Durable Progression-free Survival Research Articles

Stereotactic Body Radiotherapy for Extracranial Oligometastatic Disease from Head and Neck Primary Cancers: A Systematic Review and Meta-Analysis.

Stereotactic body radiotherapy (SBRT) is increasingly used to treat disease in the oligometastatic (OM) setting due to mounting evidence demonstrating its efficacy and safety. Given the low population representation in prospective studies, we performed a systematic review and meta-analysis of outcomes of HNC patients with extracranial OM disease treated with SBRT. A systematic review was conducted with Cochrane, Medline, and Embase databases queried from inception to August 2022 for studies with extracranial OM HNC treated with stereotactic radiotherapy. Polymetastatic patients (>five lesions), mixed-primary cohorts failing to report HNC separately, lack of treatment to all lesions, nonquantitative endpoints, and other definitive treatments (surgery, conventional radiotherapy, and radioablation) were excluded. The meta-analysis examined the pooled effects of 12- and 24-month local control (LC) per lesion, progression-free survival (PFS), and overall survival (OS). Weighted random-effects were assessed using the DerSimonian and Laird method, with heterogeneity evaluated using the I2 statistic and Cochran Qtest. Forest plots were generated for each endpoint. Fifteen studies met the inclusion criteria (639 patients, 831 lesions), with twelve eligible for quantitative synthesis with common endpoints and sufficient reporting. Fourteen studies were retrospective, with a single prospective trial. Studies were small, with a median of 32 patients (range: 6-81) and 63 lesions (range: 6-126). The OM definition varied, with a maximum of two to five metastases, mixed synchronous and metachronous lesions, and a few studies including oligoprogressive lesions. The most common site of metastasis was the lung. Radiation was delivered in 1-10 fractions (20-70 Gy). The one-year LC (LC1), reported in 12 studies, was 86.9% (95% confidence interval [CI]: 79.3-91.9%). LC2 was 77.9% (95% CI: 66.4-86.3%), with heterogeneity across studies. PFS was reported in five studies, with a PFS1 of 43.0% (95% CI: 35.0-51.4%) and PFS2 of 23.9% (95% CI: 17.8-31.2%), with homogeneity across studies. OS was analyzed in nine studies, demonstrating an OS1 of 80.1% (95% CI: 74.2-85.0%) and OS2 of 60.7% (95% CI: 51.3-69.4%). Treatment was well tolerated with no reported grade 4 or 5 toxicities. Grade 3 toxicity rates were uniformly below 5% when reported. SBRT offers excellent LC and promising OS, with acceptable toxicities in OM HNC. Durable PFS remains rare, highlighting the need for effective local or systemic therapies in this population. Further investigations on concurrent and adjuvant therapies are warranted.

Combining Dual Checkpoint Immunotherapy with Ablative Radiation to All Sites of Oligometastatic Non-Small Cell Lung Cancer: Toxicity and Efficacy Results of a Phase 1b Trial

BackgroundAblative local treatment of all radiographically detected metastatic sites in patients with oligometastatic NSCLC increases progression free survival (PFS) and overall survival (OS). Prior studies demonstrated safety of combining stereotactic body radiation therapy (SBRT) with single agent immunotherapy. We investigated the safety of combining SBRT to all metastatic tumor sites with dual checkpoint, anti-CTLA-4 and anti-PD-L1 immunotherapy for patients with oligometastatic NSCLC. MethodsWe conducted a phase Ib clinical trial in patients with oligometastatic NSCLC with up to 6 sites of extracranial metastatic disease. All sites of disease were treated with stereotactic body radiation therapy (SBRT) to a dose of 30 – 50 Gy in 5 fractions. Dual checkpoint immunotherapy was started 7 days following completion of radiation utilizing anti-CTLA-4 (tremelimumab) and anti-PD-L1 (durvalumab) immunotherapy for a total of four cycles followed by durvalumab alone until progression or toxicity. ResultsSeventeen patients were enrolled on study, with 15 patients receiving at least one dose of combination immunotherapy per protocol. The study was closed early (17 of planned 21 patients) due to slow accrual during COVID 19 pandemic. Grade 3+ treatment related adverse events were seen in 6 patients (40%). Of these, only one was felt possibly related to the addition of SBRT to immunotherapy. Median PFS was 42 months while median OS has not yet been reached. ConclusionsDelivering ablative SBRT to all sites of metastatic disease in combination with dual checkpoint immunotherapy did not result in excessive rates of toxicity compared to historical studies of dual checkpoint immunotherapy alone. While not powered for treatment efficacy results, durable PFS and OS results suggest potential therapeutic benefit compared to immunotherapy or radiation alone in this patient population.

Extended Follow-up of ALPINE Randomized Phase 3 Study Confirms Sustained Superior Progression-Free Survival of Zanubrutinib Versus Ibrutinib for Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (R/R CLL/SLL)

