Mandrekar, Sumithra J.

AbstractBackgroundEligibility criteria and endpoints for cancer cachexia trials—and whether weight loss should be included—remain controversial. Although most cachexia trials enrol patients after initial cancer diagnosis, few studies have addressed whether weight loss well after a cancer diagnosis is prognostic.MethodsWe pooled data from non‐small cell lung cancer patients from prospectively conducted trials within the Alliance for Clinical Trials in Oncology (1998–2008), a nationally funded infrastructure. We examined (i) weight data availability and weight changes and (ii) survival.ResultsA total of 822 patients were examined. Of these, 659 (80%) were on treatment at the beginning of Cycle 2 of chemotherapy; weight was available for 656 (80%). By Cycles 3 and 4, weight was available for 448 (55%) and 384 (47%), respectively. From baseline to immediately prior to Cycle 2, 208 (32%) gained weight; 225 (34%) lost <2% of baseline weight; and 223 (34% of 656) lost 2% or more. Median survival from the beginning of Cycle 2 was 13.0, 10.9, and 6.9 months for patients with weight gain, weight loss of <2%, and weight loss of 2% or more, respectively. In multivariate analyses, adjusted for age, sex, performance score, type of treatment, and body mass index, weight loss of 2% or more was associated with poor overall survival compared with weight gain [hazard ratio (HR) = 1.66; 95% confidence interval (CI): 1.33–2.07; P < 0.001] and compared with weight loss of <2% (HR = 1.57; 95% CI: 1.27–1.95; P < 0.001). Although weight loss of <2% was not associated with poorer overall survival compared with weight gain, it was associated with poorer progression‐free survival (HR = 1.24; 95% CI: 1.01–1.51; P = 0.036). Similar findings were observed in a separate 255‐patient validation cohort.ConclusionsWeight should be integrated into cancer cachexia trials because of its ease of frequent measurement and sustained prognostic association.

TPS9077 Background: ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial) is a clinical trial platform of the National Cancer Institute that offers biomarker analysis for high-risk resected non-small cell lung cancer (NSCLC) to support randomized trials of novel adjuvant therapies within the National Clinical Trials Network (NCTN). EA5142, a trial of adjuvant nivolumab for patients (pts) without EGFR / ALK alterations, has completed enrollment. Given the survival benefit seen with 1st-line chemo-immunotherapy (chemo-IO) for advanced NSCLC without EGFR / ALK alterations, there was compelling rationale for the launch of a trial offering concurrent immunotherapy with adjuvant chemo. Here we report updated enrollment to ALCHEMIST as of Jan 14, 2020. Methods: ALCHEMIST includes a screening trial (A151216, 5362 registered) that enrolls pts with completely resected clinical stage IB (≥4 cm)–IIIA (per AJCC 7) NSCLC. Tissue and blood are collected, biomarker testing includes EGFR sequencing, ALK FISH and PD-L1 IHC. 733 active sites are enrolling across the NCTN. Pts with EGFR mutations may enroll to adjuvant erlotinib vs observation (A081105, 352 randomized); those with ALK fusions may enroll to adjuvant crizotinib vs observation (E4512, 99 randomized). A trial offering adjuvant nivolumab vs observation regardless of PD-L1 status (EA5142, 935 randomized) recently completed enrollment. To support ongoing investigation of adjuvant immunotherapy, ALCHEMIST is adding A081801 (opens spring 2020). Pts will be randomized to one of 3 arms: chemo-IO with pembrolizumab during and after chemo vs sequential chemo followed by pembrolizumab vs chemo alone. Pts with pathological N2 nodes are eligible and can undergo postoperative radiotherapy after completing chemo. Pts are eligible if enrolled to A151216, negative for EGFR and ALK alterations, and with PD-L1 testing completed (required for stratification). Local testing for EGFR, ALK and PD-L1 will be accepted for enrollment; central testing will not delay randomization. Pts may not have received any therapy except surgery for the lung cancer and must be age >18, Eastern Cooperative Oncology Group performance status 0-1, have no active autoimmune disease requiring systemic treatment within 2 years, must not be pregnant or nursing, have no active second malignancy within 3 years and meet standard organ function values. By building off the ongoing ALCHEMIST platform, we hope to facilitate rapid enrollment to A081801 across participating NCTN sites. Clinical trial information: NCT02194738.

