Citations

Background: Relapsed/refractory (R/R) Classic Hodgkin lymphoma (cHL) remains a significant clinical challenge. We hypothesized that using immune checkpoint blockade to activate the immune cells in the tumor microenvironment, and concurrently targeting tumor cells with the CD30 targeting antibody-drug conjugate brentuximab vedotin (BV) could overcome tumor resistance. E4412 is an intergroup Phase 1/2 ECOG-ACRIN sponsored study of the combinations of BV, nivolumab (N), and ipilimumab (I) in patients with R/R cHL. Here we present the efficacy and safety data on the full adult cohort of patients treated in Phase 2 randomized between BV/N and BV/N/I. Methods: Patients with confirmed R/R cHL were randomized between the doublet of BV/N with BV 1.8mg/kg and N 3mg/kg and BV/N/I with I 1mg/kg. BV and N were administered every 3 weeks, and I every 12 weeks for up to 1 year for BV and up to 2 years for N and I. Results: One hundred twenty-six patients were enrolled and treated; 8 patients (4 from each arm) were excluded from efficacy analysis based on ineligibility. Patients were not heavily pretreated, 65% had one prior line of therapy and an additional 27% had two prior lines, and 8% had more than 2 prior lines. The median age was 34; 51% of patients were male. Sixteen patients had prior BV: 10 (BV/N arm) and 6 (BV/N/I). Response: One hundred eighteen patients are evaluable for response: 61 treated with BV/N and 57 with BV/N/I. With BV/N 37 of 61 (60.7%) of patients had a complete response (CR) compared to 38 of 57 (66.7%) with BV/N/I for a difference of 6.7% (p-value 0.31). Additionally, 17 (28%) with BV/N and 12 (21%) of patients treated with BN/N/I had a partial response (PR) for an overall response rate (ORR) of 88% in both arms. In a planned analysis of patients with prior treatment with BV the CR rate was 25% in BV/N arm (2 of 8) and 60% in BV/N/I arm (3 of 5). The median follow-up for progression free survival (PFS), duration of response (DOR), and overall survival (OS) is 24.8 months and 33.7 months. The median PFS, duration of response and OS have not been reached for either arm with 24 months of follow-up ( Figure 1). In B/N 30 of 61 patients came off study to receive alternative treatments (primarily autologous stem cell transplant (SCT)) and in BV/N/I 23 of 57 patients did. Safety: Table 1 shows treatment-related Grade 3+ toxicity occurring in > 1 patient and adverse events (AE) of special interest. All 126 patients (118 eligible and 8 ineligible) are evaluable for safety. The rate of Grade 3+ treatment related toxicity is 43% (28/65) and 52% (32/61) for BV/N and BV/N/I, respectively. However, when rash is excluded the rate of treatment related toxicities is similar between the two arms 38.5% vs 39.3%. There was no grade 4 rash, and the rash was treatable in all cases with topical or oral steroids. There were no Grade 5 toxicities in either arm. Conclusion: In this randomized Phase 2 study comparing BV/N vs. BV/ N/I the difference in CR rate of 6.7% between the doublet and the triplet was not statistically significant. Additionally, the triplet had more grade 3 rash than the doublet, there was otherwise no significant difference in grade 3 or greater toxicity between the two arms. With a median follow-up of 24 months the PFS and DOR have not been reached for either arm, suggesting excellent disease control from both regimens. Differences in response for BV pre-treated patients between the two arms is intriguing especially as more patients are treated with BV in the frontline, but the sample size is too small to draw firm conclusions. Correlative studies are underway to elucidate a response vs. resistance signature, and biological understanding of differential benefit.

