On June 4, 2018 MiNA Therapeutics, the pioneer in RNA activation (RNAa) therapeutics, reported preliminary results from its ongoing Phase I study of small activating RNA (saRNA) candidate MTL-CEBPA in advanced liver cancer (Press release, MiNA Therapeutics, JUN 4, 2018, View Source [SID1234527158]). In the study, MTL-CEBPA was generally well tolerated in patients with both healthy and impaired liver function and provided evidence of anti-tumour activity. MTL-CEBPA was also found to mediate RNAa activity in white blood cells. The data are being presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in a poster titled "Preliminary results of a first-in-human, first-in-class phase I study of MTL-CEBPA, a small activating RNA (saRNA) targeting the transcription factor C/EBP-a in patients with advanced liver cancer" in the Developmental Therapeutics – Clinical Pharmacology and Experimental Therapeutics poster discussion session being held on Monday June 4, 2018 from 3:00pm to 4:15pm CDT.

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"Despite recent advances in treatment options, liver cancer remains a significant unmet medical need with numerous hurdles for therapeutic intervention. New treatment options are desperately needed, in particular for those patients with impaired liver function," said Dr. Debashis Sarker, Principal Investigator at the National Institute for Health Research Clinical Research Facility at Guy’s and St Thomas’ and King’s College London, and chief investigator of the study. "These preliminary safety data and the evidence of anti-tumour activity are very promising and I look forward to evaluating MTL-CEBPA in the dose expansion part of this Phase I clinical trial."

"We are extremely pleased with the preliminary results of this first-in-human study which include safety and tolerability of MTL-CEBPA, as well as evidence of anti-tumour activity in this very advanced, heavily pre-treated cancer patient population. In particular we have seen many patients achieve stable disease or better, including a patient with advanced hepatocellular carcinoma who has achieved over 70% tumour regression and has continued on the study for over one and half years," said Robert Habib, CEO of MiNA Therapeutics. "Additionally, analysis of patient blood samples has demonstrated upregulation of target CEBPA mRNA in white blood cells, representing a significant milestone in the development of saRNA medicines and for our platform."

MTL-CEBPA was evaluated in the dose escalation part of a Phase I clinical trial in patients with advanced liver cancer. As of the data cut-off date of March 31, 2018, 23 patients had been treated once weekly at six dose levels (ranging from 28 mg/m2 to 160 mg/m2) and 5 patients had been treated twice weekly at 70 mg/m2.

MTL-CEBPA was well tolerated in patients at all doses and no Maximum Tolerated Dose was identified. The large majority of adverse events (AEs) reported by investigators were mild to moderate in severity. 12 (43%) patients experienced AEs no higher than Grade 2. AEs of Grade 3 or higher included hyperbilirubinaemia (11%), elevated GGT (11%), hypophosphataemia (11%), anaemia (7%) and hypertension (7%). Only 3 (11%) patients discontinued treatment with MTL-CEBPA due to possible drug-related toxicities including acute coronary syndrome, hyperbilirubinaemia, and elevated GGT.

Pharmacokinetic data from this study showed that Cmax (peak plasma concentration of drug) and AUC (area under the curve) were dose proportional with no evidence of drug accumulation.

CEBPA gene expression was analysed in white blood cells of 10 patients across multiple dose levels and timepoints. The level of CEBPA gene expression was significantly higher on treatment than at baseline, supporting target engagement of MTL-CEBPA. Consistent with up-regulation of CEBPA, which has a role in myeloid differentiation, significant and repeated increases in neutrophils were observed after dosing MTL-CEBPA.

Enrollment in the dose escalation part of the Phase I clinical trial has been completed. Enrollment is starting for in the dose expansion part of the Phase I clinical trial in multiple sites in the United Kingdom and Asia. For more information, please contact us at [email protected].

About MTL-CEBPA
MTL-CEBPA consists of a double stranded RNA formulated into a SMARTICLES liposomal nanoparticle and is designed to activate the CEBPA gene. By restoring CEBPA expression to normal levels, MTL-CEBPA has been demonstrated to attenuate or reverse liver disease in a range of pre-clinical studies including models of liver cancer, liver cirrhosis, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). MTL-CEBPA is currently under evaluation in OUTREACH, a first-in-human Phase I clinical study in patients with severe liver cancer. The multi-centre Phase I study is assessing the safety and tolerability of MTL-CEBPA in patients with advanced liver cancer who are ineligible or resistant to standard therapies. To learn more about the OUTREACH clinical study, please visit our listing at clinicaltrials.gov

On June 4, 2018 Verastem, Inc. (NASDAQ:VSTM) (Verastem Oncology or the Company), a biopharmaceutical company focused on developing and commercializing medicines to improve the survival and quality of life of cancer patients, reported the presentation of five posters highlighting data for its two lead drug candidates, duvelisib and defactinib, at the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) being held June 1-5, 2018 in Chicago (Press release, Verastem, JUN 4, 2018, View Source;p=RssLanding&cat=news&id=2353079 [SID1234527157]).

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Duvelisib is a first-in-class oral dual inhibitor of phosphoinositide 3-kinase (PI3K)-delta and PI3K-gamma that is currently being developed for the treatment of relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma (FL). In addition, duvelisib is being studied in other hematologic malignancies including peripheral T cell lymphoma (PTCL). In April, the U.S. Food and Drug Administration (FDA) accepted with Priority Review Verastem Oncology’s New Drug Application for duvelisib, which has an FDA target action date of October 5, 2018. Defactinib is an oral small molecule inhibitor of focal adhesion kinase (FAK) and is currently being evaluated in combination with immunotherapeutic agents for the treatment of various cancers including pancreatic, ovarian and non-small cell lung cancer, and mesothelioma.

"The DUO crossover extension data reported at ASCO (Free ASCO Whitepaper) this year build upon the previously reported positive Phase 3 DUO study results and further support duvelisib’s potential as an oral treatment option for patients with relapsed or refractory CLL/SLL," said Diep Le, MD, PhD, Chief Medical Officer of Verastem Oncology. "Post-crossover, oral duvelisib monotherapy demonstrated robust clinical activity with a 73% overall response rate (ORR) and a 15-month median PFS in the 89 patients that had previously received ofatumumab on DUO and subsequently progressed . Duvelisib monotherapy also demonstrated a manageable safety profile, with results from this study consistent with the well-characterized safety profile of duvelisib monotherapy in previous studies. It is encouraging to see such a robust response to duvelisib monotherapy, similar to response observed in the parent DUO study, in patients that had failed an additional line of therapy and needed a new treatment option."

