Citations

Abstract Abstract 728 Background: LM, an antibody-drug conjugate (ADC), is designed to specifically kill CD56+ cancer cells and contains a potent maytansinoid cytotoxic agent (DM1) attached to a CD56-targeting antibody. MM shows CD56 expression in >70% of cases. LM has demonstrated single agent clinical activity and an acceptable safety profile in relapsed/refractory (rel/ref) MM patients. Preclinical studies showed enhanced anti-MM activity when LM was combined with Len/Dex. To further study the safety and efficacy of LM in combination with Len/Dex, a phase I study was conducted in rel/ref patients. This abstract reports updated results on the safety and efficacy of LM/Len/Dex and preliminary results on the pharmacokinetics (PK) and immunogenicity studies. Methods: Primary study objectives were to determine the safety, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), anti-MM activity and PK of LM in combination with standard oral (PO) doses of Len (25 mg po, daily on days 1–21) and Dex (40 mg po on D 1, 8, 15, and 22) in CD56+ rel/ref MM patients who have received at least 1 prior therapy. LM was given intravenously (IV) on D 1, 8, and 15 on a 28-day cycle. Dose escalation was conducted in new cohorts of patients to define the MTD, which was then further evaluated in a dose-expansion cohort. Adverse events (AEs) were assessed using CTCAEv3 criteria, and dose-limiting toxicity (DLT) determination was based on the occurrence of AEs that were probably or definitely attributed to the study regimen. Efficacy was assessed using the International Myeloma Working Group (IMWG) criteria. Enrollment has completed and 16 patients remain on study. Results: Forty-four patients were enrolled, 41 are currently evaluable for safety and 32 are evaluable for efficacy. The median number of prior therapies was 2 (range 1–11), 62% of patients had prior Len exposure and 33% were Len refractory. LM doses of 75 (N = 11), 90 (N=4), and 112 (N =6) mg/m2 were evaluated in the dose-escalation phase. The most common AE was peripheral neuropathy (PN), which occurred more frequently at higher LM doses (55% at 75 mg/m2 and 100% at 90 and 112 mg/m2); Grade 3 PN was seen only in patients treated at 90 mg/m2 or above. PN emerged, in most cases, in cycles >3 and was manageable with LM dose modification. During dose escalation, 1 patient experienced Grade 4 neutropenia and hyperuricemia. The 75 mg/m2 LM dose was considered the MTD based on overall tolerability and the lower incidence of PN observed, and was further tested to determine its suitability as the RP2D in the dose expansion portion of the study (N=23 patients, 19 patients available for safety evaluation). Grade 1–2 PN occurred in 8 patients (42%) and grade 3 PN was observed only in 1 pt in the dose-expansion cohort. Two patients developed grade 3 tumor lysis syndrome (TLS). Other grade 3 AEs reported in 1 patient each (5%) in the dose-expansion cohort consisted of neutropenia, thrombocytopenia, anemia, hemolytic anemia, and LDH increase. Efficacy was observed across all dose levels and the overall response rate (ORR) was 59%, including 1 patient each with stringent complete response (sCR) and complete response (CR), 8 patients with very good partial remission (VGPR), and 9 patients with partial remission (PR). No immunogenicity against the antibody (HAHA) or DM1 component (HADA) of LM was detected. PK results from 18 patients treated at 75 mg/m2 indicate LM Cmax and exposure in this combination regimen is consistent with LM monotherapy. Conclusions: Based on all available safety data, 75 mg/m2 was considered the RP2D. LM at 75mg/m2 in combination with Len and Dex has shown objective evidence of clinical activity with an acceptable safety profile. Disclosures: Off Label Use: Lorvotusumab mertansine is not FDA approved for treatment of multiple myeloma alone or in combination with lenalidomide and dexamethasone as is investigated in this trial. Running:ImmunoGen, Inc.: Employment. Murphy:ImmunoGen, Inc.: Employment. Guild:ImmunoGen, Inc.: Employment. Carrigan:ImmunoGen, Inc: Employment. Ladd:ImmunoGen, Inc.: Employment. Wolf:ImmunoGen, Inc.: Employment, Equity Ownership. O'Leary:ImmunoGen, Inc.: Employment. Ailawadhi:Millenium Pharmaceuticals: Speakers Bureau.

