Post-transplantation lymphoproliferative disorders (PTLD) are a heterogenous group of abnormal lymphoid proliferations that occur after solid organ transplant (SOT) or hematopoietic transplantation. PTLDs consist of a disease spectrum ranging from hyperplasia to aggressive lymphomas with 60-70% being Epstein-Barr virus positive. The majority of cases are B-cell, although 10-15% are of T-cell origin or rarely Hodgkin lymphoma. Recent SOT series suggest PTLD occurs at a median of 36-40 months after transplant. Clinically, extra-nodal disease is common (up to 75-85%) including CNS involvement, which is seen in 10-15% of all cases. Since the first report over 40 years ago, PTLD has remained one of the most morbid complications associated with SOT. However, recent data suggests improved survival in the modern era, especially with the integration of early rituximab-based therapy. These studies utilized first line rituximab (+/- chemotherapy) together with reduced immune suppression (RI) for monomorphic and polymorphic PTLD. It will be critical in future studies to determine which PTLDs are most amenable to initial therapy with RI alone, versus RI/rituximab, versus RI/rituximab/chemotherapy. Additionally, novel therapeutics, such as adoptive immunotherapy, should continue to be explored.

High-dose melphalan 200 mg/m2 (MEL 200) is the standard of care as a conditioning regimen for autologous hematopoietic stem cell transplantation (AHSCT) for multiple myeloma (MM). We compared a novel conditioning combination incorporating busulfan, melphalan, and bortezomib (BUMELVEL) versus standard MEL 200 in newly diagnosed patients undergoing AHSCT for MM. Between July 2009 and May 2012, 43 eligible patients received BUMELVEL conditioning followed by AHSCT. BU was administered i.v. daily for 4 days to achieve a target area under the concentration-time curve total of 20,000 mM·min based on pharmacokinetic analysis after the first dose. MEL 140 mg/m2 (MEL 140) and VEL 1.6 mg/m2 were administered i.v. on days −2 and −1, respectively. Outcomes were compared with a contemporaneous North American cohort (n = 162) receiving MEL 200 matched for age, sex, performance status, stage, interval from diagnosis to AHSCT, and disease status before AHSCT. Multivariate analysis of relapse, progression-free survival (PFS), and overall survival (OS) was performed. The median follow-up was 25 months. No transplant-related mortality was observed in the study cohort at 1 year. PFS at 1 year was superior in the BUMELVEL cohort (90%) in comparison with 77% in MEL 200 historical control subjects (P = .02). Cumulative incidence of relapse was lower in the BUMELVEL group versus the MEL 200 group (10% at 1 year versus 21%; P = .047). OS at 1 year was similar between cohorts (93% versus 93%; P =.89). BU can be safely combined with MEL 140 and VEL without an increase in toxicities or transplant-related mortality. We observed a superior PFS in the BUMELVEL cohort without maintenance therapy, warranting further trials.

