Reddy, Pavan S.

PURPOSE To provide evidence-based recommendations to practicing clinicians on the management of patients with small-cell lung cancer. METHODS An Expert Panel of medical oncology, thoracic surgery, radiation oncology, pulmonary, community oncology, research methodology, and advocacy experts were convened to conduct a literature search, which included systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2022. Outcomes of interest included response rates, overall survival, disease-free survival or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS The literature search identified 95 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS Evidence-based recommendations were developed to address systemic therapy options, timing of therapy, treatment in patients who are older or with poor performance status, role of biomarkers, and use of myeloid-supporting agents in patients with small-cell lung cancer. Additional information is available at www.asco.org/thoracic-cancer-guidelines .

Abstract Purpose A protocol was developed to evaluate the value of an NK-1 receptor antagonist for preventing nausea and vomiting resulting from highly emetogenic chemotherapy when an olanzapine-based antiemetogenic regimen was used. Materials and Methods A221602, a prospective double-blind, placebo-controlled clinical trial, was developed to compare 2 ­olanzapine-containing antiemetic regimens, one with an NK-1 receptor antagonist (aprepitant or fosaprepitant) and one without. Trial patients had a malignant disease for which they received intravenous highly emetogenic chemotherapy (single day cisplatin ≥ 70 mg/m2 or doxorubicin plus cyclophosphamide on 1 day). Patients on both arms received commonly administered doses of a 5-HT3 receptor antagonist, dexamethasone, and olanzapine. Additionally, patients were randomized to receive an NK-1 receptor antagonist (fosaprepitant 150 mg IV or aprepitant 130 mg IV) or a corresponding placebo. The primary objective was to compare the proportion of patients with no nausea for 5 days following chemotherapy between the 2 study arms. This trial was designed to test for the noninferiority of deleting the NK-1 receptor antagonist, with noninferiority defined as a decrease in freedom from nausea by less than 10%. Results A total of 690 patients were entered on this trial, 50% on each arm. The proportion of patients without nausea for the complete 5-day study period was 7.4% lower (upper limit of the one-sided 95% confidence interval was 13.5%) in the arm without an NK-1 receptor antagonist compared with the arm with an NK-1 receptor antagonist. Conclusion This trial did not provide sufficient evidence to support that deletion of the NK-1 receptor antagonist was as good as keeping it, as a part of a 4-drug antiemetic regimen for highly emetogenic chemotherapy (ClinicalTrials.gov Identifier: NCT03578081).

12107 Background: Chemotherapy-induced nausea and vomiting (CINV), a major adverse effect of cancer treatment, can attenuate life quality. Multiple international antiemetic guidelines have recommended a 4-drug regimen (corticosteroid, 5-HT3 receptor antagonist, NK-1 receptor antagonist, and the antipsychotic medication olanzapine) for decreasing highly emetogenic CINV. This raised a question regarding whether antiemetic therapy regimens for highly emetogenic chemotherapy could be de-intensified, decreasing cost and side effects from anti-emetogenic agents. Methods: Study A221602 was developed to compare two olanzapine-containing antiemetic regimens, one with the use of an NK-1 receptor antagonist (aprepitant or fosaprepitant) and one without. Patients (pts) received intravenous highly emetogenic chemotherapy as either 1) cisplatin, given on one day, at a dose of ≥ 70 mg/m2, with or without other chemotherapy agent(s) or 2) doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2) on one day. Pts in both arms received 1) a 5-HT3 receptor antagonist (palonosetron 0.25 mg IV or ondansetron 8-16 mg IV or 16-24 mg PO,) on day one, 2) dexamethasone (12 mg PO, day one followed by 8 mg PO, days 2-4), and 3) olanzapine (10 mg/day PO, days 1 to 4). On Day 1, all agents were given prior to chemotherapy, with the exception that olanzapine could be taken prior to chemotherapy or at bedtime. Additionally, pts were randomized to receive an NK-1 receptor antagonist (fosaprepitant 150 mg IV or aprepitant 130 mg IV; 346 pts) or a matching placebo (344 pts). The primary objective was to compare the proportion of patients with no nausea for 5 days following receipt of their chemotherapy between the two study arms. Results: While there was no suggestion of outcome differences on day 1 between the two study arms, fewer pts (7.4%; upper limit of the 95% confidence interval was 13.5%) without NK-1 receptor antagonists were without nausea for the complete 5-day study period. Conclusions: Per the study design, created to exclude a 10% benefit for NK-1 receptor antagonists, the results did not provide sufficient evidence to reject the hypothesis that the 4-drug regimen was superior to the protocol 3-drug regimen (p=0.24). Support: UG1CA189823; Clinical trial information: NCT03578081.

