trop-2 Drug Conjugate, Sacituzumab Govitecan.

Purpose Trop-2, expressed in most solid cancers, may be a target for antibody-drug conjugates (ADCs) in non-small-cell lung cancer (NSCLC). We studied sacituzumab govitecan (IMMU-132), a Trop-2 ADC, for the targeting of SN-38. Patients and Methods We evaluated IMMU-132 in a single-arm multicenter trial in patients with pretreated metastatic NSCLC who received either 8 or 10 mg/kg on days 1 and 8 of 21-day cycles. The primary end points were safety and objective response rate (ORR). Progression-free survival and overall survival were secondary end points. Results Fifty-four patients were treated. In the response-assessable study population (n = 47), which had a median of three prior therapies (range, two to seven), the ORR was 19%; median response duration, 6.0 months (95% CI, 4.8 to 8.3 months); and clinical benefit rate (complete response + partial response + stable disease ≥ 4 months), 43%. ORR in the intention-to-treat (ITT) population was 17% (nine of 54). Responses occurred with a median onset of 3.8 months, including patients who had relapsed or progressed after immune checkpoint inhibitor therapy. Median ITT progression-free survival was 5.2 months (95% CI, 3.2 to 7.1 months) and median ITT overall survival, 9.5 months (95% CI, 5.9 to 16.7 months). Grade 3 or higher adverse events included neutropenia (28%), diarrhea (7%), nausea (7%), fatigue (6%), and febrile neutropenia (4%). One patient developed a transient immune response, despite patients receiving a median of 10 doses. More than 90% of 26 assessable archival tumor specimens were highly positive (2+, 3+) for Trop-2 by immunohistochemistry, which suggests that Trop-2 is not a predictive biomarker for response. Conclusion IMMU-132 was well-tolerated and induced durable responses in heavily pretreated patients with metastatic NSCLC. This ADC should be studied further in this disease and in other patients with Trop-2-expressing tumors.

Treatment of recurrent and platinum-refractory stage IV non-small cell lung cancer with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as a single agent.

The role of single-agent nab-paclitaxel in relapsed or platinum-refractory advanced non-small cell lung cancer (NSCLC) has not been well reported in Western populations. We reviewed our own institution's experience using nab-paclitaxel in these settings. We analyzed the records of stage IV NSCLC patients with relapsed or platinum-refractory disease treated with single-agent nab-paclitaxel at Weill Cornell Medical College between October 2008 and December 2013. The primary endpoint of the study was treatment failure-free survival (TFFS), defined as the time from the start of nab-paclitaxel therapy to discontinuation of the drug for any reason. The best overall response was recorded for each patient, and overall response and disease control rates were calculated. Thirty-one stage IV NSCLC patients received a median of 4 cycles (range 1-40) of nab-paclitaxel. Dose reduction or drug discontinuation due to toxicity occurred in 10 patients, mainly because of grade 2/3 fatigue or peripheral neuropathy. The overall response rate was 16.1 %, and the disease control rate was 64.5 %. Median TFFS was 3.5 months (95 % CI 1.3-5.3 months). No statistically significant difference in TFFS based on line of therapy or prior taxane exposure was identified. There was a statistically significant decrease in TFFS for patients with non-adenocarcinoma histology, although there were only five patients in this group. There was a trend toward reduction in the risk of treatment failure with increasing age. One patient remained on nab-paclitaxel therapy for over 3 years. Single-agent nab-paclitaxel was well tolerated and demonstrated efficacy in advanced NSCLC patients with relapsed or platinum-refractory disease. Further prospective clinical trials with nab-paclitaxel in these settings are warranted.

Neurocognitive function and quality of life in patients with newly diagnosed brain metastasis after treatment with intra-operative cesium-131 brachytherapy: a prospective trial.

