No abstract

Concurrent administration pembrolizumab with chemotherapy in untreated classical Hodgkin lymphoma (CHL) has not previously been studied. To investigate this combination, we conducted a single arm study of concurrent pembrolizumab with AVD (APVD) for untreated CHL. We enrolled 30 patients (6 early favorable, 6 early unfavorable, and 18 advanced stage, median age 33 years (range 18-69 years)) and met the primary safety endpoint with no observed significant treatment delays in the first two cycles. Twelve patients experienced grade 3-4 non-hematologic adverse events (AEs) most commonly febrile neutropenia (5, 17%) and infection/sepsis (3, 10%). Grade 3-4 immune-related AEs were seen in 3 patients, including ALT elevation (3, 10%) and AST elevation (1, 3%). One patient experienced an episode of grade 2 colitis and arthritis. Six (20%) patients missed at least one dose of pembrolizumab due to adverse events, primarily grade 2 or higher transaminitis (5, 17%). Among 29 response-evaluable patients, the best overall response rate was 100% and CR rate of 90%. With median follow up of 2.1 years, 2-year progression-free survival (PFS) and overall survival were 97% and 100%, respectively. To date, no patient who withheld or discontinued pembrolizumab due to toxicity has progressed. Clearance of ctDNA was associated with superior PFS when measured after cycle 2 (p=0.025) and at end of treatment (EOT, p=0.0016). None of the 4 patients with persistent disease by FDG-PET at EOT yet negative ctDNA have relapsed to date. Concurrent APVD shows promising safety and efficacy, but may yield spurious PET findings in some patients. Trial Registration Number: NCT03331341

Introduction ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) represents standard frontline therapy for classical Hodgkin lymphoma (CHL) in North America. Substituting brentuximab vedotin for bleomycin in this regimen demonstrated improved efficacy in advanced stage patients (pts) but also increased toxicity (Connors et al NEJM 2017). PD-1 inhibitors are highly active in relapsed/refractory CHL, and the first-line setting may represent the ideal time for incorporating PD1 inhibition given the relatively intact host immunity and juxtaposition of malignant cells with T cells in the tumor microenvironment. Methods This was a single arm pilot study combining pembrolizumab with AVD in untreated CHL of any stage. Eligibility requiredECOG 0-1, adequate organ function, and measurable disease. The trial intended to enroll 30 pts. AVD was given at standard doses on days 1 and 15 of a 28-day cycle. Pembrolizumab (200 mg IV) was given starting cycle 1 day 1 and every 21 days thereafter (cycle 1 day 22, cycle 2 day 15 etc.). The primary objective was to estimate the safety of delivering 2 cycles of APVD. The secondary objective was to estimate the FDG-PET2 negative (Deauville score 1-3) rate after 2 cycles of APVD. Exploratory objectives included overall and progression free survival, predictive capacity of PET2 after APVD, analysis of ctDNA as well as assessments of metabolic tumor volume. After PET2 response assessment, subjects could continue APVD for up to 6 total cycles as deemed appropriate for their stage/risk factors (including alternate systemic therapy or radiotherapy). Results All 30 subjects have enrolled and received at least 2 cycles of therapy. Median age was 32 years (range 18-69). Most pts had advanced stage (stage I n =1 (3%), stage II n=11 (37%), stage III n=7 (23%), stage IV n=11, (37%)). Thirteen (43%) pts had B symptoms at diagnosis and 5 (17%) had bulky disease. Among the 30 pts enrolled, 28 are evaluable for response (one pt declined interim-PET and further treatment and final patient will have PET2 shortly after abstract deadline.Nineteen (68%) pts were PET2 neg (5PS 1-3). No PET2+ pts have progressed to date. End of therapy (EOT) PET negativity (after 2-6 cycles) was 78% (18/23). Among the 5 pts with residual FDG uptake at EOT, only 1 (20%) has developed recurrent lymphoma. With median follow-up of 10.3 months, 1-year PFS and OS were 96% and 100%, respectively. Six (20%) pts required interruption of pembrolizumab due to toxicity, primarily grade ≥ 2 transaminitis (83%). Those with grade 2 transaminitis (2/6) completed chemotherapy prior to resolving to grade 1 and did not receive additional pembrolizumab. Those with grade ≥ 3 transaminitis (3/6) were required to permanently discontinue pembrolizumab. All transaminitis was transient and resolved with steroids and/or withholding pembrolizumab. No pneumonitis and no other grade ≥ 3 immune-related AEs were observed. Toxicities were otherwise similar to those expected with ABVD chemotherapy. No pt had a treatment delay of > 21 days during the first 2 cycles, and no pt who interrupted pembrolizumab due to toxicity has relapsed. Updated efficacy and more detailed safety data will be presented at the meeting. Conclusion Pembrolizumab + AVD without a PD-1 lead-in is safe and effective therapy for frontline HL. In this study, PET2+ following APVD does not appear to be associated with high risk of disease relapse. Additional analyses of MTV and ctDNA are ongoing to better understand these results. Concurrent APVD, without an anti-PD-1 run-in, represents a well-tolerated, and efficacious backbone that can be further evaluated in all stages of CHL. Figure 1 Figure 1. Disclosures Lynch: Incyte: Research Funding; TG Therapeutics: Research Funding; Cyteir: Research Funding; Genentech: Research Funding; SeaGen: Research Funding; Bayer: Research Funding; Juno Therapetics: Research Funding; Morphosys: Consultancy. Ujjani: ACDT: Honoraria; Kite, a Gilead Company: Honoraria; Gilead: Honoraria; TG Therapeutics: Honoraria; Janssen: Consultancy; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Atara Bio: Consultancy; Loxo: Research Funding; Adaptive Biotechnologies: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Poh: Acrotech: Honoraria; Incyte: Research Funding; Morphosys: Consultancy. Smith: Incyte Corporation: Research Funding; Merck Sharp & Dohme Corp: Research Funding; Ignyta (spouse): Research Funding; Acerta Pharma BV: Research Funding; Portola Pharmaceuticals: Research Funding; ADC Therapeutics: Consultancy; Karyopharm: Consultancy; Ayala (spouse): Research Funding; De Novo Biopharma: Research Funding; KITE pharm: Consultancy; Genentech: Research Funding; AstraZeneca: Consultancy, Research Funding; Bristol Myers Squibb (spouse): Research Funding; Incyte: Consultancy; Bayer: Research Funding; Beigene: Consultancy, Research Funding; Millenium/Takeda: Consultancy. Shadman: Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding; Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy. Shustov: Seagen Inc.: Research Funding. Till: Mustang Bio: Consultancy, Patents & Royalties, Research Funding. Alizadeh: Gilead: Consultancy; Janssen Oncology: Honoraria; Roche: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Foresight Diagnostics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Bristol Myers Squibb: Research Funding; Forty Seven: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; CAPP Medical: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Cibermed: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Gopal: Epizyme: Consultancy, Honoraria; MorphoSys: Honoraria; Gilead: Consultancy, Honoraria, Research Funding; I-Mab bio: Consultancy, Honoraria, Research Funding; Genetech: Consultancy, Honoraria, Research Funding; Teva: Research Funding; Beigene: Consultancy, Honoraria; SeaGen: Consultancy, Honoraria, Research Funding; Incyte: Honoraria; Acrotech: Consultancy, Honoraria; Cellectar: Consultancy, Honoraria; Nurix Inc: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Astra-Zeneca: Research Funding; Agios: Research Funding; Bristol Meyers Squibb: Research Funding; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Kite: Consultancy, Honoraria.