Introduction: ALPINE, a randomized, multinational phase 3 study (NCT03734016) in patients with R/R CLL/SLL, established the statistical and clinically meaningful superiority of zanubrutinib over ibrutinib on progression-free survival (PFS) and overall response rate (ORR) and confirmed the favorable safety/tolerability profile of zanubrutinib (Brown et al. NEJM; 2022). Now, with 3 years of overall study follow-up, we report the results of an extended follow-up analysis. Methods: As previously published, patients with R/R CLL/SLL who had received ≥1 prior therapy and had measurable disease were randomized 1:1 to receive zanubrutinib or ibrutinib. Efficacy assessments, including PFS and ORR, were evaluated by the investigator based on 2008 iwCLL criteria; sensitivity analyses to confirm PFS results were also conducted. Updated safety analyses were performed. All reported P-values are descriptive. Results: Overall, 652 patients were randomized to receive zanubrutinib (n=327) or ibrutinib (n=325). As of 15 May 2023, 63.3% (n=207/327) of patients remain on zanubrutinib and 52.3% (n=170/325) remain on ibrutinib. At a median study follow-up of 36.3 months, benefit of zanubrutinib over ibrutinib was sustained (HR: 0.67 [95% CI, 0.52-0.86]; 2-sided P=.002; Fig 1). At 36 months, the PFS rates were 65.8% with zanubrutinib and 54.3% with ibrutinib. Benefits in PFS with zanubrutinib were also observed across major subgroups, including in patients with del(17p)/ TP53 mutations (HR: 0.52 [95% CI, 0.32-0.83] 2-sided P=.005) where 36-month PFS rates were 60.1% and 43.6%, respectively. Additionally, the zanubrutinib PFS benefit was confirmed in a sensitivity analysis that included only progression and death events that occurred on active treatment (HR: 0.69 [95% CI, 0.49-0.97]; 2-sided P=.031). ORR remained higher with zanubrutinib compared with ibrutinib (85.0% vs 74.8%; 2-sided P=.001). Responses deepened in both arms with CR/CRi rates of 10.1% (zanubrutinib) and 7.4% (ibrutinib); therate of PR-L or better was 90.2% vs 82.8%, respectively. Fifty-nine (18.0%) patients treated with zanubrutinib and 71 (21.8%) treated with ibrutinib had died (OS HR: 0.76 [95% CI, 0.54-1.08]); 36-month OS rates were 82.6% (zanubrutinib) and 79.7% (ibrutinib). In this extended follow-up, median treatment duration was 34.7 months (zanubrutinib) and 31.5 months (ibrutinib). Across both arms, the most common reasons for treatment discontinuation were AEs (20.2%, zanubrutinib; 24.9%, ibrutinib) and progressive disease (12.2%, zanubrutinib; 16.3%, ibrutinib). Dose interruption and dose reduction due to AEs were 59.6% vs 61.1% and 14.2% vs 17.6% with zanubrutinib vs ibrutinib, respectively. The most common AEs of any grade with zanubrutinib and ibrutinib were COVID-19 (37.3% vs 25.6%), diarrhea (17.9% vs 25.6%), and upper respiratory tract infection (25.9% vs 17.3%). Rates of any grade ≥3 AEs and serious AEs were 72.2% vs 75.6% and 49.7% vs 57.4% with zanubrutinib vs ibrutinib, respectively. Most commonly reported grade ≥3 AEs were neutropenia (17.3% vs 16.4%) and hypertension (15.1% vs 12.0%). Rates of serious infections were 30.6% in each treatment arm. Discontinuation rates due to cardiac disorders were lower with zanubrutinib (0.6% [n=2]) vs ibrutinib (4.6% [n=15]). Overall cardiac events remain lower with zanubrutinib, including atrial fibrillation/flutter (6.2% vs 16.0%; 2-sided P<.0001). Across this study, no grade 5 AEs due to cardiac disorders were observed with zanubrutinib but were reported in 6 patients (1.9%) with ibrutinib ( Table 1). Conclusions: ALPINE was the first study to demonstrate PFS superiority in a head-to-head comparison of BTK inhibitors. At a median follow-up of 3 years, the study showed sustained PFS benefits of zanubrutinib over ibrutinib. The durable PFS benefits with zanubrutinib were observed across major subgroups, including multiple sensitivity analyses. The overall safety/tolerability profiles were consistent with previous reports for both treatments. The cardiac safety profile remained favorable for zanubrutinib compared with ibrutinib, with no new safety signals emerging with longer follow-up. With over 3 years of treatment, zanubrutinib continues to be a more efficacious and better tolerated treatment than ibrutinib for patients with R/R CLL/SLL. At time of presentation, data with further follow-up will be presented.

Th17-inducing dendritic cell vaccines stimulate effective CD4 T cell-dependent antitumor immunity in ovarian cancer that overcomes resistance to immune checkpoint blockade

BackgroundOvarian cancer (OC), a highly lethal cancer in women, has a 48% 5-year overall survival rate. Prior studies link the presence of IL-17 and Th17 T cells in the tumor...

Comparison of Baseline 68Ga-FAPI and 18F-FDG PET/CT for Prediction of Response and Clinical Outcome in Patients with Unresectable Hepatocellular Carcinoma Treated with PD-1 Inhibitor and Lenvatinib.

Fibroblast activation protein contributes to immunosuppression and resistance to immunotherapies. This study aimed to compare baseline 68Ga-labeled fibroblast activation protein inhibitor (68Ga-FAPI) PET/CT and 18F-FDG PET/CT in response and survival prediction in unresectable hepatocellular carcinoma (uHCC) patients treated with the combination of programmed cell death 1 (PD-1) inhibitor and lenvatinib. Methods: In this prospective cohort study, 22 patients with uHCC who underwent baseline 18F-FDG and 68Ga-FAPI PET/CT and soon began taking a combination of PD-1 inhibitor and lenvatinib were recruited. Semiquantitative indices of baseline PET/CT were measured as 18F-FDG SUVmax, metabolic tumor volume, total lesion glycolysis, 68Ga-FAPI SUVmax, 68Ga-FAPI-avid tumor volume (FTV), and total lesion fibroblast activation protein expression (TLF). The primary endpoint was durable or nondurable clinical benefit after treatment, and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: The overall response rate of the combination therapy was 41% (9/22). Fifty percent of patients had durable clinical benefit. Median PFS and OS were 4.8 and 14.4 mo, respectively. Patients with nondurable clinical benefit showed a significantly higher FTV and TLF than those with durable clinical benefit, whereas 18F-FDG parameters overlapped. A higher 68Ga-FAPI-avid tumor burden (FTV > 230.46 cm3 or TLF > 961.74 SUVbody weight⋅cm3) predicted both shorter PFS (4.0 vs. 13.5 mo, P = 0.016) and shorter OS (7.8 mo vs. not reached, P = 0.030). Patients with a higher metabolic tumor burden (metabolic tumor volume > 206.80 cm3 or total lesion glycolysis > 693.53 SUVbody weight⋅cm3) showed a shorter OS although the difference did not reach statistical significance (P = 0.085). In multivariate analysis, a higher 68Ga-FAPI-avid tumor burden (hazard ratio [HR], 3.88 [95% CI, 1.26-12.01]; P = 0.020) and macrovascular invasion (HR, 4.00 [95% CI, 1.06-15.14]; P = 0.039) independently predicted a shorter PFS, whereas a higher 68Ga-FAPI-avid tumor burden (HR, 5.92 [95% CI, 1.19-29.42]; P = 0.035) and bone metastases (HR, 5.88 [95% CI, 1.33-25.93]; P = 0.022) independently predicted a shorter OS. Conclusion: Volumetric indices on baseline 68Ga-FAPI PET/CT were potentially independent prognostic factors to predict durable clinical benefit, PFS, and OS in uHCC patients treated with a combination of PD-1 and lenvatinib. Baseline 68Ga-FAPI PET/CT may facilitate uHCC patient selection before combination therapy.