Background There is limited prospective or comparative data evaluating the HRQoL impact of intensive chemotherapy (IC) in older adults (age ≥60 years) with AML. In the recent EA E2906 phase 3 study of '7&3' (daunorubicin & cytarabine) vs. clofarabine (CLO), a putative lower intensity therapy, we incorporated a prospective patient-reported outcomes (PRO) assessment of HRQoL and fatigue to understand treatment impact from the patients' (pts) perspective. Methods E2906 study design and results have been presented previously [n=727, med. age 68 years (range 60-86), randomized 1:1 to ‘standard’ ‘7&3‘ & high dose cytarabine (Arm A) vs. single agent CLO (Arm B), as remission induction (Step 1) and consolidation (Step 2), respectively]. There was no difference in composite complete remission (CCR, 50%) or 30-day mortality rates (8.5%), and in primary analysis CLO was inferior for Overall Survival. HRQoL was a key secondary protocol endpoint. PROs assessed HRQoL and leukemia-specific symptoms and concerns using Functional Assessment of Cancer Therapy-Leukemia scale (FACT-Leu), & Fatigue using FACT-Fatigue subscale. PROs were administered at prespecified time points: (1) Baseline; (2) Cycle 1 at nadir (approx. Day 15); (3) End of Step 1 restaging (approx. D 40); (4) Beginning of Step 2 (1 st consolidation, approx. D 45); and (5) 2 nd cycle consolidation/End Step 2 (approx. D 60). The FACT-Leu Trial Outcome Index ( TOI) was calculated by summing physical well-being, functional well-being, and leukemia-specific concerns subscales to create a single composite score. Higher TOI scores correspond to better HRQoL. The primary endpoint was to evaluate TOI difference from randomization to day 30 after induction therapy between arms, evaluated using Wilcoxon rank sum test. We also compared Clinically Meaningful differences (CMiD) in TOI (defined as patient change ≥½ standard deviation from baseline TOI) between arms, using the X2 test. Pts not completing at least 2 assessment forms (including baseline) were excluded. Testing of constructs of Physical Well-being (PWB), Functional, Leukemia & Fatigue scales demonstrated high Cronbach's a values (a >0.7) except for PWB (a=0.672) at a single time point (End of Step 2). Results Baseline TOI was available for n=489, and 364 pts (n=182 each Arm) were evaluable in this planned analysis. Evaluating CMiD during Cycle 1 induction, pts in Arm B were less likely to experience ‘Worse’ TOI score (32% vs. 40.7%, Arm A), more likely to maintain stable TOI scores (49.1% vs. 39%, Arm A), and had a similar proportion of ‘Better’ TOI scores (20.3%, A vs. 18.9%, B) although differences were not significant (p=0.1389). Conversely in cycle 1 consolidation, more patients in Arm A experienced Better TOI (45.1% vs. 29.2%, Arm B), fewer had stable TOI (45.1% vs. 58.3%, Arm B), and rates of ‘Worse’ TOI were similar (9.8%, A vs 12.5%, Arm B), again differences were not significant (p=0.2616). There was no difference in Fatigue scores between Arms (p=0.49). We evaluated whether TOI and Fatigue scores could predict the ability to complete protocol therapy. In univariate analysis baseline TOI (p=0.0059) and Fatigue (p=0.0057) were associated with Step 1 completion, however on multivariate analysis (adjusting for age, sex, and Arm) were no longer significant [TOI, Odds Ratio (OR) 1.03 (0.98-1.08, p=0.27); Fatigue, OR 1.03 (0.96-1.11, p=0.42)]. There was a borderline association of TOI with Step 2 completion [TOI OR 1.10 (1.00-1.23, p=0.06)]. Using a multivariable linear mixed effects model, we observed similar and significant changes in TOI scores in both Arms, demonstrating the effect of IC & CLO on HRQoL (Figure). Comparing to baseline, TOI scores decreased significantly at C1 induction nadir (-4.0873, p<0.0001), and increased by 5.0762 (p=0.0004) at end Step 1, by 6.9047 at cycle 1 consolidation (p<0.0001), and by 11.4601 (p<0.0001) at end Step 2. Differences were mainly apparent in those who achieved CCR, and there was significant attrition in PRO responses in non-CCR pts. Conclusions Older adults experienced significant improvement in HRQoL after nadir regardless of therapy, and those achieving CCR report significantly higher scores. We did not observe differences in leukemia specific HRQoL or fatigue between treatment Arms (7&3 vs. CLO). Patient-reported HRQoL & Fatigue was not predictive of completion of protocol therapy. These results serve as a benchmark for expectations with IC in older adults.

