Knopp, Michael V.

Background FDG-PET is used in staging and response assessments in patients (pts) with DLBCL. An analysis of 158 pts with DLBCL receiving R-CHOP or DA-EPOCH-R on CALGB/Alliance 50303 failed to show an association between the interim PET (iPET, after cycle 2 of therapy) visual 5-point scale score (5-PS) by central review and progression-free survival (PFS) or overall survival (OS), but did show a significant association between percent change in FDG uptake from baseline to after cycle 2 (∆SUV) and PFS/OS (Schoder et al. 2020). As central review of FDG-PET is not feasible in routine practice, we retrospectively compared local vs central readings, and determined associations from local imaging data with PFS/OS. Methods 126 pts at baseline and 109 at iPET had local imaging data submitted across 21 institutions. Visual scores 1-3 defined PET- and scores 4-5 defined PET+ disease. ∆SUV was defined as the percent change in the maximum SUV at any site (maxSUV) from baseline to iPET. Continuous ∆SUV and categorized ∆SUV (<66% vs >66%) were analyzed. Differences in quantitative measures were calculated as the local minus central result. The Kappa statistic estimated agreement in PET and ∆SUV groups between local and central review. PFS and OS distributions for local PET and ∆SUV groups were landmarked at iPET, estimated with the Kaplan-Meier method, and compared using the log-rank test. Results At baseline, maxSUV was reported locally and centrally in 118 pts. Median maxSUV was 24.3 (range: 5.9-77.3) by local review and 24.3 (range: 5.9-77.0) by central review. The median difference in maxSUV was 0 (range: -12.9 to 21.9), with 50% of differences between -1.1 and 0.1, and 90% of differences between -7.8 and 4.1. In 106 pts with visual iPET 5-PS results, 52 (49.1%) were PET+ by local review and 37 (34.9%) by central review. Agreement in local and central review was moderate (kappa=0.53), occurring in 81 pts (76.4%; 32 PET+ and 49 PET-). Disagreement occurred in 25 patients, 20 with local PET+ but central PET- and 5 with local PET- but central PET+. iPET maxSUV was reported locally and centrally in 90 pts. Median maxSUV was 3.4 (range: 0-18.3) by local review and 3.3 (range: 1.2-18.2) by central review. The median difference in maxSUV was 0 (range: -8.6 to 2.4), with 50% of differences between -0.3 and 0.4, and 90% of differences between -4.4 and 1.8. ∆SUV was calculated in 87 pts. Median ∆SUV was 84.6% (range: -3.0% to 95.9%) by local review and 85.1% (range: -34.9% to 95.8%) by central review. The median difference in ∆SUV was -0.3 (range: -19.6 to 31.9), with 50% of differences between -2.1 and 1.1, and 90% of differences between -7.1 and 12.3. ∆SUV was <66% in 12 (13.8%) pts by local review and 12 pts by central review. Agreement in local and central review was high (kappa=0.81), occurring in 83 pts (95.4%; 10 with ∆SUV <66%, 73 with ∆SUV >66%). Disagreement occurred in 4 pts, 2 in each direction. Using local data, PFS and OS estimates were numerically lower in pts with iPET+ vs iPET- disease, but did not reach statistical significance (p=0.12 and p=0.15). Two-year estimates for PFS were 79% (95% CI 68-91%) and 89% (95% CI 81-98%), and 2-year estimates for OS were 84% (95% CI 75-95%) and 96% (95% CI 91-100%) in pts with iPET+ and iPET-, respectively. In contrast, ∆SUV groups were significantly associated with PFS and OS (p=0.03 and p=0.002). Two-year estimates for PFS were 56% (95% CI 34-94%) and 87% (95% CI 79-95%) and 2-year estimates for OS were 56% (95% CI 34-94%) and 93% (95% CI 88-99%) in pts with ∆SUV <66% and ∆SUV >66%, respectively. Conclusion Agreement in visual 5-PS at iPET was moderate; most discrepancies arose from a local