Abstract Background: Triple negative breast cancer (TNBC), generally considered aggressive with few options beyond standard chemotherapy, is currently experiencing a period of optimism, with multiple trials showing increased efficacy of platinum containing regimens (with and without PARP-inhibition), and more recently, immunotherapy. In I-SPY 2, veliparib/carboplatin (VC) and the immune checkpoint inhibitor pembrolizumab (Pembro) graduated in the TN subtype. As part of the I-SPY 2 biomarker program, we previously identified the signature PARPi7, a measure of DNA repair deficiency (DRD), as predicting response to VC. As well, immune signatures, including one representing dendritic cells, predicted response to Pembro. Here we investigate the overlap between these biomarkers to identify patient subgroups more likely to respond to immunotherapy or platinum-based therapy and estimate response rates to VC and Pembro in patients positive for one, both, or neither biomarker. Methods: 153 TNBC patients (Control: 85; VC: 39; Pembro: 29) were considered in this analysis. Continuous DNA repair deficiency and immune signatures assayed at the pre-treatment time point were evaluated as published (Wolf, 2017; Danaher, 2017). To identify optimal dichotomizing thresholds, 2-fold cross-validation was repeated 500 times. Bayesian logistic regression was used to estimate pCR rates by arm for patient subsets defined by biomarker combinations. Our study is exploratory with no claims for generalizability; and this analysis does not adjust for multiplicities. Results: Using the optimal dichotomizing cutpoints, 54% of TNBC patients are classified as DRD+, and 67% Immune+. As expected, DRD+ patients have a high estimated pCR rate to VC (75%); and Immune+ patients have a high estimated pCR rate to Pembro (82%). Combining these biomarkers, 40% of TNBC are positive for both biomarkers, 40% for only one biomarker (26% Immune+/DRD-, 14% Immune-/DRD+), and 20% for neither. The Immune+/DRD+ TN subset predicted sensitive to both VC and Pembro has a higher estimated pCR rate to both VC and Pembro relative to control (estimated pCR rates: VC: 75%, Pembro: 73% vs. control: 18%). In contrast, the Immune+/DRD- group, predicted to be sensitive to Pembro, has the highest pCR rate to Pembro (VC: 48%, Pembro: 83% vs. control 21%), whereas the Immune-/DRD+ group is most responsive to VC (VC: 63%, Pembro: 41% vs. control 29%). For the 20% of Immune-/DRD- TNBC patients, their estimated response rates are lower than the biomarker-positive patients (VC: 27%, Pembro: 43% vs. control: 19%). Conclusion: Molecular phenotypes capturing immune activation and DNA repair deficiency may predict response of TNBC and help prioritize selection of platinum or immunotherapy containing regimens. Citation Format: Denise M. Wolf, Christina Yau, Julia Wulfkuhle, Emanuel Petricoin, Lamorna Brown-Swigart, Gillian Hirst, Smita Asare, I-SPY 2 Consortium, Douglas Yee, Angela DeMichele, Hope Rugo, Olufunmilayo Olopade, Rita Nanda, Minetta Liu, Laura Esserman, Laura van t' Veer. Integration of DNA repair deficiency and immune biomarkers to predict which early-stage triple-negative breast cancer patients are likely to respond to platinum-containing regimens vs. immunotherapy: The neoadjuvant I-SPY 2 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2679.

AbstractThe role of consolidation post autologous stem cell transplant in light chain amyloidosis is not well defined. We retrospectively identified patients who had light chain amyloidosis and underwent autologous stem cell transplant at the Mayo Clinic. Consolidation was defined as any treatment given after the day 100 evaluation post‐transplant to maintain or deepen the response. We identified 471 patients, of whom 72 (15%) received consolidation. Patients receiving consolidation had more advanced disease (Mayo 2012 stage ≥II in 67% vs 52%, P = .02), and had lower day 100 response rates (very good partial response or better: 35% vs 84%, P < .001). After consolidation, rates of very good partial response improved from 24% to 28%, and rates of complete response improved from 11% to 40%. Patients with less than very good partial response who received consolidation, had better progression‐free survival (median of 22.4 vs 8.8 months, P < .001), and the benefit was greater in those who deepened their response (median of 41 vs 8.8 months, P < .001). In patients with less than very good partial response, there was a trend for better overall survival in patients who responded to consolidation (median of 125.8 vs 74.4 months, P = .07). In patients who achieved very good partial response, or better, at day 100 post autologous stem cell transplant, consolidation did not improve progression‐free or overall survival. Consolidation after autologous stem cell transplant for light chain amyloidosis improves progression‐free survival for patients who achieve less than very good partial response.