Abstract Background Black race is associated with worse outcomes in early breast cancer. We evaluated clinicopathologic characteristics, the 21-gene recurrence score (RS), treatment delivered, and clinical outcomes by race and ethnicity among women who participated in the Trial Assigning Individualized Options for Treatment. Methods The association between clinical outcomes and race (White, Black, Asian, other or unknown) and ethnicity (Hispanic vs non-Hispanic) was examined using proportional hazards models. All P values are 2-sided. Results Of 9719 eligible women with hormone receptor–positive, HER2-negative, node-negative breast cancer, there were 8189 (84.3%) Whites, 693 (7.1%) Blacks, 405 (4.2%) Asians, and 432 (4.4%) with other or unknown race. Regarding ethnicity, 889 (9.1%) were Hispanic. There were no substantial differences in RS or ESR1, PGR, or HER2 RNA expression by race or ethnicity. After adjustment for other covariates, compared with White race, Black race was associated with higher distant recurrence rates (hazard ratio [HR] = 1.60, 95% confidence intervals [CI] = 1.07 to 2.41) and worse overall survival in the RS 11-25 cohort (HR = 1.51, 95% CI = 1.06 to 2.15) and entire population (HR = 1.41, 95% CI = 1.05 to 1.90). Hispanic ethnicity and Asian race were associated with better outcomes. There was no evidence of chemotherapy benefit for any racial or ethnic group in those with a RS of 11-25. Conclusions Black women had worse clinical outcomes despite similar 21-gene assay RS results and comparable systemic therapy in the Trial Assigning Individualized Options for Treatment. Similar to Whites, Black women did not benefit from adjuvant chemotherapy if the 21-gene RS was 11-25. Further research is required to elucidate the basis for this racial disparity in prognosis.

503 Background: TAILORx established that endocrine therapy (ET) alone is non-inferior to adjuvant chemotherapy (CT) plus ET in EBC and a 21-gene RS of 11-25, with some benefit if ≤50 years (y) with RS 16-25 (PMID: 29860917). We evaluated whether clinical risk (tumor size & histologic grade) provides additional prognostic information to RS, a secondary trial objective. Methods: Clinical risk by was assessed by Adjuvant! (version 8.0) using MINDACT criteria (PMID 27557300), defined as low clinical risk (LCR - tumor ≤3 cm and low grade, <2 cm and intermediate grade, or ≤1 cm and high grade) or high clinical risk (HCR -not meeting LCR criteria). Results: Of 9427 women with RS and clinical risk information, 70% were LCR and 30% HCR, with comparable distribution by age ( ≤50 vs. >50). The RS was 26-100 in 9% of LCR and 27% of HCR patients, with similar distributions by age. Although LCR/HCR provided additional prognostic information in each RS category for iDFS, including RS 0-10 (9-year rates 86.7% vs. 75.7% LCR vs. HCR), 11-25 (85.4% vs. 78.9%), and 26-100 (82.0% vs. 70.4%), iDFS rates were similar irrespective of CT (no vs. yes) in the entire RS 11-25 cohort whether LCR (85.8% vs. 85.1%) or HCR (79.8% vs. 77.9%). DRFI rates were also similar irrespective of CT in the RS 11-25 cohort or > 50y group whether LCR (96.0% vs. 96.1% overall; 96.5% vs. 96.0% > 50y) or HCR (92.3% vs. 89.9% overall; 91.7% vs. 90.7% >50y). For women ≤50y, the absolute reduction in distant recurrence from CT with a RS of 16-20 (N=923) was -0.2% (standard error [SE]±2.1%) for LCR vs. 6.5%(SE±4.9%) for HCR (vs. 1.6%[SE±1.9%] overall), whereas for a RS 21-25 (N=492) it was 6.4% (SE±4.9%) for LCR vs. 8.6% (SE±6.2%) for HCR (vs. 6.5%[SE±3.7%] overall). Conclusions: Clinical risk stratification provides additional prognostic information to the 21-gene RS, but not prediction of CT benefit in the overall TAILORx population or those > 50y, and facilitates more refined estimates of absolute CT benefit for women ≤50y with a RS 16-25. (Funded by National Cancer Institute, Komen Foundation, Breast Cancer Research Foundation). Clinical trial information: NCT00310180.