AbstractBackgroundTobacco use is associated with adverse outcomes among patients diagnosed with cancer. Socioeconomic determinants influence access and utilization of tobacco treatment; little is known about the relationship between neighborhood socioeconomic disadvantage (NSD) and tobacco assessment, assistance, and cessation among patients diagnosed with cancer.MethodsA modified Cancer Patient Tobacco Use Questionnaire (C‐TUQ) was administered to patients enrolled in nine ECOG‐ACRIN clinical trials. We examined associations of NSD with (1) smoking status, (2) receiving tobacco cessation assessment and support, and (3) cessation behaviors. NSD was classified by tertiles of the Area Deprivation Index. Associations between NSD and tobacco variables were evaluated using logistic regression.ResultsA total of 740 patients completing the C‐TUQ were 70% male, 94% White, 3% Hispanic, mean age 58.8 years. Cancer diagnoses included leukemia 263 (36%), lymphoma 141 (19%), prostate 131 (18%), breast 79 (11%), melanoma 69 (9%), myeloma 53 (7%), and head and neck 4 (0.5%). A total of 402 (54%) never smoked, 257 (35%) had formerly smoked, and 81 (11%) were currently smoking. Patients in high disadvantaged neighborhoods were approximately four times more likely to report current smoking (odds ratio [OR], 3.57; 95% CI, 1.69–7.54; p = .0009), and more likely to report being asked about smoking (OR, 4.24; 95% CI, 1.64–10.98; p = .0029), but less likely to report receiving counseling (OR, 0.11; 95% CI, 0.02–0.58; p = .0086) versus those in the least disadvantaged neighborhoods.ConclusionsGreater neighborhood socioeconomic disadvantage was associated with smoking but less cessation support. Increased cessation support in cancer care is needed, particularly for patients from disadvantaged neighborhoods.

Abstract Background: While cigarette smoking has declined among the U.S. general population, sale and use of non-cigarette alternative tobacco products (ATP; e.g., e-cigarettes, cigars) and dual use of cigarettes/ATPs are rising. Little is known about ATP use patterns in cancer survivors enrolled in clinical trials. We investigated prevalence of tobacco product use, and factors associated with past 30-day use, among patients with cancer in national trials. Methods: Cancer survivors (N = 756) enrolled in 9 ECOG-ACRIN clinical trials (2017–2021) completed a modified Cancer Patient Tobacco Use Questionnaire (C-TUQ) which assessed baseline cigarette and ATP use since cancer diagnosis and in the past 30 days. Results: Patients were on average 59 years old, 70% male, and the mean time since cancer diagnosis was 26 months. Since diagnosis, cigarettes (21%) were the most common tobacco product used, followed by smokeless tobacco use (5%), cigars (4%), and e-cigarettes (2%). In the past 30 days, 12% of patients reported smoking cigarettes, 4% cigars, 4% using smokeless tobacco, and 2% e-cigarettes. Since cancer diagnosis, 5.5% of the sample reported multiple tobacco product use, and 3.0% reported multiple product use in the past 30 days. Males (vs. females; OR 4.33; P = 0 < 0.01) and individuals not living with another person who smokes (vs. living with; OR, 8.07; P = 0 < 0.01) were more likely to use ATPs only versus cigarettes only in the past 30 days. Conclusions: Among patients with cancer, cigarettes were the most prevalent tobacco product reported. Impact: Regardless, ATPs and multiple tobacco product use should be routinely assessed in cancer care settings.

6036 Background: E3311 is a phase II randomized study of intermediate risk HPV+ OPC patients who underwent TOS by credentialed surgeons and were then treated by pathology-guided, deintensified post-operative treatment. Recent retrospective population data suggest that time to post-operative radiotherapy (PORT) > 6 weeks is associated with worse progression-free survival (PFS). Methods: We retrospectively analyzed demographics, pathologic characteristics, and oncologic outcomes in E3311 by time to initiation of PORT (short vs long, exploring both 6 and 7 weeks postop as the cutpoint). Binary and categorical variables were compared using a chi-square test (or a Fisher’s exact test for small sample sizes). Ordinal variables were compared using a Wilcoxon rank sum test. PFS and overall survival (OS) were estimated using the Kaplan-Meier method and compared using a log-rank test, which was stratified by intermediate- (Arms B/C) vs high-risk (Arm D). Results: Among 321 evaluable patients, the median time to initiation of PORT was 5.1 weeks (range 0.7-15.7); 5.0 (0.7-15.7) for Arm B, 5.1 (2.4-7.0) for Arm C, 5.6 (3.6-7.9) for Arm D. No significant difference in PFS or OS was observed whether PORT commenced by 6 or 7 weeks postoperatively, compared with longer time to initiation of PORT (p = 0.62 and 0.65, p = 0.30 and p = 0.41, respectively). 3-yr PFS rates were 93.5% (95% CI: 89.4%, 96.0%) among those treated ≤6 weeks, and 91.2% (95% CI: 81.4%, 95.9%) among those treated > 6 weeks; 3-yr OS rates were 96.1% (95% CI: 92.7%, 98.0%) among those treated ≤6 weeks, and 94.1% (95% CI: 84.9%, 97.8%) among those treated > 6 weeks. No significant differences in outcomes were observed between intermediate risk treatment arms (deintensified (50Gy) or standard dose (60Gy) RT). Additional demographic and pathologic characteristics, including primary site, margin status, histologic grade, stage, and extranodal extension were not significantly different between those with short vs long time to PORT, whether 6 or 7 weeks was used as the cutpoint. There were more T2 tumors in those treated > 7 weeks postop (84% vs. 49%, p = 0.007). PS = 1 patients were more numerous among those with shorter time to PORT (10% vs 0%, with the 7 week cutpoint). Conclusions: In contrast to retrospective NCDB data, intermediate- and high-risk HPV+ OPC patients enrolled on E3311 had favorable 3-yr PFS and OS rates that were not significantly worse when adjuvant therapy was started > 6 wks or > 7wks. These results argue against a survival advantage for initiation of PORT within 6 or 7 weeks for early-stage HPV+ OPC managed with high-quality transoral resection. The optimal time window to initiate PORT in HPV+ OPC patients remains to be determined. Clinical trial information: NCT01898494 .