Long-term follow up of selinexor maintenance in patients with TP53wt advanced or recurrent endometrial cancer: A pre-specified subgroup analysis from the phase 3 ENGOT-EN5/GOG-3055/SIENDO study.

427956 Background: Molecular characterization is important to inform treatment decisions for patients with endometrial cancer (EC). Wild type TP53 ( TP53wt) is found in ~75% of newly diagnosed EC and 50% of advanced/recurrent tumors; there are no specific targeted therapies available for patients with TP53wt EC. Selinexor is an investigational oral XPO1 inhibitor that drives nuclear retention and functional activation of wild type tumor suppressor proteins, including p53. Methods: SIENDO (NCT03555422) was a phase 3 double-blind study evaluating selinexor vs placebo as maintenance therapy in patients with advanced/recurrent EC following response to prior systemic therapy. The primary endpoint was progression-free survival (PFS), which was previously presented at the ESMO plenary in March 2022. Preliminary analysis of a pre-specified exploratory subgroup of patients with TP53wt EC showed a decrease in risk for progression or death with a median PFS of 13.7 months with selinexor as maintenance therapy vs 3.7 months with placebo at the time of primary PFS analysis. The safety and efficacy of selinexor as maintenance therapy was now further assessed with long-term follow-up in the pre-specified subgroup of patients with TP53wt EC. Results: 113 patients with TP53wt EC were randomly assigned to receive selinexor vs placebo as maintenance therapy (selinexor, n=77/placebo, n=36). As of data cutoff on Nov 30, 2022, median follow-up was 20.3 months, with 26.3% and 22.9% patients still on selinexor and placebo treatment, respectively. Median PFS for the TP53wt subgroup was 20.8 months with selinexor vs 5.2 months with placebo (HR [Stratified by chemotherapy response CR vs PR] 0.46; 95% CI (0.27, 0.79), nominal one-sided p=0.002). Efficacy was observed regardless of MSS/MSI status. The most common adverse events (AEs) of any grade (selinexor/placebo) were nausea (90%/34%), vomiting (61%/11%) and diarrhea (38%/34%); and most common grade 3+ AEs included: neutropenia (18%/0%), nausea (12%/0%), and thrombocytopenia (9%/0%). TEAEs leading to discontinuations were reported in 15%/0% of patients, respectively. Conclusions: Long-term follow-up of a pre-specified subgroup analysis showed durable PFS benefit with selinexor maintenance in TP53wt EC, which offers the potential to prolong response to prior systemic therapy. These data suggest that TP53 status is a robust prognostic biomarker for EC and selinexor may provide meaningful benefit in patients who have TP53wt tumors. A phase 3 trial is underway to further investigate the safety and efficacy of selinexor as maintenance therapy in patients with advanced or recurrent TP53wt EC (NCT05611931). Updated PFS and results in additional molecular subtypes (MSS/MSI) of the TP53wt subgroup will be included at the time of presentation. Clinical trial information: NCT03555422 .

Effect of the killing style of individual CAR T cells on the clinicopathological behavior of therapeutic products in the clinic.

2548 Background: CAR T cell products that signal through CD28 and 41BB are highly effective against B lineage leukemia, despite exhibiting distinct efficacy and toxicity profiles in patients. Specifically, CD28 has been linked to higher upfront lytic activity and toxicity, while 41BB induces longer CAR T cell persistence and more durable progression free survival. We reasoned that the killing style of individual CAR T cells can explain the clinicopathological behavior of CAR T cell products in the clinic. Methods: We studied the cellular kinetics of CD28 and 41BB signaling CD19 CAR T cell products approved in the clinic, their single cell killing behavior in high throughput, the molecular composition of the lipid rafts inside the CAR immune synapse (CARIS) they form with their target cells, and their CARIS mechanical properties, then corroborated these findings in one kinetic model to explain their distinct clinicopathological behavior in the clinic. Results: We discovered that tumor encounter polarizes CD28 CAR T cell products to a predominance of more differentiated CD8 effectors that rely on short-lived highly lethal synapses with tumor cells. CD28 CAR T cell mediated synapses are characterized by fast mechanical buildup and resolution and brisk shuttling of CAR and other associated molecules into the CARIS and rapid polarization of the killing machinery in a manner that supports a mastery of serial killing mediated by perforin and granzymes. In contrast, 41BB responds to tumor stimulation by a Th2 -polarizing cytokine milieu that robustly expands a balanced CD4/CD8 population of effectors preserving a central memory phenotype. 41BB CAR T cells engage in lengthier synapses characterized by slower accumulation of CAR molecules in a mechanically tonic CARIS and rather collaborative yet lengthy Fas ligand-mediated killing process. Conclusions: We show here that CAR T cell signaling domains mediate distinct killing dynamics that can explain their behavior in patients. By understanding and potentially modulating these dynamics, the CAR T cell functionality and toxicity can be rationally optimized.

Retrospective analysis of the multikinase inhibitor (MKI) pazopanib in differentiated thyroid carcinoma (DTC) in the beyond-first-line setting.

e18097 Background: Sorafenib and lenvatinib are FDA-approved MKIs for locally recurrent or metastatic, progressive, DTC refractory to radioactive iodine treatment. Cabozantinib showed a survival benefit in radioiodine-refractory DTC previously treated with sorafenib and/or lenvatinib and was granted FDA approval. Our study aims to investigate the benefit of other MKIs in DTC beyond the first-line setting. Methods: DTC patients (pts) treated with multiple lines of MKIs from August 2018 to July 2022 at Mayo Clinic across all sites were identified. Electronic medical records were reviewed. 6-month, 12-month, and 18-month progression-free survival (PFS) were calculated for all lines of therapy using RECIST 1.1 criteria. Results: Among the 9 pts identified, 4 were male. The median age was 65 years (43-75). Most pts (60%) had papillary thyroid cancer. All pts received lenvatinib as first line treatment. The 6, 12 and 18-month PFS were 89%, 89%, and 55% respectively. 6 pts discontinued lenvatinib due to progression of disease (PD). 3 pts discontinued it due to adverse effects (AEs), which included hemoptysis (1 pt), severe rash (1 pt) and multiple psychiatric manifestations (1 pt). 8 pts received pazopanib, and 1 patient received cabozantinib with ipilimumab (1 dose) and nivolumab (6 months - discontinued due to myocarditis) as second-line therapy. Among them, 1 patient received pembrolizumab plus everolimus for 2 months before receiving pazopanib. The 6, 12 and 18-month PFS were 55%, 22%, and 11% respectively. All pts ceased treatment due to eventual PD, and there were no toxicity-related discontinuations. 5 pts subsequently received third-line MKIs, including cabozantinib (3 pts), pazopanib (1 pt), and lenvatinib (1 pt). The pt who received lenvatinib had discontinued it as first line therapy due to toxicity. The 2 pts treated with third-line cabozantinib and the pt rechallenged with lenvatinib showed no PD at 12-months and no toxicity related discontinuation. Conclusions: Pazopanib was associated with durable PFS and good tolerability when offered after PD or intolerance on lenvatinib in this retrospective analysis, warranting a randomized prospective study. [Table: see text]