LBA1 Background: In hormone receptor (HR)-positive, HER2-negative, axillary node (AN)-negative breast cancer, the 21-gene expression assay (Oncotype DX Recurrence Score [RS]) is prognostic for distant recurrence, prognostic for low recurrence with endocrine therapy alone if low (0-10), and predictive of chemotherapy benefit if high (26 or higher). We performed a prospective, randomized trial of endocrine therapy (ET) versus chemoendocrine therapy (CET) in women with a mid-range RS of 11-25. Methods: Eligibility criteria included women 18-75 years of age with HR-positive, HER2-negative, axillary node (AN)-negative breast cancer and tumors 1.1-5.0 cm in size (or 0.6-1.0 cm and int/high grade) and agreed to have chemotherapy assigned or randomized based on the RS. Women with a mid-range RS (11-25) were randomized to receive ET or CET. The primary endpoint was invasive disease-free survival (iDFS), and the trial was designed to show non-inferiority for ET alone by not rejecting equality (hazard ratio [HR] margin up to 1.322 for omission of chemotherapy, 1-sided type I error rate 10%, type II error rate 5%). The target sample size was adjusted to compensate for non-adherence to randomized treatment, and the protocol-specified final analysis was triggered after 835 iDFS events. Results: Of the 10,253 eligible women enrolled between 4/7/06-10/6/10, 6711 (65.5%) had a RS of 11-25 and adequate information. There were 836 iDFS events at final analysis with a median followup of 90 months. ET was non-inferior to CET for iDFS (HR 1.08, 95% confidence intervals [CI] 0.94, 1.24, p=0.26) in the intention-to-treat (ITT) population. ET was also non-inferior for distant recurrence-free interval (DRFI; HR 1.03, p=0.80), recurrence-free interval (RFI; HR 1.12, p=0.28), and overall survival (OS; HR 0.97, p=0.80). Nine year rates were similar for iDFS (83.3% vs. 84.3%), DRFI (94.5% vs. 95.0%), RFI (92.2% vs. 92.9%), and OS (93.9% vs. 93.8%). Recurrence accounted for 338 (41.6%) the first iDFS event, of which 199 (23.8%) were distant recurrences. Treatment interaction tests were significant for age (iDFS p=0.03; RFI p= 0.02), but not menopause, tumor size, grade, or RS (continuous or RS 11-15, 16-20, 21-25). Conclusions: In women with HR-positive, HER2-negative, AN-negative breast cancer and a RS of 11-25, adjuvant ET was not inferior to CET in the ITT analysis. (Funded by NCI, BCRF, and Komen Foundation.) Clinical trial information: NCT00310180.

Abstract Background: Postmenopausal women with significant osteopenia/osteoporosis are at increased risk of fracture, a risk that is exacerbated by the use of Aromatase Inhibitors (AIs). Bisphosphonates may be used for these patients because there is no known interaction with estrogen and/or progesterone receptors (ER, PR). This study evaluated the concurrent use of zoledronic acid in patients with significant osteopenia or osteoporosis who received initial adjuvant letrozole therapy for primary BC, to determine if further bone mineral density (BMD) loss could be prevented.Methods: Postmenopausal women with Stage I-IIIa, ER and/or PR + BC, no evidence of metastatic disease, and a BMD T-score &lt; -2.0 were treated with daily letrozole 2.5 mg/d, vitamin D 400 international units/d, calcium 500 mg twice daily, and 4 mg I.V. zoledronic acid every 6 months (for 5 years). The BMD was measured at baseline and at one year. Kruskall-Wallis p-value methodology was used as the method of statistical analysis. Since this was a single-arm study, the analysis plan was primarily descriptive. The primary endpoint was the mean change in lumbar spine (LS) BMD at 1 year.Results: 60 patients were enrolled; 46 completed 1 year of treatment. Mean patient age was 67 years, with 44% having taken prior tamoxifen. At 1 year (see figure 1), LS BMD increased 2.66% (p=0.01), femoral neck (FN) BMD increased 4.81% (p=0.01), and any measured endpoint (within the LS or FN) increased 4.55% (p=0.0052). 7% of patients experienced a fracture vs.13% with a pre-existing history of fracture before enrollment. No patients had disease recurrence during year 1. Toxicity was minimal with arthralgia as the most common complaint. There were no reports of osteonecrosis of the jaw.Conclusion: Zoledronic acid prevents additional bone loss in postmenopausal women with significant osteopenia or osteoporosis initiating letrozole. Treatment with zoledronic acid was associated with an improvement in BMD. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2103.