Jonathan Pachter, PhD, Chief Scientific Officer of Verastem Oncology, commented, "The presented research by Drs. Casulo and Weaver continues to provide important evidence that the dual PI3K-delta/PI3K-gamma inhibitory activity of duvelisib results in beneficial anti-tumor effects on both the cancer cells and their supportive tumor microenvironment (TME) which has the potential to enhance clinical efficacy and improve outcomes for patients battling CLL/SLL and FL."

Dr. Le added, "Dr. Andrea Wang-Gillam presented initial results from an ongoing Phase 1 study evaluating our lead FAK inhibitor defactinib in combination with pembrolizumab and gemcitabine in patients with advanced pancreatic cancer. The triplet appears to be well tolerated, the recommended Phase 2 dose has been established, and the expansion phase of the study is ongoing. In addition, promising signs of clinical activity have been observed with 3 pancreatic cancer patients treated beyond 250 days, including a confirmed partial response and the other 2 patients with stable disease. All 3 of these patients have also shown meaningful reductions (57-96%) in the pancreatic cancer marker CA19-9. Analysis of paired biopsies have also shown that this treatment induced desirable biomarker changes including increased proliferating CD8+ T cells and reduced immunosuppressive Tregs and macrophages. Treatment of pancreatic cancer represents a very important unmet need for patients, and these initial results are certainly encouraging."

Details for the ASCO (Free ASCO Whitepaper) 2018 presentations are as follows:

Duvelisib

Title: The efficacy of duvelisib monotherapy following disease progression on ofatumumab monotherapy in patients with relapsed/refractory CLL or SLL in the DUO crossover extension study
Lead author: Dr. Bryone Kuss, Flinders Medical Centre
Abstract #: 7533
Summary: In the previously reported Phase 3 DUO study oral duvelisib monotherapy achieved a statistically significant improvement in median progression-free survival (mPFS) compared to ofatumumab in patients with relapsed or refractory CLL/ SLL (13.3 months versus 9.9 months, respectively; HR=0.52; p<0.0001), along with a manageable safety profile (Flinn, ASH (Free ASH Whitepaper) 2017). The results reported here are from the open-label, DUO crossover extension study where patients with confirmed progressive disease (PD) following treatment with ofatumumab in DUO were given the option to receive treatment with duvelisib. Duvelisib 25mg BID was administered until PD, intolerance, death, or study withdrawal and responses were determined by investigators using modified IWCLL/IWG criteria.

Among the 89 evaluable patients (median three prior therapies (range 2-8), oral duvelisib monotherapy achieved a 73% overall response rate (ORR; 95% CI: 64, 82; 5% complete response with incomplete marrow recovery (CRis), 68% partial responses [PRs]) in the extension study. While on ofatumamab in the DUO study, these 89 patients had a 28% ORR (95% CI: 19, 37; 1% complete response (CR), 27% PRs). The mPFS for duvelisib in the extension study was 15 months (95% CI: 10, 17). While on ofatumamab in the DUO study, these 89 patients had a mPFS of 9 months (95% CI: 9, 11), per investigator’s assessment. Notably, 83% of patients in the duvelisib arm post-crossover had >50% reductions in the size of their target nodal lesions. These same 89 patients had 27% reductions in the size of their target nodal lesions in the DUO ofatumumab arm. Median exposure to duvelisib in the extension study was 32 weeks. The safety profile of duvelisib monotherapy was manageable and consistent with what was observed in the Phase 3 DUO study. The most common Grade ≥3 treatment-emergent adverse events were neutropenia (22%), diarrhea (17%), colitis (9%), pneumonia (9%), rash (5%) and pyrexia (4%). These data build upon the previously reported positive DUO results and further support oral duvelisib monotherapy as an effective oral treatment option for patients with relapsed or refractory CLL/SLL.

A copy of the poster presentation will be available here.

Title: The effect of duvelisib, a dual inhibitor of PI3K-δ,γ, on components of the tumor microenvironment in previously untreated follicular lymphoma
Lead author: Dr. Carla Casulo, University of Rochester, Wilmot Cancer Center
Abstract #: 7579
Summary: In previously reported data from the CONTEMPO trial, treatment-naive FL patients treated with duvelisib in combination with rituxumab had an ORR of 93% (36% CRR), and an ORR of 89% (41% CRR) was observed for patients treated with duvelisib in combination with obinutuzumab. In this study, blood samples from healthy volunteers and FL patients treated in the CONTEMPO study, both pre- and post-duvelisib treatment, were analyzed. Ex vivo and in vitro PI3K-γ assays and PI3K-δ assays, with PI3K-δ-selective (idelalisib, TGR-1202, IPI-3063) and PI3K-γ-selective (IPI-549) inhibitors were compared.

Duvelisib and idelalisib potently inhibited LPS-induced human monocytes via PI3K-δ, compared with the PI3K-γ selective IPI-549. For TGR-1202, the IC50 was below the recommended Phase 2 dose (RP2D) clinical exposure. Duvelisib and IPI-549 potently inhibited PI3K-γ dependent fMLP-stimulated human monocytes compared to idelalisib and TGR-1202. In FL patients treated with duvelisib, these PI3K-γ and PI3K-δ selective assays were inhibited 1-4 hours post treatment. Consistent with a PI3K-γ mechanism, both duvelisib and IPI-549 inhibited macrophage polarization to M2, reduced CXCL12-induced macrophage migration, and blocked CXCL12-induced T cell migration, which was not observed with PI3K-δ inhibitor IPI-3063. Collectively, these results support the thesis that duvelisib disrupts PI3K- δ,γ function in FL patients inhibiting the TME through cancer-supportive macrophages and T cells.

A copy of the poster presentation will be available here.