PET+ result when central review called PET-. Differences in maxSUV and ∆SUV tended to be small. Grouping ∆SUV resulted in only 4 discrepancies (4.6%). Similar to the previous analysis using central data, the separation in PFS and OS curves using local data for ∆SUV was greater than by visual 5-PS. Encouragingly, the agreement in ∆SUV of <66% vs ≥66% was high between local and central review. Overall agreement however may be unduly influenced by the large proportion of pts with ∆SUV ≥66%, with less certainty in agreement for pts with ∆SUV <66%. Larger prospective studies comparing local and central imaging data are warranted to best determine the utility of local imaging in clinical trials. Support: P30 CA008748, U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. ClinicalTrials.gov Identifier: NCT00118209 (CALGB 50303) Disclosures Kahl: Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy; Pharmacyclics LLC: Consultancy; Genentech: Consultancy; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy. Friedberg:Astellas: Consultancy; Acerta Pharma - A member of the AstraZeneca Group, Bayer HealthCare Pharmaceuticals.: Other; Portola Pharmaceuticals: Consultancy; Seattle Genetics: Research Funding; Roche: Other: Travel expenses; Kite Pharmaceuticals: Research Funding; Bayer: Consultancy. Leonard:MEI Pharma: Consultancy; Sutro: Consultancy; Bayer: Consultancy; BMS/Celgene: Consultancy; GenMab: Consultancy; Roche/Genentech: Consultancy; Gilead/Kite: Consultancy; ADC Therapeutics: Consultancy; Regeneron: Consultancy; Epizyme: Consultancy; Miltenyi: Consultancy; AstraZeneca: Consultancy; Karyopharm: Consultancy. Bartlett:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Millennium: Research Funding; Merck: Research Funding; Kite, a Gilead Company: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Forty Seven: Research Funding; BMS/Celgene: Research Funding; BTG: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Acerta: Consultancy; Affimed Therapeutics: Research Funding; ADC Therapeutics: Consultancy; Autolus: Research Funding.

Abstract As part of a randomized, prospective clinical trial in large cell lymphoma, we conducted serial fluorodeoxyglucose positron emission tomography (FDG-PET) at baseline, after 2 cycles of chemotherapy (interim PET [i-PET]), and at end of treatment (EoT) to identify biomarkers of response that are predictive of remission and survival. Scans were interpreted in a core laboratory by 2 imaging experts, using the visual Deauville 5-point scale (5-PS), and by calculating percent change in FDG uptake (change in standardized uptake value [ΔSUV]). Visual scores of 1 through 3 and ΔSUV ≥66% were prospectively defined as negative. Of 524 patients enrolled in the parent trial, 169 agreed to enroll in the PET substudy and 158 were eligible for final analysis. In this selected population, all had FDG-avid disease at baseline; by 5-PS, 55 (35%) remained positive on i-PET and 28 (18%) on EoT PET. Median ΔSUV on i-PET was 86.2%. With a median follow-up of 5 years, ΔSUV, as continuous variable, was associated with progression-free survival (PFS) (hazard ratio [HR] = 0.99; 95% confidence interval [CI], 0.97-1.00; P = .02) and overall survival (OS) (HR, 0.98; 95% CI, 0.97-0.99; P = .03). ΔSUV ≥66% was predictive of OS (HR, 0.31; 95% CI, 0.11-0.85; P = .02) but not PFS (HR, 0.47; 95% CI, 0.19-1.13; P = .09). Visual 5-PS on i-PET did not predict outcome. ΔSUV, but not visual analysis, on i-PET predicted OS in DLBCL, although the low number of events limited the statistical analysis. These data may help guide future clinical trials using PET response-adapted therapy. This trial was registered at www.clinicaltrials.gov as #NCT00118209.