Brentuximab vedotin plus doxorubicin and dacarbazine innonbulky limited-stage classical Hodgkin lymphoma.

ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) with or without radiation has been the standard treatment for limited-stage Hodgkin lymphoma (HL) but carries risks of bleomycin lung injury and radiation toxicity. Brentuximab vedotin (BV) is approved with AVD for stage III-IV HL, but carries increased risks of peripheral neuropathy (PN) and neutropenic fever, likely due to overlapping toxicity between BV and vinblastine. We therefore evaluated BV in combination with AD for 4 or 6 cycles based on interim positron emission tomography response. Thirty-four patients with nonbulky stage I-II HL were enrolled. Risk was early favorable in 53% and unfavorable in 47%. The overall and complete response rates (CRRs) were 100% and 97%, respectively, with a 5-year progression-free survival (PFS) of 91%. No differences in outcome were observed based on stage (I vs II) or risk status (early favorable vs unfavorable). The most common adverse events were nausea (85%), peripheral sensory neuropathy (59%), and fatigue (56%). There were no cases of grade-4 neutropenia or neutropenic fever, and no patient received granulocyte-colony stimulating factor. Most cases of PN were grade 1, and no patient experienced grade ≥3 PN. BV-AD produced a high CRR and durable PFS with most patients requiring 4 cycles of therapy. Compared with BV-AVD, the toxicity profile appeared improved, with predominantly grade 1 reversible PN and no case of grade 4 neutropenia or neutropenic fever. This regimen warrants further study in HL and may serve as a backbone for the addition of novel agents. This trial is registered on clinicaltrials.gov (NCT02505269).

TIGIT inhibition and lenalidomide synergistically promote antimyeloma immune responses after stem cell transplantation in mice.

Autologous stem cell transplantation (ASCT) with subsequent lenalidomide maintenance is standard consolidation therapy for multiple myeloma, and a subset of patients achieve durable progression-free survival that is suggestive of long-term immune control. Nonetheless, most patients ultimately relapse, suggesting immune escape. TIGIT appears to be a potent inhibitor of myeloma-specific immunity and represents a promising new checkpoint target. Here we demonstrate high expression of TIGIT on activated CD8+ T cells in mobilized peripheral blood stem cell grafts from patients with myeloma. To guide clinical application of TIGIT inhibition, we evaluated identical anti-TIGIT antibodies that do or do not engage FcγR and demonstrated that anti-TIGIT activity is dependent on FcγR binding. We subsequently used CRBN mice to investigate the efficacy of anti-TIGIT in combination with lenalidomide maintenance after transplantation. Notably, the combination of anti-TIGIT with lenalidomide provided synergistic, CD8+ T cell-dependent, antimyeloma efficacy. Analysis of bone marrow (BM) CD8+ T cells demonstrated that combination therapy suppressed T cell exhaustion, enhanced effector function, and expanded central memory subsets. Importantly, these immune phenotypes were specific to the BM tumor microenvironment. Collectively, these data provide a logical rationale for combining TIGIT inhibition with immunomodulatory drugs to prevent myeloma progression after ASCT.

Outcomes of Therapies and Resistance Mutations Following Non-Covalent Bruton's Tyrosine Kinase Inhibitor Treatment for Patients with Chronic Lymphocytic Leukemia and Richter Transformation