e20004 Background: IB is a Bruton’s tyrosine kinase inhibitor that showed superior progression-free survival compared with BR in CLL patients (pts) 65 years or older in a randomized phase 3 trial (Woyach et al, NEJM 2018). Pts receiving IB had higher rates of atrial fibrillation (AFIB) and hypertension (HTN); BR pts had higher rates of hematologic toxicity. Differences in treatment duration for BR (6 cycles) and IB (until progression) complicated adverse event (AE) comparisons. Here we use an exploratory approach to compare toxicity burden between arms and provide assessment of AFIB, HTN and infections (INF). Methods: AEs were reported for each of cycles 1-6 and then every 3 cycles until progression or nonprotocol CLL therapy. Only grade (gr) 3-4 AEs were reported thereafter until death. A simple global AE score was calculated for each pt by summing grades of all gr 1-4 AEs and dividing by the number of cycles over which AEs were submitted. Results: 537 pts began therapy (176 BR, 361 IB). 68% on BR completed all 6 cycles. At a median follow-up of 38 months, 64% remained on IB. Treatment discontinuation for AE occurred in 10% and 14% of BR and IB pts. Overall, median AE score was 1.8 (interquartile range (IQR) 0.9-3.3) and 3.8 (IQR 2.3-5.9) in BR and IB arms (p < 0.01). For cycles 1-6, median AE score was 6.2 (IQR 3.8-9.0) and 4.8 (IQR 3.0-7.2) in BR and IB arms (p < 0.01). In the IB arm, median AE score post 6 cycles decreased significantly to 3.4 (IQR 1.9-5.6) (p < 0.01). Gr 3 or higher cumulative rates of AFIB, HTN, and INF over time appear in the table. 100 pts (26/176 BR, 74/361 IB) had 137 severe INF (39% respiratory: 16 BR, 37 IB; 25% skin: 3 BR, 31 IB; 12% GU: 3 BR, 13 IB; 25% other: 12 BR, 22 IB). There were 7 gr 5 INF (3 BR, 4 IB), none confirmed fungal. Conclusions: There was no difference in treatment discontinuation rates for AE. Overall toxicity burden was significantly higher for IB, although IB toxicity burden decreased after 6 cycles. Toxicity burden was significantly higher in cycles 1-6 for pts receiving BR. Risk of severe AFIB, HTN, and INF is highest in the first year of IB. A simple AE score provides valuable information, especially when evaluating regimens of varying length. Clinical trial information: NCT01886872 . Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org ; Pharmacyclics; ClinicalTrials.gov Identifier: NCT01886872. [Table: see text]