Background Ladiratuzumab vedotin (LV) is an investigational anti-LIV-1 antibody-drug conjugate with a protease-cleavable linker to monomethyl auristatin E (MMAE). LIV-1 is highly expressed in metastatic triple negative breast cancer (TNBC). LV mediated delivery of MMAE drives antitumor activity through cytotoxic cell killing and has been shown to induce immunogenic cell death (ICD). LV monotherapy has demonstrated encouraging activity in TNBC. Anti-PD-(L)1 agents are emerging as part of the TNBC treatment paradigm and showing promising activity. Combining LV and pembrolizumab (pembro) may result in complementary, as well as synergistic, activity through LV-induced ICD that creates a microenvironment favorable for enhanced anti-PD-(L)1 activity. Methods This ongoing phase 1b/2 study evaluates safety, tolerability, activity, and recommended phase 2 dose of LV + pembro (NCT03310957; 2017-002289-35) in a dose-finding (Part A) followed by expansion phase (Part B) as front-line therapy for TNBC patients (pts). Eligible pts receive LV 2.0 mg/kg or 2.5mg/kg + pembro 200mg every 3 wks. Pts must have TNBC per ASCO/CAP guidelines (absence of HER2, estrogen receptor, and progesterone receptor expression) and are not pre-selected for either LIV-1 or PD-L1 expression. Tumor assessment is performed every 6 weeks per RECIST v1.1. Results As of 23 May 2019, a total of 51 pts have received LV + pembro (7 and 44 pts at LV 2.0 and 2.5 mg/kg, respectively). Nineteen pts enrolled in dose finding (7 and 12 at LV 2.0 and 2.5 mg/kg, respectively) and 32 pts enrolled in dose expansion all at LV 2.5 mg/kg. Median age was 55 yrs (range: 30, 82), ECOG 0/1 was 47%/53%, and invasive ductal carcinoma histology was 69%. All patients were first-line for LA/M TNBC, and 24% of pts had de novo mTNBC at initial diagnosis. Two pts experienced dose-limiting toxicities (DLT) out of 12 pts enrolled at LV 2.5 mg/kg in Part A: Grade 3 colitis and Grade 3 diarrhea. No DLT was observed at LV 2.0mg/kg. Of the 51 pts evaluable for safety (defined as all pts who received any amount of LV or pembro), 44 (86%) reported treatment emergent adverse events (TEAEs). Most common TEAEs across the 2 LV dose levels were nausea (53%); fatigue (45%); diarrhea (43%); alopecia (33%); constipation and hypokalemia (29% each); vomiting (27%); decreased appetite (25%); abdominal pain (24%); decreased weight (22%); and neutropenia and peripheral sensory neuropathy (20% each). Across the 2 dose levels, the most common Grade 3+ AEs were neutropenia (16%); diarrhea, fatigue, hypokalemia, and maculo-papular rash (8% each); and abdominal pain, increased ALT, and urinary tract infection (6% each). The most common SAEs were abdominal pain and constipation (6% each). In this ongoing trial, 26 pts were followed for at least 3 months with an opportunity for 2 post-baseline disease assessments. Among these 26 pts, the confirmed objective response rate was 54% (95% CI, 33.4, 73.4). Two additional pts have a single scan showing PR and are pending confirmatory assessment. Updated data will be provided at the meeting. Conclusion LV + pembro appears tolerable with a manageable safety profile to date. Preliminary efficacy data show encouraging clinical activity as first-line therapy in pts with unresectable LA/M TNBC. Citation Format: Hyo (Heather) Han, Sami Diab, Carlos Alemany, Reva Basho, Ursa Brown-Glaberman, Jane Meisel, Timothy Pluard, Javier Cortes, Patrick Dillon, Johannes Ettl, Sherko Kuemmel, Luis Manso Sanchez, Mafalda Oliveira, Joyce O'Shaughnessy, Steven Papish, Rajni Sinha, Danielle Sterrenberg, Erica Stringer-Reasor, Michaela Tsai, Rafael Villanueva Vazquez, Rachel Wuerstlein, Yinghui Wang, Zejing Wang, Valentina Boni. Open label phase 1b/2 study of ladiratuzumab vedotin in combination with pembrolizumab for first-line treatment of patients with unresectable locally-advanced or metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD1-06.

TPS1110 Background: There are currently no curative treatments for patients with metastatic triple-negative breast cancer (mTNBC), and prognosis for this disease is very poor. Emerging treatment combinations of anti-programmed death ligand 1 (PD-L1) agents with chemotherapy have shown promise in mTNBC. SGN-LIV1A, or ladiratuzumab vedotin (LV), is a novel investigational humanized IgG1 antibody-drug conjugate (ADC) directed against LIV-1, which is highly expressed in breast cancer cells. LV mediates delivery of monomethyl auristatin E (MMAE), which drives antitumor activity through cytotoxic cell killing and induces immunogenic cell death (ICD). Preliminary results from an ongoing phase 1 study of LV monotherapy has shown LV to be well tolerated and to have encouraging antitumor activity in patients with mTNBC. Combining LV and pembrolizumab may result in complementary, as well as synergistic, activity through LV-induced ICD that creates a microenvironment favorable for enhanced anti-PD-L1 activity. Methods: This single-arm, open-label, phase 1b/2 study evaluates the safety and antitumor activity of LV in combination with pembrolizumab as first-line therapy for patients with unresectable locally advanced or mTNBC (NCT03310957, 2017-002289-35). Patients must have measureable disease per RECIST v1.1, an ECOG score of 0 or 1, and no prior cytotoxic or anti-PD-L1 treatment for advanced disease. This study has 2 parts that are enrolling sequentially: a dose-finding phase that starts at LV 2.5 mg/kg + pembrolizumab 200 mg intravenously every three weeks, and a dose expansion phase. The primary objectives are to evaluate the safety/tolerability and objective response rate of LV + pembrolizumab, and identify the recommended phase 2 dose of LV. The secondary objectives are to assess duration of response, disease control rate, progression-free survival, and overall survival. Additional objectives include assessing PD-L1 and LIV-1 expression-response relationship. Study enrollment is ongoing in the US and EU. Clinical trial information: NCT03310957.

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