Citations

Abstract Background In 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Based on the preclinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, ECOG-ACRIN E1105 trial was developed to determine if the addition of bevacizumab to a chemotherapy and trastuzumab combination for first-line therapy would improve progression-free survival (PFS) in patients with HER2-positive MBC. Findings: 96 patients were randomized to receive standard first-line chemotherapy and trastuzumab with or without bevacizumab between November 2007 and October 2009, and 93 began protocol therapy. Induction therapy was given for 24 weeks, followed by maintenance trastuzumab with or without bevacizumab. 60% (56/93) began carboplatin and 74% (69/93) completed 6 cycles of induction therapy. Primary endpoint was PFS. Median PFS was 11.1 and 13.8 months for placebo and bevacizumab arms, respectively (hazard ratio [HR] 95%, Confidence Interval [Cl] for bevacizumab vs. placebo: 0.73 [0.43–1.23], p = 0.24), and at a median follow-up of 70.7 months, median survival was 49.1 and 63 months (HR [95% Cl] for OS: 1.09 [0.61–1.97], p = 0.75). The most common toxicities across both arms were neutropenia and hypertension, with left ventricular systolic dysfunction, fatigue, and sensory neuropathy reported more frequently with bevacizumab. Conclusions In this trial, the addition of bevacizumab did not improve outcomes in patients with metastatic HER2-positive breast cancer. Although the trial was underpowered due to smaller than anticipated sample size, these findings corroborated other clinical trials during this time.

Abstract Background: R/R FL is an incurable disease and outcomes worsen with successive relapses. A high unmet need remains for therapies that improve tumor control and extend survival after relapse. Odronextamab, an off-the-shelf CD20×CD3 bispecific antibody, demonstrated compelling efficacy, generally manageable safety, and maintenance of pt-reported overall quality of life scores from baseline in an interim analysis of the ELM-2 study (NCT03888105) in heavily pretreated pts with R/R FL (Villasboas et al. ASH 2023). Here, for the first time, we present the primary analysis of R/R FL in ELM-2. Methods: IV odronextamab was administered in 21-day cycles (C) until disease progression/unacceptable toxicity. Steroid prophylaxis and step-up dosing (0.7/4/20 mg) were used in C1 to mitigate the risk of cytokine release syndrome (CRS), followed by 80 mg on Days (D) 1, 8, and 15 of C2-4. Maintenance dosing continued at 160 mg Q2W, or Q4W if complete response (CR) was durable for 9 months (mo). Primary endpoint was objective response rate (ORR) per Lugano criteria by independent central review (ICR). Secondary endpoints included CR rate, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Primary analysis was performed when 128 pts had ≥52 weeks’ follow-up. Results: At data cutoff (Oct 20, 2023), 128 pts with FL Grade (Gr) 1-3a were evaluable for efficacy and safety: median age 61 yrs (range 22-84); FLIPI risk score 3-5 57.8%; POD24 49.2%; median 3 prior lines of therapy (2-13); 71.9% refractory to last treatment (Tx); 74.2% refractory to an anti-CD20 antibody. The median no. of Tx cycles was 19.4 (0.1-95.9); 95.3% and 85.2% of pts completed C1 and C4, respectively.Median efficacy follow-up was 20.1 mo; ORR was 80.5% and CR rate was 73.4% confirmed by ICR. Responses were durable (median DOR 22.6 mo; median DOCR 25.1 mo). Median PFS was 20.7 mo and 24-mo PFS was 46.1%. Median OS was not reached and 24-mo OS was 70.1%.The odronextamab safety profile was generally manageable and consistent with previous reports. Tx-emergent adverse events (AEs) occurred in all pts (Gr ≥3 85.9%); 15.6% had AEs leading to Tx discontinuation. With 0.7/4/20 mg step up (n=60), CRS events were mostly low grade (Gr 1 45.0%; Gr 2 10.0%; Gr 3 in 1 pt), occurred mostly in C1, and resolved in a median of 2 days; ICANS was reported in 1 pt (Gr 2). Infection rates were consistent with heavily pretreated, immunosuppressed pts (Leonard et al. JCO 2019; Hayne et al. BBMT 2020), occurring in 79.7% (102/128) of pts (Gr 4/5 14.0%; COVID-19 36.7% [Gr 5 6.3%]).Conclusion: Odronextamab demonstrated deep and durable responses in heavily pretreated pts with R/R FL; 91% of responders achieved CR, correlating with favorable PFS and OS at 24 mo. Odronextamab had a generally manageable safety profile and a low incidence of Gr 3 CRS/ICANS. Odronextamab could offer an important off-the-shelf Tx option for pts with heavily pretreated R/R FL. Citation Format: Geoffrey Chong, Michal Taszner, Silvana Novelli, Seok-Goo Cho, Jose C. Villasboas, Ana Jiménez Ubieto, Benoît Tessoulin, Michelle Poon, David Tucker, Jan Walewski, Yuqin Song, Emmanuel Bachy, Stephanie Guidez, Aranzazu Alonso, Deepa Jagadeesh, Stefano Luminari, Laura Magnano Mayer, Elżbieta Iskierka-Jażdżewska, Monica Tani, Jingxian Cai, Amulya Uppala, Saleem Shariff, Jurriaan Brouwer-Visser, Aafia Chaudhry, Hesham Mohamed, Srikanth Ambati, Tae Min Kim. Primary analysis of the Phase 2 ELM-2 study: Odronextamab in patients (pts) with relapsed/refractory follicular lymphoma (R/R FL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT243.