Abstract In appropriately selected patients with AL amyloidosis, autologous stem cell transplant (ASCT) is an established treatment modality with excellent outcomes and decreasing transplant related mortality (TRM) over time. We report on 15‐year overall survival (OS) in 159 patients undergoing ASCT from 1996 to 2003, with median follow up of 17.1 years. Day 100 TRM was 13.2% (n = 21). The OS of ≥15 years was observed in 30% (47/159) of patients. Patients surviving ≥15 years were younger (53 vs 56 years, P = .02), less likely to have lambda as the involved light chain (62% vs 78%, P = .03) and were less likely to have heart involvement (32% vs 56%, P = .005). Median OS of patients with heart involvement vs not was 4.0 vs 11.1 years, P = .006 and actuarial 15‐year OS was 23% vs 43%, respectively. A higher proportion of patients with OS ≥15 years received full‐dose melphalan conditioning (81% vs 61%, P = .01), and achieved day 100 complete response (CR) (64% vs 24%, P < .001). Median OS amongst patients who achieved CR vs not was 19.3 vs 5.4 years, P < .001. Heart involvement, receiving full‐dose melphalan and achieving CR remained independent predictors of OS. AL amyloidosis and related complications were the cause of death in 52% of patients overall (1‐5 years post‐transplant: 81%; 5‐10 years: 62% and 10‐15 years: 55%). These results reinforce the key role of ASCT in AL amyloidosis. With improvements in TRM and more options for relapsed disease, we expect the long‐term survival post‐transplant to improve significantly in the future.

2631 Background: Response to immune checkpoint inhibitors has been associated with immune activation and mutational load within a tumor. Previous results in other tumors have implicated MHC II protein tumor cell expression as a response predictor to immune checkpoint inhibitors. In the I-SPY 2 TRIAL, the anti-PD1 therapeutic antibody pembrolizumab (P) was available to HER2-negative subtypes and graduated in both the HR+/HER2- and TNBC signatures. Pre-specified biomarker analysis was performed to test tumor MHC II expression as a predictor of response to P in the I-SPY 2 TRIAL based on its central role in tumor antigen presentation. Methods: 156 patients (P: 67, controls: 89) had RPPA and pCR data. RPPA-based quantitative data for pan-MHC II protein isotypes HLA-DR/DP/DQ/DX and HLA-DR protein isotype was obtained from LCM-enriched tumor epithelium, and protein levels were assessed for association with pCR in the P and control arms separately using the Wilcoxon Rank Sum test (p < 0.05). Analysis was also performed in the HR+ and HR- subgroups. Markers were analyzed individually; p-values are descriptive and were not corrected for multiple comparisons. Results: Across all P- treated patients, the HLA class II molecules –DR and -DR/DP/DQ/DX had a positive association with response to P (p = 0.014 and p = 0.001). Expression of HLA-DR/DP/DQ/DX also had a positive association with response to P in HR+ tumors. Neither of these associations were seen in the control arm samples. Conclusions: The observation of elevation of MHC II protein expression in HER2- responding patients treated with P suggests that activation of antigen peptide exchange facilitated by these molecules in T and B cells may enhance response to P treatment.

Abstract ctDNA analysis offers a non-invasive approach for monitoring response and resistance to treatment. Serial ctDNA testing during neoadjuvant therapy (NAT) may provide early indicators of emerging resistance and disease progression. In this study, we analyzed ctDNA from high-risk early breast cancer patients who received NAT and definitive surgery in the I-SPY 2 TRIAL (NCT01042379). We hypothesize that (1) assessment of ctDNA levels early in treatment will improve the performance of molecular and imaging-based predictors of pathologic complete response (pCR) to NAT; and (2) levels of ctDNA after NAT are associated with residual cancer burden and recurrence [distant recurrence free survival (DRFS)]. Methods: ctDNA analysis was performed in 84 high-risk stage II and III breast cancer patients randomized to neoadjuvant investigational agent (n=52), AKT inhibitor MK-2206 (M) in combination with paclitaxel (T) followed by doxorubicin and cyclophosphamide (AC) (M+T-&gt;AC), or standard-of-care (T-&gt;AC) (n=32). HER2+ patients also received trastuzumab (H). Serial plasma was collected before NAT (T0), early treatment (3 weeks, T1), between regimens (12 weeks, T2), and after NAT prior to surgery (T3). Mutational profiles derived from pretreatment tumor biopsy and normal matched DNA whole exome sequencing were used to design personalized assays targeting 16 patient-specific somatic variants to detect ctDNA in serial plasma. Results: Of the 84 patients in this study, 43% were HR-/HER2- (TNBC), 35% HR+/HER2-, and 23% HER2+. In total, 74% (61 of 83), 35% (28 of 79), 14% (9 of 65), and 8% (5 of 61) were positive for ctDNA at timepoints T0, T1, T2, and T3, respectively. At T0, ctDNA positivity and levels (average number of mutant molecules detected per mL) were significantly associated with increased tumor burden (by clinical and MRI examination), more aggressive tumor biology (as reflected in higher Mammaprint scores and grade) and subtype (HER2+ and TNBC). Twenty-seven percent (27%) of the 84 patients achieved a pCR and all patients who were ctDNA-positive at T3 (n=5) did not achieve a pCR. Currently, data are being collected to: (1) assess the relationship of ctDNA and MRI imaging in predicting tumor response to therapy; (2) examine the relationship of ctDNA levels before and after NAT with 3-year DRFS and event-free survival (EFS). The results of these analyses will be presented at the SABCS 2018 meeting. Conclusions: Our study provides a platform to evaluate the clinical significance of ctDNA for serial monitoring of response to NAT. Accurate and early response prediction by highly sensitive ctDNA analysis can facilitate a timely and judicious change in treatment to improve patients' chances of achieving a pCR. Finally, personalized ctDNA testing may complement imaging and pathologic evaluation of tumor response to fine-tune pCR as a surrogate endpoint for improved DRFS and EFS. Citation Format: Magbanua MJM, Brown-Swigart L, Hirst GL, Yau C, Wolf D, Ma AA, Bergin E, Venters S, Sethi H, Wu H-T, Salari R, Tin T, Sawyer S, Louie M, Zimmermann B, Lin C-HJ, Keats J, Liang WS, Cuyugan L, Enriquez D, Tripathy D, Chien AJ, Forero A, DeMichele A, Liu M, Delson AL, Asare S, Esserman L, van't Veer L, I-SPY 2 Consortium. Personalized serial circulating tumor DNA (ctDNA) analysis in high-risk early stage breast cancer patients to monitor and predict response to neoadjuvant therapy and outcome in the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD2-01.