Title: The PRIMO study: A phase 2 study of duvelisib efficacy and safety in patients with relapsed or refractory peripheral t-cell lymphoma (PTCL)
Lead author: Dr. Steven Horwitz, Memorial Sloan Kettering Cancer Center
Abstract #: TPS7590
Summary: This poster describes the PRIMO study, a Phase 2 open-label clinical trial evaluating duvelisib monotherapy in adult patients with PTCL, one of the most aggressive forms of non-Hodgkin lymphoma (NHL). The study employs a dose optimization phase (DOP) and an Expansion Phase (EP). The primary objectives are to identify the optimal dose of duvelisib in PTCL and examine the efficacy, safety, and tolerability of duvelisib at the optimal dose. The study is expected to enroll up to 120 patients with histologically confirmed PTCL subtypes of PTCL-NOS, angioimmunoblastic TCL, anaplastic large cell lymphoma, and natural-killer TCL. Disease responses will be measured by PET-CT scanning as assessed by an independent review committee per IWG criteria. The primary endpoint is ORR (CR + PR) in all patients receiving the optimal dose for at least 1 cycle in either phase. Secondary endpoints include safety, duration of response, and PFS. This study is open for enrollment. Duvelisib has been granted Fast Track designation by the U.S. Food and Drug Administration (FDA) for the treatment of patients with PTCL who have received at least one prior therapy.

A copy of the poster presentation will be available here.

Title: Duvelisib inhibition of chemokines in patients with CLL (DUO study) and iNHL (DYNAMO study)
Lead author: Dr. David Weaver, Verastem Oncology
Abstract #: 12048
Summary: PI3K-δ inhibition directly targets proliferation and survival of malignant leukemia and lymphoma cells, while PI3K-γ inhibition modulates the TME through key support cells, including tumor-associated macrophages, nurse-like stroma and T cells, and via soluble factors stimulating tumor growth, survival and migration. Serum samples from patients in the Phase 3 DUO study in relapsed/refractory CLL/SLL and the Phase 2 DYNAMO study in relapsed/refractory indolent NHL were collected at baseline and at C2D1 and used for correlative studies of 24 chemokines, cytokines and serum factors.

In serum samples from the DUO study, CCL1, CCL17, CXCL9, CXCL10, CXCL11, and IL-10 were reduced in patients treated with duvelisib (median 43.8%) but not in those treated with ofatumumab (p≤0.0009). Eight chemokines were reduced in both treatment arms, but the level of reduction was significantly greater for duvelisib-treated patients (median 64.6% for duvelisib versus 26.8% for ofatumumab [p≤0.001]). Many of the chemokines inhibited following duvelisib treatment are associated with the TME, including TNFα, IL-10, IL2Rα, IL12P40, CCL1, CCL17, CCL19, CXCL9, CXCL10, CXCL11, and CXCL13. In serum samples from the DYNAMO study, 13 corresponding chemokines were also inhibited (p≤0.008), including TME factors. Reductions occurred rapidly (by C2D1) in both studies. In DUO, there was a correlation between duration of response and reduction of the following chemokines: CCL17, CXCL11, IL-6, TRAIL, VEGF-D and TPO. These data support the hypothesis that treatment with duvelisib results in significant reduction of chemokines potentially derived from the tumor cells and TME and that further investigation of the effects of duvelisib on TME pharmacodynamic markers is warranted.

A copy of the poster presentation will be available here.

Defactinib

Title: Phase I study of defactinib combined with pembrolizumab and gemcitabine in patients with advanced cancer
Lead author: Dr. Andrea Wang-Gillam, Washington University in St. Louis
Abstract #: 2561
Summary: FAK is consistently hyperactivated in multiple tumor types including pancreatic ductal adenocarcinoma (PDAC). Previously reported preclinical research showed that FAK and PD-1 inhibitors elicit significant tumor regression, and a maximal response is achieved by combining FAK and PD-1 inhibitors with gemcitabine, suggesting the need for a cytotoxic agent to bolster antigen presentation. In this ongoing Phase 1, dose-escalation study, defactinib is being evaluated in combination with Merck’s PD-1 inhibitor pembrolizumab and gemcitabine in patients with PDAC.

The dose escalation cohort has been completed with a total of 20 patients with refractory solid tumors. Of the 15 patients evaluable for treatment response, 1 (7%) achieved a confirmed PR and 8 (53%) achieved stable disease (SD). Of the 8 PDAC patients, 1 (13%) achieved a confirmed PR and 3 (38%) achieved SD. The median time on treatment was 132 days for all evaluable patients and 158 days for patients with PDAC. Paired biopsies from PDAC patients showed increased proliferating CD8+ T cells and decreased T regs in patients with controlled disease compared to patients with progressive disease. The combination regimen was well tolerated with no dose limiting toxicities, and therefore the RP2D dose was established as defactinib (400mg BID, Days 1-21), pembrolizumab (200mg, Day 1) and gemcitabine (1,000mg/m2, Day 1 and 8). The common treatment-emergent adverse events were anorexia (50%), fatigue (40%), diarrhea (40%), fever (40%) and vomiting (35%), but nearly all were Grade 1/2. There was 1 case of Grade ≥3 diarrhea. An expansion cohort in patients with PDAC is currently ongoing.

A copy of the poster presentation will be available here.

About Duvelisib

Duvelisib is a first-in-class investigational oral, dual inhibitor of phosphoinositide 3-kinase (PI3K)-delta and PI3K-gamma, two enzymes known to help support the growth and survival of malignant B-cells and T-cells. PI3K signaling may lead to the proliferation of malignant B- and T-cells and is thought to play a role in the formation and maintenance of the supportive tumor microenvironment.1,2,3 Duvelisib was evaluated in late- and mid-stage extension trials, including DUO, a randomized, Phase 3 monotherapy study in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL),4 and DYNAMO, a single-arm, Phase 2 monotherapy study in patients with refractory indolent non-Hodgkin lymphoma (iNHL).5 Both DUO and DYNAMO achieved their primary endpoints. Verastem Oncology’s New Drug Application (NDA) requesting the full approval of duvelisib for the treatment of patients with relapsed or refractory CLL/SLL, and accelerated approval for the treatment of patients with relapsed or refractory follicular lymphoma (FL) was accepted for filing by the U.S. Food and Drug Administration (FDA), granted Priority Review and assigned a target action date of October 5, 2018. Duvelisib is also being developed by Verastem Oncology for the treatment of peripheral T-cell lymphoma (PTCL), and is being investigated in combination with other agents through investigator-sponsored studies.6 Information about duvelisib clinical trials can be found on www.clinicaltrials.gov.