PURPOSE The phase III Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial found no difference in overall survival (OS) in patients with metastatic colorectal cancer receiving first-line chemotherapy in combination with either bevacizumab or cetuximab. We investigated the potential prognostic and predictive value of HER2 amplification and gene expression using next-generation sequencing (NGS) and NanoString data. PATIENTS AND METHODS Primary tumor DNA from 559 patients was profiled for HER2 amplification by NGS (FoundationOne CDx). Tumor tissue from 925 patients was tested for NanoString gene expression using an 800-gene panel. OS and progression-free survival (PFS) were the time-to-event end points. RESULTS High HER2 expression (dichotomized at median) was associated with longer PFS (11.6 v 10 months, P = .012) and OS (32 v 25.3 months, P = .033), independent of treatment. An OS benefit for cetuximab versus bevacizumab was observed in the high HER2 expression group ( P = .02), whereas a worse PFS for cetuximab was seen in the low-expression group ( P = .019). When modeled as a continuous variable, increased HER2 expression was associated with longer OS (hazard ratio [HR], 0.83 [95% CI, 0.75 to 0.93]; adjusted P = .0007) and PFS (HR, 0.82 [95% CI, 0.74 to 0.91]; adjusted P = .0002), reaching a plateau effect after the median. In patients with HER2 expression lower than median, treatment with cetuximab was associated with worse PFS (HR, 1.38 [95% CI, 1.12 to 1.71]; adjusted P = .0027) and OS (HR, 1.28 [95% CI, 1.02 to 1.59]; adjusted P = .03) compared with that with bevacizumab. A significant interaction between HER2 expression and the treatment arm was observed for OS ( P intx = .017), PFS ( P intx = .048), and objective response rate ( P intx = .001). CONCLUSION HER2 gene expression was prognostic and predictive in CALGB/SWOG 80405. HER2 tumor expression may inform treatment selection for patients with low HER2 favoring bevacizumab- versus cetuximab-based therapies.

115 Background: Randomized clinical trials provide the best evidence for the effects of a new treatment. However, the use of a placebo control arm may present practical and ethical concerns for enrolled patients and treating providers. The CRC ARCAD global database includes a total of 1,673 individual patient data (IPD) treated with placebo plus best supportive care in a salvage-line setting for refractory mCRC. By using placebo IPD, we have proposed to construct a synthetic control arm for clinical trials (Yoshino T. et al., Nature Medicine 2023). Methods: From 40,889 IPD from 59 studies in ARCAD mCRC database, 723 placebo pts were selected from 4 placebo-controlled randomized studies in a salvage-line setting (CORRECT, RECOURSE, CONCUR and TERRA). We analyzed the impact of baseline patient characteristics and various prognostic factors on outcome in the placebo control. Results: The adjusted hazard ratios (HRs) (95% confidence interval [CI]) were 0.52 (0.40-0.67) for the number of metastatic sites (1 vs 2+), 0.71 (0.59-0.84) for ECOG performance status (PS) (0 vs 1), 0.54 (0.45-0.66) for liver metastases (No vs Yes), 0.54 (0.40-0.71) for peritoneal metastases (No vs Yes), and 0.51 (0.38-0.70) for Royal Marsden Hospital (RMH) Score (consisting of albumin level, number of metastatic sites, and LDH level) (0-1 vs 2-3). Conclusions: Number of metastatic sites, ECOG PS, liver metastasis, peritoneal metastasis and RMH Score were significant prognostic factors in patients with mCRC receiving placebo in a salvage-line setting. Further prognostic factors should be investigated to increase the accuracy of the proposed synthetic control arm. [Table: see text]