No abstract

e17009 Background: [68Ga]-PSMA-11 positron emission tomography (PSMA PET) detects sites of biochemically recurrent prostate cancer (BCR) at higher rates than conventional imaging. We hypothesized that PSMA PET would lead to high change in management (CIM) rates in this setting. Methods: We prospectively recruited patients (pts) with BCR, defined as confirmed PSA > 0.2 ng/mL > 6 weeks post-surgery or PSA ≥2 ng/mL above nadir post-radiation therapy, to undergo Ga-68 PSMA-11 PET. Some also had equivocal lesions on CT, MRI, bone scan, or fluciclovine PET obtained prior to PSMA PET. Pre-PET intended treatment, PSA (ng/mL), and PSA doubling time (PSAdt, months) from most recent 3 values were recorded prior to imaging. Post-PET treatment (intended or actual) was collected from medical record. CIM was categorized as major (change in or addition of treatment modality) vs minor (change within treatment modality, such as altered radiation field). Any lesion with uptake above blood pool was interpreted as positive for prostate cancer by an experienced PET reader (DLC). All values were represented as the median [interquartile range, IQR]. Kruskal Wallis analysis tested for significant differences among groups. Results: 44 pts with BCR age 71 [10] with Gleason scores (GS) at diagnosis of 6 (N = 2), 7 (N = 23), 8 (N = 5), and 9 (N = 13) enrolled, 14/44 with equivocal lesions on conventional imaging. 42 had post-PSMA PET treatment decisions available in medical records for CIM analysis. Time from PSA nadir to PSA at time of PSMA PET was 5 [7.25] months. PSMA PET was positive in 33 (8/33 with equivocal lesions on prior imaging; 7 local disease only; 11 regional nodal metastases, 2/11 also with local disease; and 15 with distant metastases, 4/15 also with local disease, 9/15 with regional nodal metastases), negative in 6, and equivocal in 5 pts. Of those with distant metastases, 8 had oligometastases, defined as 3 or fewer distinct sites (1 site = single nodal region or single bone lesion), 4 in bones and 4 in distant nodes. CIM rate was 71% (30/42) overall, 65.5% (16/29 major, 3/29 minor) in pts with BCR and negative conventional imaging; 84.6% (11/13, all major) in pts with equivocal lesions on conventional imaging. Of the patients with major CIM, a treatment modality was added in 21/27, modality switched in 3/27, and a modality removed in 3/27. PSA was significantly lower (p = 0.04) for those with negative or equivocal PSMA PET (0.5 [2.7]) than those with localized disease (4.1 [2.8]), regional nodal (1.1 [3.4]) or distant metastases (3.8 [5.3]), but not PSAdt (p = 0.2, negative/equivocal PET 5 [6.5], localized 15 [36], regional nodal metastases 11 [13], distant metastases 6 [6]). Conclusions: PSMA PET may impact decision making in pts with BCR after treatment of localized prostate cancer, particularly for those with equivocal findings on conventional imaging, regardless of clinical risk at diagnosis. Clinical trial information: NCT04777071.