4541 Background: PROSPER is a phase 3 National Clinical Trials Network study that accrued pts with clinical stage ≥T2 or TanyN+ RCC of any histology planned for radical/ partial nephrectomy. Pts were randomized to perioperative nivo followed by primary tumor resection and 9 cycles of nivo postoperatively or standard surgery followed by observation. To address concerns that core kidney bx might 1) not provide accurate diagnosis and 2) delay surgery due to adverse events (AEs) or scheduling, the study was amended from requiring all patients to undergo core bx prior to treatment for confirmation of RCC, to only require bx in patients randomized to the nivo arm. Herein, we report the accuracy and safety of primary tumor core bxs in predicting final histology and nuclear grade by both site and central pathology review as well as time from enrollment to surgery. We also report AEs of preoperative nivo. Methods: Concordance of both core bx and primary tumor by site and central pathology review of histology and grade (1-2 vs 3-4) are reported, along with the Cohen’s Kappa value, which measures the agreement and concordance (kappa=0 is no concordance and 1 is highest). AEs relating to core bxs and preoperative nivo, as well as time from enrollment to surgery for each arm, comparing pre- and post-amendment (dropping bx requirement in surgery alone arm) are also reported. Results: 387/404 pts in the nivo arm and 171/415 pts in the surgery alone arm had core bxs. 632 patients had both central pathology and site review available. 41 of all randomized patients (819) were considered as non-RCC and 26/41 were identified via bx. The median times from enrollment to surgery for nivo and control arms pre-amendment were 32d vs 19 d, and post-amendment were 21 d vs 14 d, respectively. The median (25th-75th percentile) number of days from last preoperative nivo to surgery was 14 d (9-20). AEs related to core bx, generally from bleeding, were reported in 13/558 (2.3%) pts. 2/13 bxs resulted in life-threatening complications. 21/353 (6%) of pts receiving nivo pre-surgery had ≥ grade 3-5 AE attributed to nivo. 181/353 (51%) pts had any grade AE attributed to nivo. Concordance between bxs and primary tumor pathologies for determining histological subtype was Kappa = 0.62. Agreement between central pathology and originating site review of primary tumor for determining nuclear grade was Kappa = 0.56, and concordance of histology was Kappa = 0.78. Conclusions: The PROSPER trial use of core bxs in advance of neoadjuvant therapy was generally safe, largely consistent with primary tumor histology and grade, and did not delay resection of the primary tumor. AEs of preoperative nivo were consistent with nivo AEs in metastatic disease. This approach is valid for future neoadjuvant trials. Clinical trial information: NCT03055013 .

Abstract Purpose: Paclitaxel is a widely used anticancer therapeutic. Peripheral neuropathy is the dose-limiting toxicity and negatively impacts quality of life. Rare germline gene markers were evaluated for predicting severe taxane-induced peripheral neuropathy (TIPN) in the patients of European ancestry. In addition, the impact of Cytochrome P450 (CYP) 2C8, CYP3A4, and CYP3A5 metabolizer status on likelihood of severe TIPN was also assessed. Experimental Design: Whole-exome sequencing analyses were performed in 340 patients of European ancestry who received a standard dose and schedule of paclitaxel in the adjuvant, randomized phase III breast cancer trial, E5103. Patients who experienced grade 3–4 (n = 168) TIPN were compared to controls (n = 172) who did not experience TIPN. For the analyses, rare variants with a minor allele frequency ≤ 3% and predicted to be deleterious by protein prediction programs were retained. A gene-based, case–control analysis using SKAT was performed to identify genes that harbored an imbalance of deleterious variants associated with increased risk of severe TIPN. CYP star alleles for CYP2C8, CYP3A4, and CYP3A5 were called. An additive logistic regression model was performed to test the association of CYP2C8, CYP3A4, and CYP3A5 metabolizer status with severe TIPN. Results: Cytochrome P450 oxidoreductase (POR) was significantly associated with severe TIPN (P value = 1.8 ×10−6). Six variants were predicted to be deleterious in POR. There were no associations between CYP2C8, CYP3A4, or CYP3A5 metabolizer status with severe TIPN. Conclusions: Rare variants in POR predict an increased risk of severe TIPN in patients of European ancestry who receive paclitaxel.