Background: Non-covalent Bruton's Tyrosine Kinase inhibitors (ncBTKi) have shown excellent clinical activity for patients (pts) with relapsed and/or refractory chronic lymphocytic leukemia (CLL) and Richter Transformation (RT). However, some pts treated with ncBTKi develop progressive disease (PD). In addition, acquired BTK mutations (mut) at the time of PD on ncBTKi were recently described, although the frequency at which these mut occur has not been reported. Currently, data regarding treatment sequencing post ncBTKi are lacking but are critical to guide further treatment selection. Methods: We conducted a retrospective, multicenter study of pts treated with any ncBTKi for CLL or RT who have discontinued ncBTKi for any reason. Using a standardized template we collected: pt and disease characteristics (including prior therapies, cytogenetic/molecular characteristics), demographics, clinical response to ncBTKi and subsequent therapies, and survival. Data on 2 lines of therapies (LOT) following ncBTKi were collected for each pt. Primary endpoint was overall response rate (ORR) for therapies following ncBTKi. Progression free survival (PFS) was estimated using the Kaplan Meier method. We also collected next generation sequencing (NGS) data for CLL pts who discontinued ncBTKi. Analyses were performed using STATA 17.0. Results: We identified 63 pts (48 CLL, 15 RT) treated with who then discontinued ncBTKi. Baseline characteristics at ncBTKi start are presented in Table 1. Median number of prior therapies was 4 (1-10), and most pts received prior covalent BTKi (93.7%) and venetoclax (57.1%). At ncBTKi start, 84.8% of patients had unmutated IGHV, 48.8% had a TP53 mut and 37.0% had a complex karyotype. ORR to ncBTKi was 58.8% for the CLL cohort (PR 54.4%, PR-L 4.4%) and 46.7% for the RT cohort (CR 6.7%, PR 40%). Median duration of ncBTKi exposure prior to discontinuation was 9 (1-27) and 4 (1-12) months for CLL and RT, respectively. Overall, 73.7% of the combined cohort progressed on ncBTKi. Specific reasons for ncBTKi discontinuation included: CLL PD (n=26, 41.2%), PD of existing RT (n=7), death not secondary to PD or toxicity (n=6), other reason (n=6), stem cell transplant (SCT, n=5), toxicity (n=4), PD of CLL to RT (n=4), MD/pt preference (n=2), CAR T (n=2), and sudden death on therapy (n=1). Following ncBTKi, 76.2% of pts (n=48) received another LOT. Therapies and responses are presented in Table 1. Common treatment strategies were: chemo+/-immunotherapy (CIT) (n=16, ORR 18.8%), CD19-directed CAR T-cell therapy (n=7, ORR 85.7%), allogeneic SCT (n=6, ORR 83.3%), and venetoclax-based therapy (n=10, ORR 70.0%). 27.3% of therapies administered post ncBTKi were administered on a clinical trial. For CLL pts, median PFS for first LOT following ncBTKi was 14 months (n=25 pts, Figure 1). For the RT cohort, the median PFS for the first LOT following ncBTKi discontinuation was 6 months (median follow-up 2.5 months). Importantly, median PFS for venetoclax following ncBTKi discontinuation for CLL pts was 14 months (8 pts, 87.5% venetoclax-naive, median follow-up 10.5 months). 49.2% of the overall cohort has died, with 58.6% of deaths due to CLL or RT (n=17 of 29 pts with available data). 15 CLL pts who discontinued ncBTKi for PD had end of treatment NGS data available. For these pts, at the start of ncBTKi, BTKC481 mut and PLCG2 mut were present in 38.5% and 33%, respectively. At end of ncBTKi treatment, novel (not C481) BTK mut were identified in 9 of 15 pts (60.0%). These included mut in BTKL528W (n=6), BTKV416L (n=2) and BTKT474I (n=2); 1 pt had mut in both BTKT474I and BTKL528W. Additionally, 4 pts had pre-existing mut in PLCG2 that persisted at PD. Overall, 11 of 15 (73.3%) of CLL pts had a novel BTK mut and/or a persistent PLCG2 mut at PD on ncBTKi. Conclusions: We report results from the first series of CLL and RT pts following ncBTKi discontinuation. CIT for RT and CLL yielded poor outcomes, while CAR T-cell therapy and allogeneic SCT had high ORR warranting further investigation. Most importantly, venetoclax has clinical activity (high ORR, durable PFS) for CLL pts following ncBTKi discontinuation suggesting CLL pts can stay within the BTKi class prior to switching to venetoclax. In addition, at PD 73% of pts had a novel BTK mut and/or the persistence of a PLCG2 mut conferring resistance to ncBTKis. Overall, these results highlight an unmet need for novel therapeutic strategies for pts who require treatment following ncBTKi. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

First-Mind: Final Analysis from a Phase Ib, Open-Label, Randomized Study to Assess Safety of Tafasitamab or Tafasitamab + Lenalidomide in Addition to R-CHOP in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma

Introduction Both CD20 and CD19 are selectively and strongly expressed on the surface of diffuse large B-cell lymphoma (DLBCL) cells. For newly diagnosed and untreated DLBCL, the anti-CD20-targeted R-CHOP regimen is the standard of care. Tafasitamab, a humanized, Fc-modified, anti-CD19 monoclonal antibody, in combination with lenalidomide (LEN), has received regulatory approvals for the treatment of adult patients with R/R DLBCL not otherwise specified, including DLBCL arising from low-grade lymphoma, and who are ineligible for ASCT. A treatment strategy targeting both of these B cell surface molecules, and supplemented by LEN to enhance the cytotoxicity activity of tafasitamab and rituximab, may limit target evasion and reduce resistance to R-CHOP. First-MIND (NCT04134936) is a Phase Ib randomized study to assess the safety and tolerability of R-CHOP + tafasitamab ± LEN in patients with previously untreated and newly diagnosed DLBCL, and an International Prognostic Index (IPI) score of 2-5. The primary analysis demonstrated the feasibility of adding tafasitamab + LEN to R-CHOP without impairing its dosing and scheduling, with toxicities similar to those expected with R-CHOP alone (ASH 2021; #3556). The combination of R-CHOP and tafasitamab + LEN as first-line therapy is being investigated further in the global, randomized, Phase III frontMIND study (NCT04824092) in untreated patients with DLBCL and an IPI score of 3-5. Here, we report the 18-month follow-up analysis from the First-MIND study in all patients and in patients with an IPI score of 3-5. Methods Eligible patients were randomized 1:1 to six 21-day (D) cycles of either R-CHOP (R-CHOP, D1-5) + tafasitamab (12 mg/kg IV, D1, 8, 15) (Arm T) or R-CHOP + tafasitamab + LEN (25 mg orally, D1-10) (Arm T/L). The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Secondary endpoints included overall response rate (ORR) and PET-negative complete response (CR) rate at end of treatment (EoT). Safety was assessed using the NCI CTCAE V5.0, and tumor measurements by PET/CT or PET/MRI at EoT were performed according to Lugano 2014 criteria. Minimal residual disease (MRD) was assessed using immunoglobulin gene next-generation sequencing in cell-free DNA. Results At the data cut-off (May 5, 2022), of the 66 patients randomized (Arm T, n=33; Arm T/L, n=33), a total of 27 patients (40.9%) were still on study (Arm T, n=13; Arm T/L, n=14) with a median follow-up of 17.6 months for progression-free survival (PFS). Baseline characteristics were well balanced: 60.6% of patients in Arm T and 66.7% in Arm T/L had an IPI score of 3-5; 94.0% and 87.9% had an ECOG PS of 0-1, respectively; and 93.9% of patients in both Arms were Ann Arbor stage III/IV. ORR at EoT visit and best response across all visits were higher in Arm T/L, as were 18-month DoR, PFS, and OS rates (Table 1). In patients treated in Arm T/L and with an IPI score of 3-5 (n=22), ORR and 18-month DoR, PFS, and OS rates were comparable with the overall Arm T/L cohort (Table 1). The 12-month PFS rate by MRD status at EoT in Arm T/L was 100% in MRD-negative patients (n=12) (Figure 1) and 67% in MRD-positive patients (n=3). MRD-negativity at Cycle 2 Day 1 appeared to be predictive for durable PFS responses. The frequency of Grade ≥3 TEAEs was 72.7% in Arm T and 90.9% in Arm T/L; the most common TEAEs were neutropenia, anemia, leukopenia, and thrombocytopenia in both arms. Serious TEAEs occurred in 42.4% in Arm T and 51.5% in Arm T/L, with no difference between treatment arms in the incidence of febrile neutropenia (15.2%), and an incidence of infections and infestations of 9.1% in Arm T and 6.1% in Arm T/L. Conclusion Adding tafasitamab in combination with LEN to R-CHOP shows numerically higher clinical efficacy than adding tafasitamab alone, and is consistent with the synergy between tafasitamab and LEN, leading to durable responses in treatment-naïve patients with DLBCL. The long-term safety profile of tafasitamab ± LEN when added to R-CHOP showed no new safety signals to those reported previously. Although the sample size is limited, patients with an IPI score of 3-5 treated with tafasitamab + LEN + R-CHOP showed efficacy comparable to that of the overall treatment arm cohort, including MRD-negative patients who remained disease-free for ≥18 months. frontMIND will further evaluate tafasitamab + LEN + R-CHOP in previously untreated patients with high-intermediate and high-risk (IPI score 3-5) DLBCL. Funding MorphoSys AG Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