Abstract Background: The plasma cell labeling index (LI), a slide-based measure of the percentage of bone marrow plasma cells in the S-phase of cell cycle, is a powerful prognostic tool in multiple myeloma (MM). A high LI is a marker of poor outcome, and is a useful adjunct to cytogenetics and fluorescent in-situ hybridization to risk-stratify MM patients. It has been shown to provide additional prognostic information in International Staging System (ISS) stages 1 and 2 patients treated with conventional chemotherapy ± autologous stem cell transplantation. However, the impact of a high LI is not known in patients receiving novel agents that have been integrated into the current treatment paradigm of newly diagnosed MM. The objective of this study was to determine the value of LI in patients treated with thalidomide-dexamethasone (Thal/Dex) or lenalidomide-dexamethasone (Len/Dex). Patients and Methods : Data from 125 newly diagnosed MM patients enrolled in clinical trials with either thalidomide (200mg/d) plus dexamethasone (Thal-Dex; n=50), or lenalidomide (25 mg/d on days 1–21 of a 4-week cycle) plus dexamethasone (Len-Dex; n=75) as initial therapy, were utilized. Patients within both the studies were categorized into 2 LI groups based on baseline LI: high (≥1%) vs. low (&lt;1%) LI. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan Meier method, and compared between the two LI groups within the Thal Dex and Len-Dex studies using log rank tests. Results : The median follow-up for patients on Thal-Dex and Len-Dex was 7.5 and 3 years, respectively. 36% (18/50) of patients in the Thal-Dex study and 35% (26/75) in the Len-Dex study had high LI. The baseline patient-characteristics, including age, stage (ISS), lactate dehydrogenase, calcium, hemoglobin and creatinine were comparable between the 2 studies. The median OS for patients receiving Thal-Dex was 4.7 years (95% CI 3.1–8.1); 2.3 years (95% CI 1.3–4.6) for patients with LI ≥1 compared to 6.9 years (95% CI: 3.9–NA) for those with LI &lt;1 (P=0.02). The median OS for patients on Len-Dex was not reached for either the high or low LI group (P=0.80). The median PFS for all Thal-Dex patients was 1.7 years (95% CI: 1.4–3.1); 1.3 years (95% CI: 0.2–2.0) for patients with high LI vs.2.3 years (95% CI: 1.3–3.3) for patients with low LI; P = 0.01. The median PFS for Len-Dex patients was 2.6 years (95% CI: 1.8–3.1) years, and no significant difference was observed between the 2 LI groups, with PFS of 2.3 years (95% CI: 1.4–3.1) for patients with high LI, and 3.1 years for patients in the low LI group. Due to a shorter median follow-up of Len-Dex patients, a separate analysis censoring all patients in both the studies at 3 years was performed with similar results. Conclusion : LI remains a significant determinant of PFS and OS in newly diagnosed MM patients treated with Thal-Dex, with high baseline LI predicting poorer outcome. In contrast, during first 3 years of follow-up, the unfavorable prognostic effect of LI is not apparent with Len-Dex therapy, and longer follow-up is needed to determine if Len-Dex therapy overcomes the poor prognostic effect of high LI. Figure Figure

Abstract Introduction: Immunotherapy is most likely to work in a setting of low tumor burden, making vaccine strategies attractive as maintenance therapy post autologous peripheral blood stem cell transplantation (PBSCT) for multiple myeloma (MM). However, it is difficult to ascertain the effects of the vaccines from delayed responses to the transplant. A novel immunotherapeutic, APC8020 (Mylovenge), was studied as consolidation therapy after for MM post PBSCT (Mayo vaccine trial). Mylovenge is prepared from autologous antigen presenting cells, including dendritic cells, partially purified from an unmobilized leukapheresis product by gradient density isolation and then incubated for two days with autologous serum containing M protein obtained pretransplant. We report long term results of the Mayo vaccine trial compared retrospectively to a consecutive cohort of MM patients who underwent autologous stem cell transplant at Mayo Clinic during the same time period. Methods: The Mayo vaccine trial patients had transplants between July of 1998 and May of 2001. Using these cutoff dates we analyzed 151 total MM patients, 27 from the vaccine trial (9 newly diagnosed and 18 relapsed) and 124 from database (DB) (50 newly diagnosed patients and 74 relapsed). The median (range) of follow-up for alive patients in vaccine trial is 6.5 years (2.9 – 8), and in the DB is 7.1 years (6 – 8). Two-sided Fisher’s exact tests and stratified log rank tests (with newly diagnosed or relapsed as the stratum) were used to compare baseline patient characteristics and time to event distributions (overall survival – OS, progression free survival – PFS, and time to progression – TTP) between the two groups. Results: The median (range) of age in vaccine trial and DB was 56 (30–69) and 57 (36–71) years respectively. There were no significant differences in the known prognostic factors including PCLI, B2M, and CRP. The median (95% confidence interval - CI) TTP for the vaccine trial and DB patients was 1.5 years (1.3 – 2.4) and 1.6 years (1.3 – 1.8); stratified log rank p value = 0.46. The median (95% CI) PFS for the vaccine trial and DB patients was 1.5 years (1.3 – 2.4) and 1.5 years (1.1 – 1.8), stratified logrank p value = 0.30. The median (95% CI) OS for the vaccine trial and DB patients was 5.3 years (4.0 -N/A), and 3.4 years (2.7 – 4.6); stratified logrank p value = 0.02. Conclusions: Despite the fact that no difference was seen in TTP or PFS, post-transplant vaccine therapy was associated with prolonged survival. This is similar to what has been reported in other tumor systems including prostate cancer and glioblastoma multiforme. This approach warrants further investigation, including preclinical studies aimed at optimizing the immune response and randomized trials to define the role of vaccine therapy in myeloma. Figure Figure