107 Background: The "No Placebo Initiative" demonstrated that the survivals of patients (pts) receiving placebo in a salvage-line setting, exhibited no significant difference across trials (CORRECT, RECOURSE, CONCUR and TERRA). Therefore, we believe that a nomogram can be generated using the ARCAD database to predict survival of pts who completed standard therapy. Methods: Of 40,889 Individual patient data (IPD) from 59 studies, 723 pts received placebo from 4 randomized studies were pooled. The potential prognostic factors considered include BMI and Age. Imputed datasets were constructed by a multiple imputation method since the original dataset contains some missing values. Overall survival (OS) was defined as the time from randomization to death from any cause. Multivariate Cox proportional hazards models for OS were estimated based on the variables showing clinically and statistically significant by univariate analysis. Prediction performance of the final model was evaluated using the concordance index for survival data and calibration plots. Results: From univariate and multivariate analysis, ECOG performance status, Royal Marsden Hospital score (calculated by albumin level, LDH level, and number of metastatic site), primary site location, liver meta, peritoneal meta were selected as variables. We successfully developed a highly accurate nomogram to predict post-standard treatment prognosis for pts with mCRC. Concordance index for OS was 0.66. Conclusions: Although further validation in other cohorts is needed, this nomogram could be very useful to estimate the survival for clinical practice and enrolling in clinical trials. [Table: see text]

AbstractBackgroundPatient‐reported outcomes (PROs) are a better tool for evaluating the experiences of patients who have symptomatic, treatment‐associated adverse events (AEs) compared with clinician‐rated AEs. The authors present PROs assessing health‐related quality of life (HRQoL) and treatment‐related neurotoxicity for adjuvant capecitabine versus platinum on the Eastern Cooperative Oncology Group‐American College of Radiology Imaging Network (ECOG‐ACRIN) EA1131 trial (ClinicalTrials.gov identifier NCT02445391).MethodsParticipants completed the National Comprehensive Cancer Network Functional Assessment of Cancer Therapy–Breast Cancer Symptom Index (NFBSI‐16) and the Functional Assessment of Cancer Therapy–Gynecologic Oncology Group neurotoxicity subscale (platinum arm only) at baseline, cycle 3 day 1 (C3D1), 6 months, and 15 months. Because of early termination, power was insufficient to test the hypothesis that HRQoL, as assessed by the NFBSI‐16 treatment side‐effect (TSE) subscale, would be better at 6 and 15 months in the capecitabine arm; all analyses were exploratory. Means were compared by using t‐tests or the Wilcoxon rank‐sum test, and proportions were compared by using the χ2 test.ResultsTwo hundred ninety‐six of 330 eligible patients provided PROs. The mean NFBSI‐16 TSE subscale score was lower for the platinum arm at baseline (p = .02; absolute difference, 0.6 points) and for the capecitabine arm at C3D1 (p = .04; absolute difference, 0.5 points), but it did not differ at other times. The mean change in TSE subscale scores differed between the arms from baseline to C3D1 (platinum arm, 0.15; capecitabine arm, −0.72; p = .03), but not from baseline to later time points. The mean decline in Functional Assessment of Cancer Therapy–Gynecologic Oncology Group neurotoxicity subscale scores exceeded the minimal meaningful change (1.38 points) from baseline to each subsequent time point (all p < .05).ConclusionsDespite the similar frequency of clinician‐rated AEs, PROs identified greater on‐treatment symptom burden with capecitabine and complemented clinician‐rated AEs by characterizing patients’ experiences during chemotherapy.