968TiP A phase II, multicenter study of lazertinib as consolidation therapy in patients with locally advanced, unresectable, EGFR mutation positive non-small cell lung cancer (stage III) who have not progressed following definitive, platinum-based, chemoradiation therapy (PLATINUM trial)

The PACIFIC trial has demonstrated that durable progression free survival (PFS) and sustained overall survival (OS) benefit with durvalumab as consolidation therapy after concurrent chemoradiation therapy (CCRT). In a subgroup analysis, the effect was not proven in patients with EGFR mutation positive. There is an unmet need for consolidative therapy after CCRT in patients with unresectable stage III EGFR mutation positive. A recent ADAURA trial showed that osimertinib had a significant prolongation of PFS in the postoperative adjuvant treatment in EGFR mutation positive patients.

Anti-Angiogenic Therapy in ALK Rearranged Non-Small Cell Lung Cancer (NSCLC).

The management of advanced lung cancer has been transformed with the identification of targetable oncogenic driver alterations. This includes anaplastic lymphoma kinase (ALK) gene rearrangements. ALK tyrosine kinase inhibitors (TKI) are established first-line treatment options in advanced ALK rearranged non-small cell lung cancer (NSCLC), with several next-generation ALK TKIs (alectinib, brigatinib, ensartinib and lorlatinib) demonstrating survival benefit compared with the first-generation ALK TKI crizotinib. Still, despite high objective response rates and durable progression-free survival, drug resistance inevitably ensues, and treatment options beyond ALK TKI are predominantly limited to cytotoxic chemotherapy. Anti-angiogenic therapy targeting the vascular endothelial growth factor (VEGF) signaling pathway has shown efficacy in combination with platinum-doublet chemotherapy in advanced NSCLC without a driver alteration, and with EGFR TKI in advanced EGFR mutated NSCLC. The role for anti-angiogenic therapy in ALK rearranged NSCLC, however, remains to be elucidated. This review will discuss the pre-clinical rationale, clinical trial evidence to date, and future directions to evaluate anti-angiogenic therapy in ALK rearranged NSCLC.

P1197: AXICABTAGENE CILOLEUCEL (AXI-CEL) IN COMBINATION WITH RITUXIMAB FOR THE TREATMENT OF RELAPSED/REFRACTORY (R/R) LARGE B-CELL LYMPHOMA (LBCL): OUTCOMES OF THE PHASE 2 ZUMA-14 STUDY

Background: Despite the success of axi-cel, ≈60% of patients have no response or relapse within ~2 y after treatment (Jacobson C, et al. ASH 2021. #1764), highlighting the need for more therapeutic strategies. In preclinical studies, rituximab augmented CD19 chimeric antigen receptor (CAR) T-cell function and increased tumor reduction and survival in murine models via synergistic targeting with CAR T-cells (Mihara K, et al. Br J Haematol. 2010). Aims: Here, we report outcomes of ZUMA-14, a Phase 2, multicenter study of axi-cel in combination with rituximab in pts with R/R LBCL after ≥2 lines of systemic therapy. Methods: Eligible patients were ≥18 y with R/R LBCL. Patients received one rituximab dose (375 mg/m2) on Day -5, a conditioning regimen of cyclophosphamide and fludarabine on Days -5, -4, and -3, and a single axi-cel infusion of 2×106 CAR T cells/kg on Day 0. Starting on Day 21 post–axi-cel infusion, patients received 1 rituximab dose every 28 days for up to 5 doses. The primary endpoint was investigator-assessed complete response (CR) rate. Secondary endpoints included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and biomarker assessments. The analysis reported here occurred after all treated patients had ≥12 months of follow-up. Results: As of 12/2/21, 27 patients were enrolled, and 26 received axi-cel and ≥1 rituximab dose (15 patients received all 6 rituximab doses); 1 patient discontinued treatment due to an adverse event (AE). Median age was 63 y (range, 38-82), 54% were male, 81% had stage III/IV disease, 62% had extranodal disease, 38% had elevated lactate dehydrogenase, and 85% had an age-adjusted International Prognostic Index (aaIPI) ≥1 (35% aaIPI=2). The CR rate was 65% (95% CI, 44%-83%), and the ORR was 88% (95% CI, 70%-98%). With a median follow-up of 17 months, 65% of the patients had ongoing response, with 57% ongoing in CR. Medians for DOR, PFS and OS were not reached. The estimated DOR and PFS rates at 12 months were 64% and 56%, respectively. The estimated 12-month OS rate was 76%, and 6 patients (23%) died of progressive disease. Most patients (92%) experienced Grade ≥3 AEs. Grade ≥3 cytopenias were reported in 85% of patients, with 38% ongoing on Day 30. Grade ≥3 neurologic events (NEs) occurred in 4 patients (15%); there was no Grade ≥3 cytokine release syndrome (CRS). Median times to onset of CRS and NEs were 4 days (range, 1-7 days) and 6 days (range, 3-32 days), respectively, with median durations of 5 days (range, 2-15 days) and 7 days (range, 1-39 days). No patients experienced myelodysplastic syndrome. Median peak CAR T-cell levels were comparable to the ZUMA-1 pharmacokinetic profile. Immune-modulating cytokines, including granzyme B, IL-6, CXCL10, IFN-γ and IL-2, were induced in patients following axi-cel and rituximab infusion and were more prominently elevated in responders vs non-responders. Peak rituximab levels were also elevated in responders vs non-responders. Summary/Conclusion: Results from ZUMA-14 demonstrated that axi-cel in combination with rituximab elicited a high CR rate and durable PFS with no new safety signals detected in patients with R/R LBCL.