Abstract Background: The explosion in new treatment options targeting immune checkpoints, HER signaling, DNA repair deficiency, AKT, and other pathways calls for updated breast cancer subtypes beyond HR and HER2 status to predict which patients will respond to which treatments. Here we leverage the I-SPY 2 TRIAL biomarker program over the past 8 years across 10 treatment arms to elucidate a minimal set of biomarkers that may improve response prediction in a modern treatment context, and to investigate which new patient phenotypes are identified by these response-predictive biomarkers. Methods: 986 patients were considered in this analysis. Treatments included paclitaxel alone (or with trastuzumab (H) in HER2+) or combined with investigational agents: veliparib/carboplatin (VC); neratinib; MK2206; ganitumab; ganetespib; AMG386; TDM1/pertuzumab (P); H/P; and pembrolizumab (Pembro). 24 prospectively defined, mechanism-of-action and pathway-based expression and phospho-protein signatures/biomarkers assayed from pre-treatment biopsies were previously found to be predictive in a particular agent/arm in pre-specified analysis. Here we evaluate these biomarkers in all patients. We assessed association between each biomarker and response in the population as a whole and within each arm and HR/HER2 subtype using a logistic model. To identify optimal dichotomizing thresholds for select biomarkers, 2-fold cross-validation was repeated 500 times. Our analysis is exploratory and does not adjust for multiplicities. Results: Our initial set of 24 predictive biomarkers reflects DNA repair deficiency (n=2), immune activation (n=7), ER signaling (n=2), HER2 signaling (n=4), proliferation (n=2), phospho-activation of AKT/mTOR (n=2), and ANG/TIE2 (n=1) pathways, among others. Biomarkers reflecting similar biology are correlated and cluster together. We make use of this correlation structure to reduce the dimensionality of the biomarker set to five predictive signals: proliferation, DNA repair deficiency (DRD), immune-engaged (Immune+), luminal/ER (lum), and HER2-activated. These biomarkers, when dichotomized, identify patient groups with differential predicted sensitivities to I-SPY 2 agents and are present at different proportions within receptor subtypes. For instance, in the HER2- subset, Immune+/DRD+ patients are predicted sensitive to both VC and Pembro, and account for 39% of TN, but only 12% of HR+HER2-. On the other end of the spectrum, only 17% of TN are Immune-/DRD-, compared to the majority (56%) of HR+HER2-. There are also subsets of patients positive for only one marker. For the HER2+ subset, 67% are HER2-activated+, and 25% lum+; of these HER2-activated+ patients are more likely to be Immune+ (44%), vs 23% in lum+. HER2-activated+/Immune+ patients have higher predicted sensitivity to HER2-targeted agents than lum+ or Immune- patients. In all, these molecular phenotypes predict sensitivity to one or more I-SPY 2 investigational agents for 75% of the ˜ 1000 patients. Conclusion: Molecular phenotypes reflecting proliferation, immune engagement, HER2-activation, luminal/ER-signaling, and DNA repair deficiency may provide a roadmap to guide treatment prioritization for emerging therapeutics. Citation Format: Wolf DM, Yau C, Wulfkuhle J, Petricoin E, Campbell M, Brown-Swigart L, Hirst G, Asare S, Zhu Z, Lee EP, Delson A, Pohlmann P, I-SPY 2 TRIAL Consortium, Hylton N, Liu MC, Symmans F, DeMichele A, Yee D, Berry D, Esserman L, van 't Veer L. Identifying breast cancer molecular phenotypes to predict response in a modern treatment landscape: Lessons from ˜1000 patients across 10 arms of the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-02.