Background: Robust models exist to predict risk-adjusted mortality following congenital heart surgery. It is known that underlying diagnosis modifies predicted risk of operations, and institution-level outcomes vary based on their unique case mix. We therefore evaluated risk-adjusted outcomes for a subset of diagnosis-procedure (D-P) combinations within the Society of Thoracic Surgeons' (STS) congenital heart surgery database (CHSD). Methods: A clinician panel identified the most frequently encountered D-P combinations in CHSD between 07/2017 and 06/2021. Candidate modeling techniques were compared in a random 80% development cohort. Model performance was assessed using internal and cross-validation calibration, discrimination plots and optimism adjusted C-statistics. The final selected model was evaluated in the 20% validation sample. Results: The chosen subset of D-P combinations represented 45,384 of 87,589 (52%) unique episodes of surgical care in CHSD during this time-period. The development cohort (36,350 episodes) had 1.8% mortality (667 deaths). All candidate models had excellent discrimination with C-statistics ranging from 0.862 to 0.876. The model with the best combination of discrimination, calibration, and clinical face validity was a modified version of the current STS mortality risk model. This version included all current risk model variables with the addition of indicator variables for D-P combinations. In the 20% validation sample (9,034 episodes), this model was well calibrated (Figure) and had excellent discrimination (C = 0.879). Conclusion: We describe a cohort of D-P combinations widely encountered in the STS CHSD. Further, we refined the existing STS CHSD risk model for application to these D-P dyads to derive empirical risk-adjusted benchmark outcomes. This approach will benefit quality improvement efforts at an institutional level and may have implications for publicly reporting congenital heart surgery outcomes.

Background: For patients with chronic lymphocytic leukemia (CLL)-the most common form of leukemia in older adults-equitable access to care is particularly challenging, as the disease is often diagnosed in community cancer centers encumbered by regional disparities. Therefore, identifying and understanding regional barriers to care is essential. In 2020, the Association of Community Cancer Centers (ACCC) developed a heat map detailing the incidence rate of CLL diagnoses across the country (Fig.1), overlayed with the locations of CLL “expert” providers, revealing the areas in the US most in need of additional CLL clinical expertise (Fig. 2). In 2022, these incidence rates were stratified by race, ethnicity, and metropolitan statistical area to identify disparities Building on these maps, ACCC set out to identify specific regional challenges to appropriate, equitable care for patients with CLL. Methods: As part of an independent education program, ACCC initiated conversations with providers about the regional barriers that patients with CLL face. Through 4 webinars in February 2023, participants from 4 regions-Northeast (New York and Maine), Northwest (Montana and Idaho), Midwest (Wisconsin, Illinois, and Iowa), and Southwest (Texas)-shared insights on challenges and exchanged ideas on strategies to improve care for patients with CLL. In addition, ACCC interviewed 3 regionally diverse cancer programs (from the US Northwest, South, and Southwest regions) that are effectively overcoming regional challenges to reach their patient populations and provide equitable care. These interviews highlighted barriers and challenges, showcased effective outreach campaigns, and explored how the outreach improved the patient journey. Findings: The following themes emerged as key challenges and potential solutions throughout all regions studied: (1) Comprehensive Diagnostic Work-up Before Treatment Initiation: A key component in caring for patients with CLL is identifying certain disease related criteria prior to formulating a treatment plan. This includes determining the disease burden, disease-related symptoms, and if the patient meets certain active disease criteria (eg, Binet Stage C or Rai Stage III or IV). Further, by utilizing genetic testing, such as the TP53 gene mutation and IGHV mutation tests, physicians can estimate time to treatment and choice of specific novel targeted therapies. (2) Understanding Patient Population Needs: Cancer programs must understand the needs of their unique patient populations to effectively address them. For example, in the Northwest, as mountainous passes can make travel dangerous at times, one local program utilizes near-campus housing/hotel space for patients for the duration of their intensive treatment. In the Southwest, addressing health insurance coverage, low health literacy, language barriers, patient-provider mistrust, and culturally competent care for undocumented individuals presents challenges to equitable care delivery. Therefore, cancer programs in this region have implemented protocols to utilize community and social services to help support these patients. (3) Developing Community Partnerships: As the median age of diagnosis with CLL is approximately 70 years old, barriers such as transportation availability, caregiver support and financial constraints could be magnified. Building trust, particularly among vulnerable communities, also presents a significant challenge. By partnering with community outreach organizations, programs can help address these issues through community resources such as ride share programs, transportation vouchers, and financial assistance programs. (4) Provider Education and Learning: Because many patients are diagnosed in community cancer programs and smaller practices where physicians do not often have experience with CLL, nationally available provider education on new developments in testing and treatments is key. Conclusions: ACCC identified regional challenges and solutions to appropriate and equitable care for patients with CLL, including the importance of comprehensive diagnostic work-up before treating, understanding the regional needs of patient populations (particularly underserved populations), building community partnerships, and engaging in targeted provider education.