About Defactinib

Defactinib is an investigational inhibitor of focal adhesion kinase (FAK), a non-receptor tyrosine kinase that mediates oncogenic signaling in response to cellular adhesion and growth factors.7 Based on the multi-faceted roles of FAK, defactinib is used to treat cancer through modulation of the tumor microenvironment and enhancement of anti-tumor immunity.8,9 Defactinib is currently being evaluated in three separate clinical collaborations in combination with immunotherapeutic agents for the treatment of several different cancer types including pancreatic cancer, ovarian cancer, non-small cell lung cancer (NSCLC), and mesothelioma. These studies are combination clinical trials with pembrolizumab and avelumab from Merck & Co. and Pfizer/Merck KGaA, respectively.10,11,12 Information about these and additional clinical trials evaluating the safety and efficacy of defactinib can be found on www.clinicaltrials.gov.

On June 4, 2018 TESARO, Inc.(NASDAQ:TSRO), an oncology-focused biopharmaceutical company, reported the results of the TOPACIO and QUADRA trials during an investor briefing held in conjunction with the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, TESARO, JUN 4, 2018, View Source [SID1234527156]).

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"The promising data presented at this year’s ASCO (Free ASCO Whitepaper) meeting demonstrated the potential of ZEJULA not only as a monotherapy treatment for women with advanced ovarian cancer, but also in combination with an anti-PD-1 antibody, to provide a meaningful clinical benefit to patients beyond those with BRCA mutations," said Mary Lynne Hedley, Ph.D., President and COO of TESARO. "Our oncology development strategy is focused on rational therapeutic combinations and niraparib and TSR-042, our anti-PD-1 antibody, are the foundation of this strategy. The TOPACIO results support the advancement of combination studies in ovarian cancer and breast cancers and we have initiated preparations for registrational trials of niraparib in combination with TSR-042 in these settings. QUADRA results demonstrated that ZEJULA is active as a late-line treatment for patients beyond those with BRCA mutations, which is the only treatment setting in which PARP inhibitors are approved today, and we intend to submit an sNDA in the fourth quarter of 2018."

TOPACIO Data Demonstrate Encouraging Activity of Niraparib in Combination with anti-PD-1 in Platinum-Resistant/Refractory Ovarian Cancer

Prior clinical studies have shown that monotherapy with PARP inhibitors or anti-PD-1 antibodies has limited efficacy in the treatment of patients with platinum-resistant/refractory ovarian cancer or triple-negative breast cancer beyond those patients with BRCA mutant tumors, and these patients generally face a poor prognosis. TOPACIO is a Phase 1/2 clinical trial designed to evaluate the safety and efficacy of niraparib plus KEYTRUDA (pembrolizumab) in patients with recurrent, platinum-resistant/refractory ovarian cancer or triple-negative breast cancer (TNBC). Following dose finding in Phase 1, niraparib was administered orally, once-daily, at a dose of 200 milligrams in combination with 200 milligrams of pembrolizumab administered intravenously on day one of each 21-day treatment cycle in two patient cohorts: platinum-resistant or refractory ovarian cancer and TNBC. Endpoints included objective response rate (ORR), duration of response (DOR) and disease control rate (DCR; CR+PR+SD).

At the time of data cutoff, of the 62 patients enrolled with ovarian cancer, 60 were evaluable for an initial response assessment. The population had been treated with a median of 2 (range of 1 to 5) prior lines of therapy; 50% had platinum-resistant ovarian cancer, 29% were platinum-refractory, 63% had received prior bevacizumab, and 21% were platinum ineligible. Data indicate an ORR (CR and PR) of 25% and a DCR of 67% in the evaluable population; ORR in the BRCAmut cohort was 25% with a DCR of 63%; ORR in the BRCAwt cohort was 24% with a DCR of 65%. Response rates were not dependent on biomarker status or platinum status. ORR was 23% (7/30) in platinum-resistant ovarian cancer patients, 24% (4/17) in platinum-refractory patients and 31% (4/13) in patients who were platinum ineligible per investigator’s assessment (typically due to prior platinum hypersensitivity, toxicities or other reasons that platinum could not be tolerated). Median DOR was 9.3 months, with 9 patients remaining on treatment. The most common grade ≥ 3 adverse events (AEs) included anemia (21%) and thrombocytopenia (9%) at a 200-milligram starting dose of niraparib. Following a successful discussion with FDA, a registration study with TSR-042 plus niraparib is being planned.

For patients with platinum-resistant ovarian cancer, response to chemotherapy is 5-18%, including the most commonly prescribed regimen in the U.S., bevacizumab plus pegylated liposomal doxorubicin1. Platinum refractory patients typically have even lower response rates and NCCN treatment guidelines recommend clinical trials for these patients2. Historical response to PARP inhibitors is 5-10% in patients without BRCA mutations who have platinum resistant disease3 and 0-14% in those with BRCA mutations and platinum refractory disease4. Response rates of 10-15% have been reported with anti-PD-1 antibodies in this ovarian cancer population5.

TOPACIO Results in Advanced Triple-Negative Breast Cancer Show Encouraging Activity of Niraparib in Combination with anti-PD-1

At the time of data cutoff, of the 55 patients enrolled with TNBC, 46 were available for an initial response assessment, 15 of whom had BRCA mutations and 5 of whom were HRRmut. In the TNBC population evaluable for initial response assessment, ORR was 28% and DCR was 50%, while in the BRCAmut population, ORR was 60% and DCR was 80%, with mPFS of 8.3 months. In the combined BRCAmut plus HRRmut population, ORR was 55% and DCR was 80%, with mPFS of 6.4 months. Median DOR has not been reached with 62% (8/13) of responders remaining on treatment, including five patients with long-term, ongoing clinical benefit for approximately one year. The combination was well tolerated with the most commonly observed grade ≥ 3 AEs including anemia (15%) and thrombocytopenia (13%). Of note, the incidence of thrombocytopenia was substantially reduced with the 200-milligram dose of niraparib in both the ovarian cancer and TNBC cohorts in comparison to what has been observed in clinical trials with a starting dose of 300 milligrams niraparib. Following a successful discussion with FDA, a registration study of niraparib plus TSR-042 is being planned.