Intraoperative permanent Cesium-131 (Cs-131) brachytherapy can provide a viable alternative to WBRT with excellent response rates and minimal toxicity. This study reports the results of the prospective trial of the impact of intraoperative Cs-131 on neurocognitive function and quality of life (QoL) in patients with resected brain metastases. Between 2010 and 2012, 24 patients with newly diagnosed metastasis to the brain were accrued on a prospective protocol and treated with Cs-131 brachytherapy seeds after surgical resection. Physicians administered the mini-mental status examination (MMSE) and functional assessment of cancer therapy-brain (FACT-Br) questionnaire to all patients before treatment and again every 2 months for the duration of 6 months with additional follow-up again at 12 months. Wilcoxon rank sum test was used to analyze statistically significant changes in MMSE over time and paired t test was used to analyze changes in FACT-BR. There was a statistical improvement in overall FACT-BR score at 4 and 6 months of follow-up when compared to baseline (162 vs. 143, P = 0.004; 164 vs. 143, P = 0.005 respectively) with a non-significant trend toward improvement at 2 and 12 months (154 vs. 143, P = 0.067; 159 vs. 149, P = 0.4). MMSE score was statistically improved at 4 and up to 12 months compared to pre-treatment MMSE (30 vs. 29, P = 0.017; 30 vs. 29, P = 0.001 respectively). Patients with brain metastasis who received intra-operative permanent Cs-131 brachytherapy implants saw an improvement of their neurocognitive status and self-assessment of QoL. In addition to the excellent local control of metastasis, this approach may contribute to the improvements in cognitive function and QOL.

Pro1170 Ala polymorphism in HER2-neu is associated with risk of trastuzumab cardiotoxicity.

BACKGROUND: Variations in single nucleotide polymorphisms (SNPs) have been associated with enhanced drug efficacy and toxicity in cancer therapy. SNP variations in the ErbB2 gene have been identified that alter the protein sequence of the HER2-neu protein, but how these polymorphisms affect prognosis and response to HER2 targeted therapy is unknown. We examined eleven ErbB2 SNPs that alter the HER2-neu amino acid sequence to determine whether any of these particular polymorphisms were associated with increased trastuzumab cardiotoxicity in a case-control study. METHODS: 140 subjects were enrolled from a single institution under Weill Cornell Medical College IRB protocol #0804009734. Patients were eligible if they had histologically or cytologically proven HER2-neu positive breast cancer and more than 3 months of trastuzumab therapy. Cases had either symptomatic CHF or a decline in LVEF of 15% (or if the LVEF <55%, a decline in LVEF of 10%) that resulted in at least temporary discontinuation of trastuzumab, whereas controls had no decline in their LVEF. Eleven ErbB2 single gene SNPs that resulted in an alteration in the HER2-neu protein amino acid sequence were studied. Single gene SNP analysis was carried out using SNP genotyping assays from genomic DNA obtained from peripheral blood or buccal swab. RESULTS: Only two of the ErbB2 SNPs (Ile 655 Val and Pro 1170 Ala) were found to have variation. There was no association between codon 665 and cardiotoxicity; however the proline variant of amino acid 1170 was more likely than the alanine variant to be found in cases with trastuzumab cardiotoxicity (35% of case patients as compared to 17% of controls, p = 0.04). This association remained significant in multivariable analysis taking into account age, race, and history of hypertension (adjusted OR = 2.60, 95% CI = 1.02, 6.62, p = 0.046). CONCLUSIONS: The Her2/neu Pro 1170 Ala polymorphism can be used to identify a subset of patients who are at increased risk of cardiotoxicity from trastuzumab therapy. Her2/neu single nucleotide polymorphisms may be useful in conjunction with other biomarkers to risk stratify patients in order to optimize clinical management.

Erratum: Non-Small-Cell Lung Cancer: Treatment of Late Stage Disease: Chemotherapeutics and New Frontiers.

[This corrects the article DOI: 10.1055/s-0033-1342961.].

Non-small-cell lung cancer: treatment of late stage disease: chemotherapeutics and new frontiers.

Systemic therapy should be considered in patients with advanced non-small cell lung cancer (NSCLC) who are no longer amenable to local therapies. Systemic therapy has been shown to improve survival and preserve quality of life in patients with a reasonable performance status. In unselected patients, the standard of care for initial therapy remains platinum-based chemotherapy. At progression, further treatment typically consists of the sequential administration of single-agent therapy, which has also been shown to improve survival and reduce cancer-related symptoms. Molecular biomarkers are essential to guide targeted agents. This analysis requires ample tumor DNA; thus adequate biopsy samples are critical to guide therapeutic options. More biomarkers are currently being validated and may potentially have specific targeted therapy. In the near future, it is likely that rapid multiplexed genotype testing will help reduce the need for large amounts of tumor for analysis and will promote personalized cancer therapy. We review recent changes in the definition of stage IV NSCLC and review current and future systemic therapeutic approaches for patients with advanced disease.