8580 Background: This pooled analysis examined the relationship between single-item and multiple-item quality of life (QOL) measures and assessed the agreement between changes in QOL and patient-reported adverse events (AE). Methods: Data from six lung cancer clinical trials involving 358 patients were pooled. All trials incorporated the UNISCALE and one of three multiple-item assessments: the Functional Assessment for Cancer Therapy-Lung, the Lung Cancer Symptom Scale, or the Symptom Distress Scale. A clinically significant decline (CSD) in QOL was defined as a 10-point drop from baseline. A CSD in AE was defined as a change from ≤ grade 2 at baseline to ≥ grade 3 post-baseline. Spearman rank correlations and Bland-Altman approach were used to assess agreement. The Kaplan-Meier method was used to evaluate the time to the first occurrence of a severe (grade 3+) AE and first CSD in QOL. Results: Correlations between the UNISCALE and multi-item assessments were modest (rho=0.49–0.66). At least one 10-point decline in the UNISCALE and multi-item assessments were reported by 58% and 40% respectively. At least one severe AE was reported in 44% of patients post-baseline. The percent agreement between experiencing a severe AE and a CSD in QOL was 49% and 59% for UNISCALE and the multi-item tools. For individual AE, the percent agreement between a CSD in AE and a CSD in QOL ranged from 37% to 50% for UNISCALE and 44% to 69% for the multi-item tools. The median time to the first CSD in QOL for UNISCALE and multi-item tools was 67 and 142 days respectively. The median time to the first occurrence of a severe AE was 304 days. Conclusions: QOL and AE provide quantifiably different information. A 10-point decline in QOL occurs earlier than CTC AE reporting. Patient reported outcomes may be more sensitive in identifying clinically relevant problems than physician rated symptom assessments. No significant financial relationships to disclose.

11119 Background: Evaluation of prognostic factors in carcinoid tumors of the lung is limited due to the rarity of disease. This study assessed Ki-67 expression and other clinical variables as prognostic factors in 262 patients. Methods: A systematic search of Mayo Clinic lung cancer epidemiology and tumor registry databases from 1997 to 2009 identified 449 consecutive patients, with 262 having available tissue blocks [40 atypical carcinoids (AC) and 222 typical carcinoids (TC)]. Clinical data were collected by chart review. Tissue blocks were reviewed by 1/3 pathologists using WHO criteria. Tumors were tested for the Ki-67 index using digital image analysis (tumor tracing) by two operators. The association and predictive value of the factors with recurrence-free and overall survival (RFS and OS) were explored using univariable Cox proportional Hazards model and concordance (c) index. Results: Age, stage, smoking history, lymph node (LN) involvement and Ki-67 index were significant prognostic factors for RFS and OS. Median follow-up on alive-patients is 5 years (range: 0.006-5). Median percentage of Ki-67 index of AC and TC were 1.61% and 0.56% (P<0.0001), respectively. Patients with Ki-67 ≥ 1% had significantly worse RFS (HR=3.69, P<0.0001) and OS (HR=3.69, P=0.0007) compared with Ki-67 < 1% group. The c-index of Ki-67 (0.65) was comparable to the pathologic distinction between AC and TC (0.62 for original diagnosis and 0.63 for central-reviewed diagnosis). Conclusions: Ki-67 index cutoff value of 1% is a valuable prognostic biomarker for pulmonary carcinoids based on this large cohort. Our data also provide strong evidence for clinical variables such as age, stage, smoking history, and LN involvement as clinical prognostic factors in pulmonary carcinoids. A prognostic calculator incorporating Ki-67 and clinical variables is under development. [Table: see text]