For patients with TNBC, the standard of care is chemotherapy6, which generally results in a median PFS in the range of three to five months, and median overall survival of ≤ 12 months7. PARP inhibitor monotherapy has demonstrated clinical activity in TNBC patients who are germline BRCA mutation carriers, but has not shown activity in breast cancer beyond gBRCAmut patients8. Anti-PD-1 antibody monotherapy has demonstrated modest activity in previously treated PD-1L positive TNBC, with an ORR of approximately 5-18% and median PFS of approximately two months9.

The TOPACIO trial is being conducted in collaboration with Merck Sharp & Dohme B.V., a subsidiary of Merck & Co., Inc., which is providing support for the trial.

QUADRA Results Demonstrate Durable Potential of ZEJULA in Late-Line Ovarian Cancer Setting Beyond Patients with BRCA Mutations

Previous studies have shown that meaningful activity of other PARP inhibitors in the late-line treatment of ovarian cancer is limited to populations with BRCA mutations. Efficacy of cytotoxic chemotherapy is limited in patients with heavily-pretreated ovarian cancer. QUADRA, a single arm study (n=463), was conducted to assess the activity of ZEJULA monotherapy in the fourth-line or greater treatment of patients with ovarian cancer, regardless of platinum or biomarker status. In QUADRA, less than 20% of patients had a BRCA mutation, 27% received niraparib as a sixth or later line therapy, two-thirds were platinum resistant or refractory (33% and 35%, respectively), and 48% were HRD positive. The majority of platinum sensitive patients who enrolled in QUADRA were considered platinum ineligible, and 62% had received prior bevacizumab. The median time from last chemotherapy until the first dose of niraparib was two months.

The primary efficacy population included fourth or fifth line patients who were previous PARPi naïve, platinum sensitive, and HRD positive (n= 45). The ORR in this population was 29% (95% CI 16-44, p=0.0003). Approximately one-third of patients (27%) enrolled in QUADRA were treated in the sixth or later line of therapy. For patients who were fourth or later line, HRD-positive and platinum sensitive (n=51), the ORR was 27%, the disease control rate (DCR; CR + PR + SD) was 69%, and DOR was 9.2 months. Among those treated in fourth or later line of therapy, clinical benefit (CR+PR+SD) rate for at least 16 weeks was 53% for patients with a BRCA mutation and 49% for patients who were HRD positive and platinum sensitive. Responses to niraparib were durable, with a median DOR of 9.4 months across the entire evaluable patient population. An estimated 44% of all responses lasted 12 months or more.

Median overall survival (OS) in all patients treated fourth line or later was 17.2 months. Median OS was 16.6 months in HRD-negative or unknown patients, 19.0 months in HRD-positive patients and 26.0 months in patients with BRCA mutations.

At a starting dose of 300 milligrams of ZEJULA, the most commonly observed grade 3 or higher adverse events were consistent with prior clinical experience and included anemia (26.3%) and thrombocytopenia (20.5%), which were generally managed via dose modifications. TESARO intends to submit a sNDA to FDA in the fourth quarter of 2018.

Investor Briefing and Webcast
TESARO will host an investor and analyst briefing in Chicago on Monday, June 4 at 6:15PM local time in conjunction with the ASCO (Free ASCO Whitepaper) Annual Meeting. A reception will begin at 6:00PM CT, preceding the presentation. During this briefing, TESARO management will provide a business overview and pipeline update and will answer questions from investors and analysts. This event will be webcast live and archived for 30 days, and may be accessed from the TESARO Investor Events and Presentations webpage at www.tesarobio.com.

About the QUADRA Clinical Trial
QUADRA is an open-label, single arm trial designed to evaluate the safety and efficacy of ZEJULA in the treatment setting of ovarian cancer. Patients were enrolled and received a starting dose of 300 milligrams of niraparib once per day. The primary endpoint of this study was objective response rate (ORR) per RECIST in the fourth and fifth-line HRD positive patients who were PARP inhibitor naïve, and platinum sensitive. Other endpoints include durability of response, disease control rate, progression free survival (PFS), overall survival (OS) and safety and tolerability.

About ZEJULA (Niraparib)
Niraparib is marketed in the United States and Europe under trade name ZEJULA. ZEJULA (niraparib) is a poly(ADP-ribose) polymerase (PARP) inhibitor indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. In preclinical studies, ZEJULA concentrates in the tumor relative to plasma, delivering greater than 90% durable inhibition of PARP 1/2 and a persistent antitumor effect.

ZEJULA (niraparib) Select Important Safety Information
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) was reported in patients treated with ZEJULA in some clinical studies. Discontinue ZEJULA if MDS/AML is confirmed.
Hematologic adverse reactions (thrombocytopenia, anemia and neutropenia) have been reported in patients treated with ZEJULA. Do not start ZEJULA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically after this time.

Hypertension and hypertensive crisis have been reported in patients treated with ZEJULA. Monitor blood pressure and heart rate monthly for the first year and periodically thereafter during treatment with ZEJULA. Closely monitor patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Based on its mechanism of action, ZEJULA can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for six months after receiving the final dose. Because of the potential for serious adverse reactions in breastfed infants from ZEJULA, advise a lactating woman not to breastfeed during treatment with ZEJULA and for one month after receiving the final dose.

On June 4, 2018 SELLAS Life Sciences Group, Inc. (NASDAQ:SLS) ("SELLAS" or "the Company") reported that interim Phase 1 data of GPS in combination with nivolumab in patients with WT1+ ovarian cancer in second or third remission after salvage chemotherapy at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Sellas Life Sciences, JUN 4, 2018, View Source [SID1234527155]). The presentation, "A phase I study of concomitant galinpepimut-S (GPS) in combination with nivolumab (nivo) in patients (pts) with WT1+ ovarian cancer (OC) in second or third remission," is being delivered by Roisin E. O’Cearbhaill, M.D., Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, during the "Gynecologic Cancer" session from 1:15 to 4:45 p.m. CT. The primary endpoint of the study is safety and assessment of toxicity, and treatment is continued until disease progression or toxicity. The secondary endpoint is immune response, and the exploratory endpoints include landmark 1-year PFS rate compared to historical controls and correlative analyses between clinical and immune responses.