Abstract Introduction For patients with Stage III/IV Hodgkin lymphoma (HL), lack of response as assessed by PET scan following cycle 2 (PET2) of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is predictive of poor clinical outcomes. SWOG Study S0816 utilized response-adapted therapy, where patients achieving a complete remission (CR) on PET2 (Deauville Score ≤ 3) continued 4 additional cycles of ABVD and those patients unable to achieve a complete remission (CR) on PET2 (Deauville Score > 3) were switched to therapy with escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) for 6 cycles. This study demonstrated a 2-year PFS of 64% in the PET2+ patients after switching to eBEACOPP, which was much higher than expected (Press 2016). Herein, we report the 5-year follow-up of survival and toxicities of the patients treated on S0816. Methods Patients with Stage III/IV HL were enrolled to S0816 from 7/1/09-12/2/12 (n=358). Eligible patients were age 18-60 years, had measurable disease, no prior lymphoma therapy, a Zubrod performance status of 0-2, and no serious medical comorbidities. Patients were treated with response-adapted therapy as above. A subset of 336 eligible and HIV-negative patients were analyzed. Of 336, 331 had central review of PET2. PFS and OS estimates were calculated using the Kaplan-Meier method. The two-sided Fisher's exact test was used to compare the rate of second cancer between patients switched to treatment eBEACOPP and those treated with continued ABVD after 2 initial cycles of ABVD. Results The median age of patients was 32 years (range, 18-60). All were Stage III/IV and 51% had an International Prognostic Score of ≥ 3. PET2 was negative in 271 patients (82%) and positive in 60 patients (18%). Of PET2+ patients, 49 (82%) switched to eBEACOPP as planned and 11 (18%) declined. Median follow-up is now 5.9 years (range, 0.2-8.3 years). Eighty-five (25%) patients have either progressed or died, for an estimated 5-year PFS of 74% (95% CI: 69%-79%; Figure 1). There were 64 (24%) events in those patients who were PET2- for a 5-year PFS of 76% (95% CI: 71-81%; Figure 2). There were 20 (33%) events in those patients who were PET2+ for a 5-year PFS of 65% (95% CI: 51-76%; Figure 2). One event occurred in a patient without central review of PET2. Nineteen patients have died for an estimated 5-year overall survival of 94% (95% CI: 91%-96%; Figure 1). Eleven (3%) patients died of HL including 6 (2%) that had PET2- and 5 (8%) that had PET2+. Other causes of death included: treatment-related toxicity [sepsis (eBEACOPP n=1), bleomycin lung injury (eBEACOPP n=1; ABVD n=1), and graft versus host disease (ABVD n=1)]; second primary cancers [(eBEACOPP n=2; cervical cancer and non-Hodgkin lymphoma (NHL)]; and unknown causes (ABVD n=2). Post-therapy grade 3 adverse events were uncommon but included 1 case each of heart failure, peripheral neuropathy, prolonged neutropenia, diarrhea, DVT (catheter-related) in patients who received continued ABVD and osteonecrosis of hips/shoulders in patients who received eBEACOPP. There were 13 (4%) cases of reported second cancers, including 7 (14%) in patients treated with eBEACOPP [1 each of myelodysplastic syndrome, kidney, melanoma, NHL, cervical, medullary thyroid, and basal cell carcinoma] and 6 (2%) in patients treated with ABVD (1 each of kidney, melanoma, NHL, bladder, prostate, and squamous cell carcinoma; 2-sided Fisher's exact P value = 0.001). Conclusions The long-term overall survival of the patients treated on S0816 remains high (94%) at 5 years. Despite historical data suggesting favorable clinical outcomes in patients with a negative PET2, nearly 25% of these patients experienced relapse events, demonstrating limitations of a PET-adapted approach and of standard frontline therapy with ABVD. In patients who were PET2+, PFS was favorable relative to historical series, but was associated with a high rate of secondary