Nivolumab (NIVO) ± ipilimumab (IPI) in patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Five-year follow-up from CheckMate 142.

3510 Background: NIVO ± IPI is approved in previously treated pts with MSI-H/dMMR mCRC in the US, EU, and Japan, based on findings from the phase 2 CheckMate 142 study (NCT02060188). NCCN guidelines include NIVO + IPI as an initial therapy option for pts with MSI-H/dMMR mCRC. Results from a ~5-year follow-up from CheckMate 142 cohorts 1–3 (C1–3) are reported here. Methods: In this non-randomized, multicohort study, pts with MSI-H/dMMR mCRC were treated as follows: C1 (2L+; NIVO 3 mg/kg Q2W), C2 (2L+; NIVO 3 mg/kg + IPI 1 mg/kg Q3W [4 doses], followed by NIVO 3 mg/kg Q2W) and C3 (1L; NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W), until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by investigator assessment (INV) per RECIST v1.1. Other key endpoints were disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), all by INV and blinded independent central review; overall survival (OS), and safety. Results: In C1 (N = 74), C2 (N = 119), and C3 (N = 45), median (range) follow-up (time from first dose to data cutoff) was 70.0 (66.2–88.7), 64.0 (60.0–75.8), and 52.4 (47.6–57.1) months (mo), respectively. ORR (95% CI) by INV was 39% (28–51), 65% (55–73), and 71% (56–84; Table) and progressive disease (PD) rates were 26%, 12%, and 16% in C1, C2, and C3, respectively. Median DOR was not reached in the 3 cohorts. The 48-mo PFS rates were 36%, 54%, and 51% and 48-mo OS rates were 49%, 71%, and 72% in C1, C2, and C3, respectively (Table). PFS and OS rates with up to 60 mo of follow-up will be presented. Safety data are shown in the table. Conclusions: With extended follow-up of ~5 years, NIVO ± IPI continued to demonstrate durable OS and PFS benefit, with no new safety signals. These updated data further support current treatment recommendations for 2L+ NIVO ± IPI and 1L NIVO + IPI for pts with MSI-H/dMMR mCRC. Clinical trial information: NCT02060188. [Table: see text]

Promising outlook with sugemalimab in non-small-cell lung cancer.

Anti-PD-L1 (durvalumab) immunotherapy after chemotherapy with external beam radiotherapy (ie, the PACIFIC regimen) is standard care for patients with unresectable stage III non-small-cell lung cancer (NSCLC). In the PACIFIC trial, 1 Faivre-Finn C Vicente D Kurata T et al. Four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC—an update from the PACIFIC trial. J Thorac Oncol. 2021; 16: 860-867 Summary Full Text Full Text PDF PubMed Scopus (153) Google Scholar this regimen showed durable progression-free survival, with the estimated number of randomly assigned patients who remained alive at 4 years being 50% in the group that received 12 months of anti-PD-L1 consolidation therapy using durvalumab following chemotherapy plus concurrent radiotherapy versus 36% in patients who received placebo alone. Preclinical studies have shown that radiotherapy can boost anti-tumour immune response and overcome resistance to current immunotherapies. Clinical studies have shown improved responsiveness to pembrolizumab (anti-PD-1 antibody) in metastatic NSCLC, and to durvalumab (anti-PD-L1 antibody) in operable NSCLC. In the PEMBRO-RT and MDACC trials, 2 Theelen W Chen D Verma V et al. Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Respir Med. 2021; 9: 467-475 Summary Full Text Full Text PDF PubMed Scopus (98) Google Scholar the best abscopal response (for non-irradiated lesions) was 20% with pembrolizumab versus 42% with pembrolizumab plus radiotherapy (odds ratio 2·96, 95% CI 1·42–6·20; p=0·0039). Median progression-free survival was 4·4 months (95% CI 2·9–5·9) with pembrolizumab alone versus 9·0 months (6·8–11·2) with pembrolizumab plus radiotherapy (hazard ratio [HR] 0·67, 95% CI 0·45–0·99; p=0·045). 2 Theelen W Chen D Verma V et al. Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Respir Med. 2021; 9: 467-475 Summary Full Text Full Text PDF PubMed Scopus (98) Google Scholar In a phase 2 trial comparing neoadjuvant durvalumab alone versus neoadjuvant durvalumab plus stereotactic radiotherapy in patients with resectable early-stage NSCLC (clinical stages I–IIIA), a major pathological response was observed in 7% of the durvalumab alone group versus 53% of the durvalumab plus radiotherapy group. 3 Altorki NK McGraw TE Borczuk AC et al. Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial. Lancet Oncol. 2021; 22: 824-835 Summary Full Text Full Text PDF PubMed Scopus (59) Google Scholar Sugemalimab versus placebo, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer (GEMSTONE-302): interim and final analyses of a double-blind, randomised, phase 3 clinical trialSugemalimab plus chemotherapy showed a statistically significant and clinically meaningful progression-free survival improvement compared with placebo plus chemotherapy, in patients with previously untreated squamous and non-squamous metastatic NSCLC, regardless of PD-L1 expression, and could be a newfirst-line treatment option for both squamous and non-squamous metastatic NSCLC. Full-Text PDF Sugemalimab versus placebo after concurrent or sequential chemoradiotherapy in patients with locally advanced, unresectable, stage III non-small-cell lung cancer in China (GEMSTONE-301): interim results of a randomised, double-blind, multicentre, phase 3 trialSugemalimab after definitive concurrent or sequential chemoradiotherapy could be an effective consolidation therapy for patients with stage III NSCLC whose disease has not progressed after sequential or concurrent chemoradiotherapy. Longer follow-up is needed to confirm this conclusion. Full-Text PDF

Outcome of allogeneic transplantation for mature T-cell lymphomas: impact of donor source and disease characteristics