Phase I/II study of oral erlotinib for treatment of relapsed/refractory glioblastoma multiforme and anaplastic astrocytoma.

We evaluated the safety and survival benefits of orally administered erlotinib monotherapy for patients with relapsed/refractory glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA). A dose escalation schedule was administered with a starting dose of 150 mg/day for the first cycle (28 days), followed by 100 mg twice daily for 14 days, and 150 mg twice daily for another 14 days. Assuming no dose limiting toxicities were observed, dosage was maintained at 150 mg BID for 10 more cycles. Disease and tumor responses were assessed after every other cycle; toxicity assessments were conducted for a minimum of 10 weeks. Patients discontinued use of enzyme-inducing anticonvulsants (EIAED) and started non-EIAEDs. Patients with previous erlotinib exposure were ineligible. Eleven patients were enrolled: 8 (73%) GBM; 3 (27%) AA. Adverse events limited study accrual, originally intended to accrue 43 patients. Nine patients (90%) experienced rash within the first 2 cycles: 7 (64%) within cycle 1; 6 (60%) reported diarrhea within the first 2 cycles. Median progress-free survival (PFS) and overall survival (OS) was 1.9 months and 6.9 months. All patients showed disease progression while on the drug. Despite the sample size, the toxicity of erlotinib supersedes any marginal benefit it as a monotherapy for relapsed/refractory GBM/AA.

Safety and maximum tolerated dose of superselective intraarterial cerebral infusion of bevacizumab after osmotic blood-brain barrier disruption for recurrent malignant glioma. Clinical article.

OBJECT: The authors assessed the safety and maximum tolerated dose of superselective intraarterial cerebral infusion (SIACI) of bevacizumab after osmotic disruption of the blood-brain barrier (BBB) with mannitol in patients with recurrent malignant glioma. METHODS: A total of 30 patients with recurrent malignant glioma were included in the current study. RESULTS: The authors report no dose-limiting toxicity from a single dose of SIACI of bevacizumab up to 15 mg/kg after osmotic BBB disruption with mannitol. Two groups of patients were studied; those without prior bevacizumab exposure (naïve patients; Group I) and those who had received previous intravenous bevacizumab (exposed patients; Group II). Radiographic changes demonstrated on MR imaging were assessed at 1 month postprocedure. In Group I patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 34.7%, a median reduction in the volume of tumor enhancement of 46.9%, a median MR perfusion (MRP) reduction of 32.14%, and a T2-weighted/FLAIR signal decrease in 9 (47.4%) of 19 patients. In Group II patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 15.2%, a median volume reduction of 8.3%, a median MRP reduction of 25.5%, and a T2-weighted FLAIR decrease in 0 (0%) of 11 patients. CONCLUSIONS: The authors conclude that SIACI of mannitol followed by bevacizumab (up to 15 mg/kg) for recurrent malignant glioma is safe and well tolerated. Magnetic resonance imaging shows that SIACI treatment with bevacizumab can lead to reduction in tumor area, volume, perfusion, and T2-weighted/FLAIR signal.

Superselective intraarterial cerebral infusion of bevacizumab: a revival of interventional neuro-oncology for malignant glioma.

Glioblastoma Multiforme (GBM) is a uniformly fatal disease with a median survival of approximately 15 months. Recent monoclonal antibody therapies such as Bevacizumab (Avastin) have been shown to be active in GBM and to prolong survival in patients with recurrent malignant glioma. Therefore, patients routinely receive intravenous (i.v.) Bevacizumab (10 mg/kg) every two weeks when they have recurred following standard therapy with chemoradiation. I.v Bevacizumab; however, can cause significant systemic side effects including bowel perforation and pulmonary embolism. In addition, the blood brain barrier (BBB) continues to provide an obstacle to the effective delivery of the antibody to the brain tumor bed. In order to overcome the BBB, and to limit the systemic toxicity of i.v. Bevacizumab, we have begun a Phase I clinical trial to test the safety of transient blood brain barrier disruption with intraarterial (IA) Mannitol followed by superselective intraarterial cerebral infusion (SIACI) of Bevacizumab. This case report describes the technical aspects of this procedure and its associated benefits and risks. This novel delivery method, which may herald the revival of Interventional Neuro-oncology, may significantly alter the way therapy is administered to patients with GBM.