malignancies. Our results emphasize the importance of long-term follow-up in this disease, and the need for better biomarkers at diagnosis of HL and less toxic approaches for patients with a positive PET2. Acknowledgment In memory of Oliver W. Press, principal investigator of this trial, who died in 2017. Disclosures Straus: DAVA Oncology: Consultancy, Honoraria; Medical Crossfire: Speakers Bureau; Millenium (Takeda): Consultancy, Research Funding; JUNO: Consultancy; Bayer: Consultancy; Onco Tracker: Consultancy; Seattle Genetics: Consultancy; Roch China: Speakers Bureau; InPractice Elselvier: Consultancy; Memorial Sloan Kettering Cancer Center: Employment. Rimsza:NanoString: Other: Inventor on the patent for the Lymph2Cx assay. Bartlett:ImaginAB: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Bristol-Meyers Squibb: Research Funding; Merck & Co: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding; Millennium: Research Funding; Janssen: Research Funding; Affimed: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding. Evens:Janssen: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Affimed: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Tesaro: Research Funding; Acerta: Consultancy. LaCasce:Seattle Genetics: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board; Research to Practice: Speakers Bureau; Humanigen: Consultancy, Honoraria. Barr:AbbVie, Gilead: Consultancy. Leonard:Gilead: Consultancy; Sutro: Consultancy; BMS: Consultancy; Juno: Consultancy; MEI Pharma: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy; Biotest: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Genentech/Roche: Consultancy; ADC Therapeutics: Consultancy; United Therapeutics: Consultancy. Kahl:Genentech: Consultancy; Celgene: Consultancy; Acerta: Consultancy; AstraZeneca: Consultancy; Juno: Consultancy; CTI: Consultancy; ADC Therapeutics: Consultancy; Abbvie: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy. Smith:BMS: Consultancy; Portola: Honoraria. Friedberg:Bayer: Honoraria.

AbstractThe investigators present results on the long-term value and limitations of early interim positron emission tomography (PET) scanning in advanced Hodgkin lymphoma.

e17580 Background: Cabozantinib is a small molecule multiple-receptor tyrosine kinase inhibitor that primarily targets MET and vascular endothelial growth factor receptor 2 (VEGFR2). We evaluated the effect of cabozantinib on BTM in RAIR DTC. We also assessed the response of BM to cabozantinib using 18F Sodium Fluoride (NaF) PET and radionuclide bone scans. Methods: This prospective analysis was performed as part of a multicenter International Thyroid Oncology Group phase II study of cabozantinibin patients with RAIR DTC who progressed on prior VEGFR-targeted therapy (NCT01811212). BTM [serum C-telopeptide (CTx), osteocalcin, N-telopeptide (NTx), procollagen type 1 (Pc1) and urinary NTx] and NaF PET or Tc-MDP scans were done at baseline and after 8 weeks of therapy. A paired t-test was used between baseline and week 8 BTM. Results: Primary study results were presented elsewhere (Shah, et al. 2015, International Thyroid Congress) showing a response rate of 36% with cabozantinib. Of 25 patients (pts) enrolled, 21 had BM, 10 of whom were on bone-modifying agents (BMA) prior to week 8. Only 2 pts had elevated BTM at baseline. In all pts who had paired BTM, there was a statistically significant decline in all BTM except NTx by week 8 (table). Pts not on BMA also had a significant decline in CTx (p 0.0003), urine NTx (p 0.0300), and Pc1 (p 0.0030) compared to baseline. 19 pts were evaluable for overall response and there was no correlation between BTM and response rate. 6/21 patients underwent paired NaF PET scans and 4/6 had minor reduction in lesion uptake at 8 weeks. Conclusions: Interestingly, most of our patients had normal baseline BTM despite BM. Cabozantinib was associated with a strikingly significant reduction in all BTM (even when BTM were within normal limits at baseline) except NTx by week 8. Minor decreases in bone lesion uptake was noted on NaF PET in 4/6 evaluable patients. Clinical trial information: NCT01811212. [Table: see text]