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Exploratory efficacy interim data from this open-label Phase 1 investigator-sponsored trial showed that GPS, when combined with a PD-1 inhibitor, demonstrated PFS of 64% at one year in an intent to treat (ITT) group of 11 evaluable patients with WT1+ ovarian cancer in second or greater remission. Among patients who received at least three doses of GPS in combination with nivolumab, PFS at one year was 70% (7/10). The historical rates with best standard treatment do not exceed 50% in this disease setting. The most common adverse events were Grade 1 or 2, including fatigue and injection site reactions. Dose limiting toxicity was observed in one patient, following the second dose of the combination. No additional adverse event burden was observed for the combination as compared to nivolumab monotherapy. WT1 is a tumor antigen that is expressed in about half of ovarian cancers. The combination induced a high frequency of T- and B-cell immune responses.

Based on these safety, clinical activity and immunogenicity data, SELLAS expects to initiate a Phase 1/2 clinical study of GPS in combination with the PD-1 inhibitor pembrolizumab in a variety of tumor types, including WT1+ ovarian cancer in the third quarter of 2018.

"Patients with advanced relapsed ovarian cancer, in which WT1 is highly expressed, have few treatment options with limited efficacy," said Angelos Stergiou, MD, ScD h.c., President & Chief Executive Officer of SELLAS. "The interim data being presented today further support the therapeutic potential of GPS in high-risk cancer populations, including ovarian cancer. In this Phase 1 trial, the combination of GPS and nivolumab showed promising clinical and immune response activity with no additional adverse event burden as compared to nivolumab monotherapy, warranting further evaluation. These data bolster our commitment to developing GPS, alone and in combination, across a wide range of cancers, and we look forward to initiating our Phase 1/2 basket trial investigating the combination of GPS with pembrolizumab in five WT1+ tumor types, including ovarian, small cell lung, colorectal and triple negative breast cancer and acute myeloid leukemia."

Of the 11 patients evaluated:

7 patients were in second remission and 4 patients were in third remission
10 patients received six total doses of GPS (800 mcg) over 12 weeks in combination with seven infusions of I.V. nivolumab (3 mg/kg) over 14 weeks
all underwent toxicity assessments with each dose of GPS, and three weeks after the completion of therapy at Week 15. Non-progressors at Week 15 were permitted to receive four additional GPS doses, administered every eight weeks.
With regard to clinical and immune responses:

in 11 evaluable patients, the landmark 1-year PFS rate was 64% in the ITT group and 70% in the ten patients who received at least three doses of GPS + nivolumab. Historical rates do not exceed 50% in this disease setting
serum levels of antigen-specific IgG, against both individual WT1 peptides within GPS and the full-length WT1 protein, were induced in 86% of patients
achievement of high titers of WT1-specific IgG post-GPS results from Immunoglobulin (Ig) M to IgG class switching, the latter being a surrogate marker of induction of activated T-helper (Th) cells after vaccination
antigen-specific T-cell responses to individual WT1 peptides were observed between Weeks 6-15, primarily CD4 T-cells and, to a smaller extent, CD8 T-cells
"Effective consolidation or maintenance strategies are needed to prevent further recurrence or to prolong remission in patients with ovarian cancer after successful salvage from a previous relapse. In this setting, immune-directed therapy with a combination of blocker nivolumab and GPS, a multivalent, heteroclitic peptide vaccine targeting WT1, an antigen expressed in about half of ovarian cancers, led to high rates of antigen-specific immunization. We anticipate that this enhanced immunogenicity will translate into a reduction in relapses in larger studies," mentioned Dr. O’Cearbhaill. She added "these encouraging interim data suggest that the combination of GPS plus PD-1 inhibitors deserves further study in WT1+ ovarian cancer."

About Galinpepimut-S (GPS):
GPS is a heteroclitic multivalent, multi-peptide cancer immunotherapeutic agent composed of four peptides, addressing over 20 epitopes, and derived from the WT1 protein, which has been ranked by the National Cancer Institute as a top priority among cancer antigens for immunotherapy. Importantly, because the WT1 antigen is overexpressed in many malignancies, and is not found in most normal tissues, GPS has the potential to be a broad immunotherapy, effective across a multitude of diverse cancer types and patient populations.

On June 4, 2018 Seattle Genetics, Inc. (Nasdaq:SGEN) reported that highlighted data from the phase 3 ECHELON-1 clinical trial evaluating ADCETRIS (brentuximab vedotin) in combination with chemotherapy in newly diagnosed stage III or IV classical Hodgkin lymphoma (HL) at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held June 1-5 in Chicago, Illinois (Press release, Seattle Genetics, JUN 4, 2018, View Source;p=RssLanding&cat=news&id=2353005 [SID1234527154]). In March 2018, the U.S. Food and Drug Administration (FDA) approved ADCETRIS in combination with chemotherapy for the treatment of adult patients with previously untreated stage III or IV classical HL based on the positive results of the phase 3 ECHELON-1 clinical trial. ADCETRIS is being evaluated globally as the foundation of therapy for HL in more than 50 ongoing clinical trials, including trials led by Seattle Genetics and its development and commercialization partner, Takeda, as well as by independent investigators.

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"For over 40 years, the standard of care for the treatment of frontline HL in North America has been combination chemotherapy with ABVD. Unfortunately, approximately 30 percent of advanced stage HL patients will not respond or relapse to this therapy," said Radhakrishnan Ramchandren, M.D., Barbara Ann Karmanos Cancer Center. "The ECHELON-1 phase 3 clinical trial is the first trial to demonstrate superior clinical activity utilizing a novel therapeutic agent, ADCETRIS, in combination with AVD in comparison to ABVD. At ASCO (Free ASCO Whitepaper) 2018, we presented outcomes specifically evaluating the North American population, which demonstrated a two-year modified progression-free survival benefit of approximately 11 percent over ABVD. Importantly, an analysis of traditional progression-free survival at two years also demonstrated a benefit for ADCETRIS plus AVD versus ABVD with a difference of 11.7 percent, a Hazard Ratio of 0.500 and a p-value of 0.002. These findings represent a significant and meaningful difference in outcomes for these patients."