Background : Allogeneic hematopoietic cell transplant (alloHCT) is the only potentially curative therapy for patients (pts) with relapsed or refractory (R/R) AML. Only a minority undergo alloHCT as they typically have dismal outcomes due to high relapse rates, especially those with TP53 mutations and active disease. Additionally, older pts cannot tolerate intensive treatment and hence are not eligible for alloHCT. 131I-apamistamab, an anti-CD45 radioimmunoconjugate, delivers high dose targeted radiation to hematopoietic cells, allowing for myeloablation and eradication of leukemic cells. 131I-apamistamab led induction and conditioning can thus provide these pts access to alloHCT potentially leading to better disease control and outcomes even in pts with the TP53 mutation. Methods: The SIERRA trial (NCT02665065) is a multi-center, randomized, controlled Phase 3 study comparing the rate of durable complete remission (dCR) lasting ≥6 months (mos) after complete remission with/without platelet recovery (CR/CRp) between two groups: 131I-apamistamab led induction and conditioning followed by alloHCT vs physician's choice of conventional care (CC). Pts were randomized (1:1) to CC or 131I-apamistamab with fludarabine and total body irradiation (2 Gy) followed by alloHCT. CR/CRp assessment was 28-56 days post alloHCT or 28-42 days post initiation of therapy in the CC group. Pts in the CC group not achieving leukemia-free state could crossover (CO) to 131I-apamistamab. We report the characteristics and outcomes of all pts with TP53 mutation who were enrolled in the SIERRA trial. Results: In total, 153 pts were randomized (CC, n=77; 131I-apamistamab, n=76). All pts who received the therapeutic dose of 131I-apamistamab (n=66) underwent HCT vs 14 (18.2%) in the CC group. Of evaluable pts, dCR rates at 6 months were 22% in the 131I-apamistamab group vs 0% in the CC group (95% CI;12.29, 34.73; p&lt;0.0001). A total of 37 pts with TP53 mutation were enrolled (CC=20; 131I-apamistamab =17) with a prevalence of 24.2%. Table 1 shows the baseline characteristics of these pts. Median overall survival (OS) for pts in the 131I-apamistamab group, who were TP53 negative was 6.37 mos compared to 5.72 mos for the TP53 mutation positive pts (HR=0.66; 95% CI [0.37, 1.18]; p=0.16). In the CC group (including CO pts), the median OS for TP53 positive pts was 2.96 mos. When the CC group without CO were analyzed, the median OS was 6.51 mos and 1.66 mos for the TP53 mutation negative and positive groups respectively (HR=0.28; 95% CI [0.12, 0.67]; p=0.0022). For TP53 mutation positive pts who received 131I-apamistamab ( 131I-apamistamab plus CO pts), the median OS was 5.49 mos compared to a median 1.66 mos in pts who did not receive 131I-apamistamab (CC pts without CO) [(HR=0.23; 95% CI [0.10, 0.52]; p=0.0002) (Figure 1)]. Conclusion: Pts with TP53 mutated R/R AML have a dismal prognosis and are seldom offered alloHCT due to high post-transplant relapse rates. 131I-apamistamab led alloHCT significantly improves survival outcomes in pts with TP53 mutations, commensurate with rates observed in pts with wildtype TP53, thereby overcoming the negative impact of this mutation. These data clearly support the use of 131I-apamistamab led induction and conditioning and alloHCT in R/R AML, including in patients with a TP53 mutation.