AbstractMature T-cell lymphomas constitute the most common indication for allogeneic hematopoietic cell transplantation (allo-HCT) of all lymphomas. Large studies evaluating contemporary outcomes of allo-HCT in mature T-cell lymphomas relative to commonly used donor sources are not available. Included in this registry study were adult patients who had undergone allo-HCT for anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) between 2008 and 2018. Hematopoietic cell transplantation (HCT) platforms compared were posttransplant cyclophosphamide-based haploidentical (haplo-)HCT, matched sibling donor (MSD) HCT, matched unrelated donor HCT with in vivo T-cell depletion (MUD TCD+), and matched unrelated donor HCT without in vivo T-cell depletion (MUD TCD−). Coprimary end points were overall survival (OS) and progression-free survival (PFS); secondary end points included nonrelapse mortality (NRM), and relapse/progression incidence (RI). A total of 1942 patients were eligible (237 haplo-HCT; 911 MSD; 468 MUD TCD+; 326 MUD TCD−). Cohorts were comparable for baseline characteristics with the exception of higher proportions of patients with decreased performance status (PS) and marrow graft recipients in the haplo-HCT group. Using univariate and multivariate comparisons, OS, PFS, RI, and NRM were not significantly different among the haplo-HCT, MSD, MUD TCD+, and MUD TCD− cohorts, with 3-year OS and PFS of 60%, 63%, 59%, and 64%, respectively, and 50%, 50%, 48%, and 52%, respectively. Significant predictors of inferior OS and PFS on multivariate analysis were active disease status at HCT and decreased PS. AITL was associated with significantly reduced relapse risk and better PFS compared with PTCL-NOS. Allo-HCT can provide durable PFS in patients with mature T-cell lymphoma (TCL). Outcomes of haplo-HCT were comparable to those of matched donor allo-HCT.

84P Predicting longer-term progression-free survival (PFS) with durvalumab after chemoradiotherapy (CRT) in unresectable stage III NSCLC using a mixture cure model (MCM)

Five-year results from the placebo-controlled phase 3 PACIFIC trial (NCT02125461) demonstrated robust and sustained overall survival (OS) and durable PFS benefit with durvalumab (given every 2 weeks up to 12 months) in pts with unresectable Stage III non-small-cell lung cancer (NSCLC) and no disease progression after platinum-based concurrent CRT. Given the potential for longer-term PFS gain in this curative-intent setting, we used MCM analysis, a common statistical model in such settings, to predict the potential longer-term PFS benefit with durvalumab.

An Oncology Simulation Model to Estimate 10-Year Progression-Free Survival and Stem Cell Transplantation for Frontline, Stage III or IV Classical Hodgkin Lymphoma Based on the 5-Year Update of the ECHELON-1 Trial: A United States Perspective

ObjectivesDoxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) is the most common frontline (1L) regimen for patients with stage III or IV classical Hodgkin lymphoma (cHL), but about 30% of patients with stage III or IV cHL have refractory or relapsed disease after ABVD treatment. Based on the 5-year update of the ECHELON-1 trial, patients on 1L brentuximab vedotin, doxorubicin, vinblastine and dacarbazine (A+AVD) continued to demonstrate a robust and durable progression-free survival (PFS) improvement vs ABVD with a 32% reduction in the risk of progression or death (HR=0.681, nominal P=0.002). Our objective was to estimate the future number of patients with cHL who are alive and progression-free over 10-years with 1L A+AVD, based on the 5-year follow-up results from ECHELON-1.MethodsAn oncology simulation model, from the United States perspective, was developed with a 1-month cycle length that estimates population-level outcomes based on annual prevalence of cHL, considering disease incidence, treatment patterns, PFS, and overall survival of commonly used treatment regimens for stage III or IV cHL. Incidence of cHL was derived from the 2019 Surveillance, Epidemiology, and End Results (SEER) Program, assuming 95% of HL is classical of which 41% is stage III or IV. To populate the base case model, treatment patterns following 1L use of ABVD (64.5%) and positron emission tomography (PET)-adapted therapy (35.5%) were varied over time and compared to A+AVD (24%). For every model cycle, patients who experienced disease progression on 1L therapy discontinued therapy and transitioned to second-line (salvage) therapy. The transition from second-line therapy to transplant is also included in the model based on patient eligibility. Model inputs were informed by 1) real-world treatment utilization; 2) treatment-specific clinical trial data, including ECHELON-1 with 5-year PFS rates of 75.3% for ABVD (95% CI: 70.0, 85.0) and 82.2% for A+AVD (95% CI: 71.7, 78.5); and 3) expert clinicians' opinions. Annual prevalence of patients living progression-free with cHL in the 1L setting with each prescribing scenario was estimated for 10 years (year 2031) with and without the availability of A+AVD.ResultsThe annual number of newly diagnosed patients with stage III or IV cHL at 10 years in 2031 was estimated at 3,586. The number of patients alive and progression-free in the 1L setting was 19,494 without A+AVD and 19,660 with A+AVD (Δ+166, 0.85% increase) in 2031. Overall, for every 100 patients prescribed A+AVD, it was predicted that an additional 6.5 patients per year achieved at least 5 years PFS and 4.2 to 4.7 fewer patients per year required a stem cell transplant (SCT), based on the 70% to 80% of eligible patient proceeding to SCT, respectively.ConclusionsThe durable PFS improvement of A+AVD vs ABVD in the 5-year follow-up data from ECHELON-1 resulted in increasing the number of patients with stage III or IV cHL who remain progression free for greater than 10 years and reducing future SCTs, based on this oncology simulation model for cHL. The significant improvement in PFS observed in the 5-year ECHELON-1 trial may translate to fewer patients with cHL developing primary refractory or relapsed disease and reduce the need for additional therapies including SCT. DisclosuresPhillips: Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Incyte: Consultancy, Other: received travel expenses from Incyte, Research Funding; ADCT, BeiGene, Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Morphosys, Pharmacyclics, Seattle Genetics: Consultancy; AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy. Migliaccio-Walle: Seagen, Inc: Consultancy. Yu: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Bloudek: Seagen, Inc: Consultancy. Liu: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Fanale: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Burke: Beigene: Consultancy, Speakers Bureau; Verastem: Consultancy; Kymera: Consultancy; Bristol Myers Squibb: Consultancy; Adaptive Biotechnologies: Consultancy; MorphoSys: Consultancy; AstraZeneca: Consultancy; Roche/Genentech: Consultancy; Kura: Consultancy; Epizyme: Consultancy; X4 Pharmaceuticals: Consultancy; SeaGen: Consultancy, Speakers Bureau; AbbVie: Consultancy.