"Our goal is to establish ADCETRIS as the foundation of care for CD30-expressing lymphomas, including HL, and the data presented at ASCO (Free ASCO Whitepaper) continue to support this goal," said Nancy Whiting, Pharm.D., Senior Vice President, Clinical Affairs at Seattle Genetics. "Multiple posters featuring additional analyses from the ECHELON-1 trial for ADCETRIS combination use in the treatment of patients with stage III or IV classical HL demonstrate superior efficacy benefit when compared with ABVD. In addition, data from an ongoing phase 2 study evaluating frontline use of ADCETRIS in older HL patients demonstrate a durable efficacy benefit with both monotherapy and combination therapy. Our data at ASCO (Free ASCO Whitepaper) highlight the substantial potential for ADCETRIS to address the needs of patients with lymphoma."

Three poster presentations highlight analyses from the ECHELON-1 phase 3 clinical trial evaluating ADCETRIS in combination with AVD (Adriamycin, vinblastine and dacarbazine) compared to ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine) in stage III or IV frontline classical HL patients. The ECHELON-1 poster presentations include the results of the North American patient population, optimizing therapy with the use of primary prophylactic growth factors (G-CSF) and improvement of modified progression-free survival (PFS) outcomes in patients who received ADCETRIS plus AVD regardless of cycle 2 PET (PET2) status. In addition, long-term follow-up from an ongoing phase 2 clinical trial in newly diagnosed older HL patients was reported.

Brentuximab Vedotin plus Chemotherapy in Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma: North American Results (Abstract #7541, poster presentation on Monday, June 4, 2018)

Of the 1,334 advanced stage classical HL patients who participated in the ECHELON-1 clinical trial, 497 patients were treated in North America, with 250 patients in the ADCETRIS plus AVD arm and 247 patients in the ABVD control arm. The North American results presented by Dr. Radhakrishnan Ramchandren, Barbara Ann Karmanos Cancer Center, are included below and a video summary of the poster presentation can be found here:

Per Independent Review Facility (IRF) assessment, the two-year modified PFS rate for patients in the ADCETRIS plus AVD arm was 84.3 percent compared to 73.7 percent in the control arm (HR 0.596; p-value=0.012), which corresponds to a difference of 10.6 percent.
Per investigator assessment, the two-year modified PFS rate for patients in the ADCETRIS plus AVD arm was 86.4 percent compared to 73.6 percent in the control arm (HR 0.516; p-value=0.002), which corresponds to a difference of 12.8 percent.
Per investigator assessment, the two-year PFS rate for patients in the ADCETRIS plus AVD arm was 88.1 percent compared to 76.4 percent in the control arm (HR 0.500; p-value=0.002), which corresponds to a difference of 11.7 percent.
Consistent improvement in modified PFS per IRF was observed among patients treated with ADCETRIS plus AVD compared with ABVD across all pre-specified subgroups, including age, disease stage, International Prognostic Score and baseline ECOG score.
On the ADCETRIS plus AVD arm, peripheral neuropathy events were observed in 80 percent of patients compared to 56 percent on the ABVD arm. In the ADCETRIS plus AVD arm, the majority of peripheral neuropathy events were Grade 1 or 2 (41 percent and 21 percent, respectively). Grade 3 events were reported in 17 percent of patients. In the ABVD arm, Grade 3 events were reported in less than one percent of patients. There were no Grade 4 events on either arm. Across both arms of the study, approximately 75 percent of the patients with peripheral neuropathy reported resolution or improvement at last follow-up.
Febrile neutropenia during treatment was reported in 20 percent of patients in the ADCETRIS plus AVD arm compared with nine percent in the ABVD arm. In the ADCETRIS plus AVD arm, 35 patients received primary prophylactic G-CSF within five days of starting treatment and nine percent (three patients) reported febrile neutropenia.
Pulmonary toxicity was reported in three percent of patients in the ADCETRIS plus AVD arm versus ten percent of patients in the ABVD arm. Grade ≥3 events were reported in two percent versus six percent of patients, in the ADCETRIS plus AVD and ABVD arms, respectively.
Improving Outcomes with Brentuximab Vedotin plus Chemotherapy in Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma (Abstract #7534, poster presentation on Monday, June 4, 2018)

During the ECHELON-1 clinical trial, an independent monitoring committee (IDMC) recommended the use of primary prophylactic G-CSF for patients in the ADCETRIS plus AVD arm of the study due to an increased risk of febrile neutropenia. In the ADCETRIS plus AVD arm, 83 patients received G-CSF primary prophylaxis (defined as receipt of G-CSF by day five of the first treatment cycle) and 579 patients did not. An analysis of these two patient populations in the ECHELON-1 study presented by Dr. David Straus, Memorial Sloan Kettering Cancer Center, included:

The two-year modified PFS rate for patients in the ADCETRIS plus AVD arm who received G-CSF primary prophylaxis was 84.6 percent compared to 81.7 percent for those who did not (HR 0.737; 95% CI, 0.396 to 1.372) and compared to 77.2 percent in the ABVD control arm (HR 0.586; 95% CI, 0.317 to 1.081).
Use of G-CSF primary prophylaxis in the ADCETRIS plus AVD arm was associated with a decrease in neutropenia (35 percent versus 73 percent), overall febrile neutropenia (11 percent versus 21 percent) and febrile neutropenia in the first treatment cycle (one percent versus 11 percent). Seven of the nine deaths that occurred in the ADCETRIS plus AVD arm were associated with neutropenia, none of whom had received primary prophylaxis with G-CSF before the onset of neutropenia.
There was no evidence of an association between use of G-CSF primary prophylaxis and pulmonary toxicity.
In the ADCETRIS plus AVD arm, incidence of peripheral neuropathy was 57 percent in patients with G-CSF primary prophylaxis versus 68 percent without.
Lastly, use of G-CSF primary prophylaxis was associated with a lower rate of ADCETRIS dose delays and dose reductions compared to those without.
Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin Lymphoma: Impact of Cycle 2 PET Result on Modified Progression-Free Survival (Abstract #7539, poster presentation on Monday, June 4, 2018)