7524 Background: A multicenter study (Z4032) compared sublobar resection (SR) to sublobar resection with brachytherapy (SRB) for stage I NSCLC. Local recurrence (LR) and overall survival (OS) rates at 3-years (3-yr) were similar between arms (see abstract 113613). This analysis combines arms, and evaluates the effect of factors previously reported to impact oncological outcomes after SR. Methods: 213 patients (pts) were evaluable for analysis. LR was defined as recurrence at the staple line (local progression), same lobe away from the staple line, or within hilar nodes. Factors assessed for impact on 3-yr outcomes were: resection type (wedge/segmentectomy), margin size (<1cm /≥1cm), margin:tumor ratio (<1/ ≥1), tumor size (≤2cm/>2cm) and staple line cytology (+/-). Results: LR occurred in 27/213 (12.6%) pts and included local progression in 12/213 (5.6%). OS rate at 3-yr was 152/213 (71.4%). Trends favored the use of segmentectomy, margin:tumor ratio≥1, tumor size ≤2cm and negative staple line cytology; no factor reached statistical significance at 3-yr. The only factor significantly (p=0.02) associated with decreased 3-yr LR was margin size ≥1cm (8.3%) compared to margin<1cm (19.3%). Conclusions: SR is a good option for high-risk pts with NSCLC. The 3-yr OS rate of 71.4% and local progression rate of 5.6% are useful benchmarks to compare to other therapies. A resection margin of at least 1 cm is desirable. Clinical trial information: NCT00107172. [Table: see text]

7509 Background: NTX-010 is a naturally occurring replication-competent picornavirus with potent and selective tropism for SCLC tumor cells expressing neuroendocrine markers. A phase I study of NTX-010 showed evidence of antitumor activity in patients with SCLC. Methods: ES-SCLC patients (pts) with SD, PR or CR after at least 4 cycles of platinum-based chemotherapy were pre-registered to confirm diagnosis of SCLC with > 1 neuroendocrine marker by a central pathology review. Eligible pts were.randomized 1:1 to placebo (B) or NTX-010 (A). NTX-010 or placebo was administered intravenously as a 1-hour infusion in 100 mL normal saline as a single dose of 1 x1011vp/kg. Viral studies to determine distribution, clearance of the virus and the presence of neutralizing antibodies were done. The primary goal of this trial was to compare the progression-free survival (PFS) of arm A to B based on a sample size of 45 patients per arm to detect an improvement in median PFS from 3 to 5 months (m). A pre-planned interim futility analysis was done after 40 PFS events, and reported here. Results: The trial is permanently closed to accrual. One-hundred and twenty pts were pre-registered, of whom 58 were randomized. Baseline age, gender, ECOG performance status, and histology were balanced between arms. Median age was 63 (range: 44 - 82). 31% of pts had a PS of 0 and 69% of 1. Grade 4 adverse events were seen in 3 (12.5%) patients in arm A and none in arm B. Based on the interim futility analysis, PFS was 1.7 m (95% CI: 1.3-3.1) for arm A and 1.7 m (95% CI: 1.4-4.3) for arm B. Pts with viral RNA at 7 (7 pts) and 14 (6 pts) days had worse PFS compared to those with no detectable levels within arm A (1.0 vs 1.6 m, p=0.02; 0.9 vs. 1.2 m, p=0.06). Median follow-up in pts is 6.1 m. The 3-month OS estimates are 83% (95% CI: 69%-100%) and 85% (70%-100%) for arms A and B respectively. Conclusions: This phase II study showed no benefit in PFS for ES-SCLC patients receiving NTX-010. Pts with detectable virus at 7 and 14 days had worse PFS. Clinical trial information: NCT01017601.