AbstractBackgroundObesity (body mass index [BMI] ≥30 kg/m2) is an important epidemiological risk factor for developing acute myeloid leukemia (AML). Therefore, the authors studied the association of obesity with clinical and genetic phenotype and its impact on outcome in adults with AML.MethodsThe authors analyzed BMI in 1088 adults who were receiving intensive remission induction and consolidation therapy in two prospective, randomized therapeutic clinical trials of the Eastern Cooperative Oncology Group‐American College of Radiology Imaging Network: E1900 (ClinicalTrials.gov identifier NCT00049517; patients younger than 60 years) and E3999 (ClinicalTrials.gov identifier NCT00046930; patients aged 60 years or older).ResultsObesity was prevalent at diagnosis (33%) and, compared with nonobesity, was associated with intermediate‐risk cytogenetics group (p = .008), poorer performance status (p = .01), and a trend toward older age (p = .06). Obesity was not associated with somatic mutations among a selected 18‐gene panel that was tested in a subset of younger patients. Obesity was not associated with clinical outcome (including complete remission, early death, or overall survival), and the authors did not identify any patient subgroup that had inferior outcomes based on BMI. Obese patients were significantly more likely to receive <90% of the intended daunorubicin dose despite protocol specification, particularly in the E1900 high‐dose (90 mg/m2) daunorubicin arm (p = .002); however, this did not correlate with inferior overall survival on multivariate analysis (hazard ratio, 1.39; 95% confidence interval, 0.90–2.13; p = .14).ConclusionsObesity is associated with unique clinical and disease‐related phenotypic features in AML and may influence physician treatment decisions regarding daunorubicin dosing. However, the current study demonstrates that obesity is not a factor in survival, and strict adherence to body surface area‐based dosing is not necessary because dose adjustments do not affect outcomes.

Introduction FDG PET/CT was prospectively studied in 287 cN0 head and neck cancer patients in ACRIN 6685, and additional analysis of neck FDG uptake upon recurrence-free survival (RFS) and overall survival (OS) was performed. Patients and Methods Two hundred eight had analyzable data. Survival analysis was performed to compare RFS and OS based on neck FDG visual assessment (VA) and SUVmax. For SUVmax, the optimal thresholds were calculated using conditional inference trees on a randomly selected 70% training data set and validated using the remaining 30% of data. Kaplan-Meier curves with log-rank tests were generated for the patient groups based on VA and optimal SUVmax thresholds, and the hazards ratios (HRs) and 95% confidence intervals (CIs) were also calculated. Hypothesis testing was set at a significance level of 0.05. Results A total of 73.9% of bilateral cN0 and 50.0% of unilateral cN0 were alive at the end of the study with the remaining being dead or lost to follow-up. Overall survival median follow-up time was 24.0 months (interquartile range, 15.8–25.3; range, 0–37.0). A total of 63.3% of bilateral cN0 and 42.5% of unilateral cN0 patients remained disease free during the study. Recurrence-free survival median follow-up time was 23.9 months (interquartile range, 12.4–25.2; range, 0–35.6). Visual assessment of necks by our panel of radiologists was significantly associated with RFS (HR [95% CI], 2.30 [1.10–4.79]; P = 0.02), but not with OS (HR [95% CI], 1.64 [0.86–3.14]; P = 0.13). The optimal SUVmax thresholds were 2.5 for RFS and 5.0 for OS. For SUVmax assessment, applying the optimal thresholds to the 30% test data yielded HRs (95% CIs) of 2.09 (0.61–7.14; P = 0.23) for RFS and 3.42 (1.03–11.41; P = 0.03) for OS. The SUVmax threshold of 5.0 was significantly associated with RFS (HR [95% CI], 5.92 [1.79–19.57]; P < 0.001). Conclusions Neck FDG uptake by VA is significant for RFS. An SUVmax threshold of 5.0 is significantly associated with OS and RFS.