Abstract Introduction: AI-induced joint symptoms negatively impact drug adherence and quality of life. Based on observations that n-3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory effects and that the mechanism of AI-induced joint symptoms may be partly due to inflammation, we hypothesized that women taking more n-3 PUFAs are less likely to develop AI-induced joint symptoms. Methods: We conducted a randomized, double-blind, placebo-controlled study comparing n-3 PUFA vs placebo in postmenopausal breast cancer patients starting adjuvant AIs. Participants were randomized to n-3 supplements [2.58 g eicosapentaenoic acid + 1.74 g docosahexaenoic acid/day; Marine Nutriceuticals, Mt. Bethel, PA] vs matched placebo for 24 weeks (wks). Primary endpoints was feasibility; secondary outcomes were self-reported symptoms as assessed by the Brief Pain Inventory short form (BPI-SF), Functional Assessment of Cancer Treatment, Breast & Endocrine Symptoms (FACTB-ES), and Stanford's Health Assessment and Disability Index (HAQ) at baseline prior to AI receipt, 12 and 24 wks. Compliance and toxicity were evaluated monthly. Serial peripheral blood n-3 PUFA levels and inflammatory cytokines (IL-6, TNFR2, IL-17) were drawn. MRI of hands/wrists was performed in selected patients using a 3 Tesla dedicated wrist coil at baseline and treatment end. Results: Forty-four women were enrolled and randomized to study drug; 42 received ≥1 cycle (4 wks) of treatment; 36 had ≥1 post treatment evaluation at wk 12 or 24. Median age was 59.5 (range 43-76); history of prior taxane (n=15, 34%). The two groups’ baseline characteristics were similar. Overall, 93% and 88% of patients took >80% of the placebo and n-3 PUFA doses, respectively. Baseline erythrocyte n-3 PUFA was similar for both groups (6.6% ± 1.6%, 7.2% ±1.9%, p=0.20), but higher in the n-3 PUFA arm by wk 24 (6.5%±1.0% vs 15.0%±3.3%, p<0.001). Most toxicities were grade 1; the n-3 PUFA arm had only 1 (2.5%) grade 3 toxicity (diarrhea). The n-3 PUFA arm reported lower mean BPI-SF scores after treatment [(-.0.28/ -0.25 at week 12/24); but not statistically significant compared to placebo (p=0.494 and 0.601)]. Based on BPI-SF, the n-3 PUFA arm reported less interference of pain symptoms compared to placebo at 12 weeks (-.72, p=0.08). This arm also had a decreased walking, activity and working (WAW) score on BPI-SF at 12 weeks (-.81 p=0.05), and reported significantly greater pain relief from medications at 12 (p=0.043) and 24 weeks (p=0.011). Both arms had similar baseline and wk 24 serum IL-6 levels; levels decreased from baseline to wk 24 in the n-3 PUFA arm (-0.54±0.25, p=0.048). There was a non-significant trend (p= 0.2) toward decreased wrist inflammation by MRI imaging at 24 wks in the n-3 PUFA arm. Conclusions: This is the first randomized pilot study to show that n-3 PUFA supplementation to prevent AI-induced joint symptoms is feasible and well tolerated. There is preliminary evidence that this intervention may help reduce the burden of AI-induced arthralgias. OSU Study #11022; ClinicalTrials.gov Identifier: NCT01478477. Grants from the National Cancer Institute (CA037447-26) to the Alliance for Clinical Trials in Oncology supported this pilot study. Citation Format: Maryam B Lustberg, Tonya Orchard, Xueliang Pan, Raquel Reinbolt, Amanda Logan, Joanne Lester, Rachel M Layman, Erin Macrae, Ewa Mrozek, Bhuvaneswari Ramaswamy, Robert Wesolowski, Michael Berger, Michael Knopp, Charles Loprinzi, Charles L Shapiro, Lisa Yee. Prevention of aromatase Inhibitor (AI)-induced joint symptoms with omega-3 fatty acid supplementation: A randomized placebo-controlled pilot study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-09-03.