A post-hoc analysis of the ECHELON-1 clinical trial was conducted to evaluate modified PFS outcomes and clinical characteristics by PET2 status per IRF. In the ADCETRIS plus AVD arm of the study, 588 patients were PET2-negative (Deauville score ≤3) and 47 were PET2-positive (Deauville score ≥4). In the ABVD arm of the study, 577 patients were PET2-negative and 58 were PET2-positive. The analysis presented by Dr. Robert Chen, City of Hope National Medical Center, included:

ADCETRIS plus AVD improved modified PFS outcomes in patients regardless of PET2 status. The modified PFS in PET2-negative patients in the ADCETRIS plus AVD arm was 85.2 percent compared to 80.9 percent in the ABVD arm (HR 0.774; 95% CI, 0.586 to 1.022). The modified PFS in PET2-positive patients in the ADCETRIS plus AVD arm was 57.5 percent compared to 42.0 percent in the ABVD arm (HR 0.609; 95% CI, 0.341 to 1.088). PET2-positive patients in the ADCETRIS plus AVD arm had superior results compared to historical controls.
The safety profile of ADCETRIS plus AVD in the ECHELON-1 trial was generally consistent with that known for the single-agent components of the regimen. There were no notable differences in the safety profile between PET2-positive or PET2-negative subgroups in either arm of the study.
Long-Term Follow-Up of Brentuximab Vedotin +/- Dacarbazine as First-Line Therapy in Elderly Patients with Hodgkin Lymphoma (Abstract #7542, poster presentation on Monday, June 4, 2018)

Long-term follow-up results were presented from an ongoing phase 2 clinical trial evaluating ADCETRIS alone or in combination with dacarbazine as frontline therapy for HL patients age 60 years or older. Data were reported from 27 patients treated with ADCETRIS monotherapy and 22 patients treated with ADCETRIS in combination with dacarbazine. The median age of patients was 78 years in the ADCETRIS monotherapy arm and 69 years in the dacarbazine combination arm. Over 60 percent of patients in each arm had stage III/IV disease at the time of diagnosis and the majority were frail with multiple comorbidities. Long-term data highlighted by Dr. Jonathan Friedberg, University of Rochester, included:

In the ADCETRIS monotherapy arm, the median observation time from first dose was 42.6 months. Estimated three-year PFS and overall survival rates were 34 percent and 71 percent, respectively, with no deaths occurring within 30 days of last treatment. Median PFS was 10.48 months and median overall survival had not yet been reached.
In the dacarbazine combination arm, the median observation time from first dose was 37.8 months. Estimated three-year PFS and overall survival rates were 52 percent and 90 percent, respectively, with no deaths occurring within 30 days of last treatment. Both median PFS and overall survival had not yet been reached.
Treatment-emergent peripheral neuropathy of any grade was observed in 24 patients (89 percent) in the ADCETRIS arm and 19 patients (86 percent) in the dacarbazine combination arm, with most Grade 1 or 2 and sensory in nature. The majority of patients with treatment-emergent peripheral neuropathy had either complete resolution or some resolution or improvement.
Adverse events leading to treatment discontinuation in the ADCETRIS monotherapy arm were peripheral sensory neuropathy (30 percent), peripheral motor neuropathy (seven percent) and orthostatic hypotension (four percent). Adverse events leading to treatment discontinuation in the dacarbazine combination arm were peripheral sensory neuropathy (36 percent); asthenia, systemic lupus erythematosus, hypotension and non-cardiac chest pain (five percent each).
ADCETRIS in combination with dacarbazine is not approved for use in frontline HL.

About ECHELON-1

ECHELON-1 is a randomized, open-label, two-arm, multi-center phase 3 study designed to compare ADCETRIS plus (Adriamycin, vinblastine and dacarbazine) to ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine) as frontline therapy in patients with previously untreated advanced classical HL. The primary endpoint is modified progression-free survival (PFS) per Independent Review Facility (IRF). Modified PFS is defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy per IRF followed by subsequent anticancer therapy. The study enrolled 1,334 patients who had histologically-confirmed diagnosis of Stage III or IV Hodgkin lymphoma and had not been previously treated with systemic chemotherapy or radiotherapy.

About Classical Hodgkin Lymphoma

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Classical Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.

According to the American Cancer Society, approximately 8,500 cases of Hodgkin lymphoma will be diagnosed in the United States during 2018 and more than 1,000 will die from the disease. Approximately half of all newly diagnosed Hodgkin lymphoma patients have Stage III/IV disease. According to the Lymphoma Coalition, over 62,000 people worldwide are diagnosed with Hodgkin lymphoma each year and approximately 25,000 people die each year from this cancer.

About ADCETRIS (brentuximab vedotin)

ADCETRIS is being evaluated broadly in more than 70 clinical trials, including two ongoing phase 3 studies: the ECHELON-2 trial in frontline mature T-cell lymphomas (also known as peripheral T-cell lymphoma) and the CHECKMATE 812 trial of ADCETRIS in combination with Opdivo (nivolumab) for relapsed/refractory Hodgkin lymphoma.

ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS injection for intravenous infusion has received FDA regular approval for five indications in adult patients with: (1) previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with chemotherapy, (2) cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation, (3) cHL after failure of auto-HSCT or failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (4) sALCL after failure of at least one prior multi-agent chemotherapy regimen, and (5) primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.

Health Canada granted ADCETRIS approval with conditions for relapsed or refractory Hodgkin lymphoma and sALCL in 2013, and non-conditional approval for post-autologous stem cell transplantation (ASCT) consolidation treatment of Hodgkin lymphoma patients at increased risk of relapse or progression.

ADCETRIS received conditional marketing authorization from the European Commission in October 2012. The approved indications in Europe are: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, (2) the treatment of adult patients with relapsed or refractory sALCL, (3) for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT, and (4) for the treatment of adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy.

ADCETRIS has received marketing authorization by regulatory authorities in 71 countries for relapsed or refractory Hodgkin lymphoma and sALCL. See select important safety information, including Boxed Warning, below.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.