On April 29, 2019 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a clinical-stage targeted oncology company, reported financial results for the first quarter ended March 31, 2019 (Press release, Mirati, APR 29, 2019, View Source [SID1234535450]).

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First Quarter Highlights

January 7th, we announced a clinical collaboration with Bristol-Myers Squibb Company to evaluate the combination of sitravatinib and nivolumab (OPDIVO), in our planned Phase 3 clinical trial in second line NSCLC patients who have progressed following prior treatment. Mirati will sponsor and fund the clinical trial and Bristol-Myers Squibb will provide nivolumab at no cost.
January 15th, we announced that we had dosed the first patient in the Phase 1/2 clinical trial of MRTX849, a novel KRAS G12C inhibitor.
January 22nd, we announced the successful completion of a public offering of common stock that provided net cash proceeds of $107.9 million.
February 19th, we announced the appointment of Faheem Hasnain as Chairman of the Board of Directors.
"In the first quarter we made significant advances across our pipeline, including the dosing of the first patient with our KRAS G12C inhibitor, MRTX849. We also strengthened our operational and strategic capabilities, highlighted by a successful public offering and the appointment of Faheem Hasnain as Chairman of the Board," said Charles M. Baum, M.D., Ph.D., President and Chief Executive Officer. "Our clinical programs continue to advance, and we are on track for a second quarter initiation of the Phase 3 randomized trial of sitravatinib plus nivolumab, versus docetaxel, in second line non-small cell lung cancer (NSCLC). The Phase 1/2 clinical trial of our KRAS G12C inhibitor, MRTX849, is ongoing and enrollment is proceeding well. We will provide an initial clinical update on MRTX849 in the second half of 2019."

Financial Results for the First Quarter 2019

Cash, cash equivalents, and short-term investments were $301.0 million at March 31, 2019, compared to $222.8 million at December 31, 2018. In January 2019, we completed a public offering of common stock that provided net cash proceeds of $107.9 million.

License and collaboration revenues relate to the Collaboration and License Agreement between the Company and BeiGene, Ltd. ("BeiGene"), dated January 7, 2018. License and collaboration revenues for the first quarter of 2019 were $1.2 million and relate to revenues earned in connection with a manufacturing supply services agreement with BeiGene. License and collaboration revenues for the first quarter of 2018 were $9.5 million and relate to the license the Company granted to BeiGene under the Collaboration and License Agreement.

Research and development expenses for the first quarter of 2019 were $34.2 million, compared to $19.7 million for the same period in 2018. The increase in research and development expenses is due to an increase in expense associated with sitravatinib and MRTX849, as well as an increase in salaries and related expense, including an increase in share-based compensation expense. The increase in sitravatinib expense is due to increased costs to support the expansion of existing and new clinical trials, and the increase in MRTX849 expense relates to the Phase 1 clinical trial, which was initiated in the first quarter of 2019. The Company recognized research and development-related share-based compensation expense of $5.2 million during the first quarter of 2019, compared to $1.5 million for the same period in 2018.

General and administrative expenses for the first quarter of 2019 were $9.8 million, compared to $5.2 million for the same period in 2018. The increase is primarily due to an increase in share-based compensation expense due to an increase in the fair value of stock options granted during the three months ended March 31, 2019 compared to the same period in 2018. The Company recognized general and administrative-related share-based compensation expense of $5.9 million during the first quarter of 2019, compared to $2.2 million for the same period in 2018.

Net loss for the first quarter of 2019 was $40.9 million, or $1.17 per share basic and diluted, compared to net loss of $14.7 million, or $0.51 per share basic and diluted for the same period in 2018.

About Sitravatinib

Sitravatinib is a spectrum-selective kinase inhibitor that potently inhibits receptor tyrosine kinases (RTKs), including TAM family receptors (TYRO3, Axl, Mer), split family receptors (VEGFR2, KIT) and RET. As an immuno-oncology agent, sitravatinib is being evaluated in combination with nivolumab (OPDIVO), an anti-PD-1 checkpoint inhibitor, in patients whose cancers have progressed despite treatment with a checkpoint inhibitor. Sitravatinib’s potent inhibition of TAM and split family RTKs may overcome resistance to checkpoint inhibitor therapy through targeted reversal of an immunosuppressive tumor microenvironment, enhancing antigen-specific T cell response and expanding dendritic cell-dependent antigen presentation.

Sitravatinib is also being evaluated as a single agent in a Phase 1b expansion clinical trial emphasizing enrollment of patients whose tumors harbor specific mutations in the CBL protein. When CBL is inactivated by mutation, multiple RTKs, including TAM, VEGFR2 and KIT, are dysregulated and may act as oncogenic tumor drivers in NSCLC and melanoma. Sitravatinib potently inhibits these RTKs and is being investigated as a treatment option for cancer patients with CBL mutations.

About MRTX849

MRTX849 is an investigational, orally-available small molecule that is designed to potently and selectively inhibit a form of KRAS which harbors a substitution mutation (G12C). KRAS G12C mutations are present in approximately 14% of NSCLC adenocarcinoma patients, 4% of colorectal cancer patients, and subsets of other types of cancer. Tumors characterized by KRAS G12C mutations are commonly associated with poor prognosis and resistance to therapy, and patients with these mutations have few treatment options. MRTX849 is being evaluated in a Phase 1/2 trial treating patients with molecularly-identified, KRAS G12C-positive advanced solid tumors.

On April 29, 2019 The Janssen Pharmaceutical Companies of Johnson & Johnson reported the submission of a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) seeking approval of a new indication for ERLEADA (apalutamide) for the treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC) (Press release, Johnson & Johnson, APR 29, 2019, View Source [SID1234535449]). The sNDA is based on findings from the Phase 3 TITAN study, whose dual primary endpoints, overall survival (OS) and radiographic progression-free survival (rPFS), were both achieved. These data will be presented at the upcoming American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting during an oral abstract session on Friday, May 31st.

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The sNDA is being reviewed by the FDA through the Real-Time Oncology Review (RTOR) program, which for certain applications allows the FDA to review data before the applicant formally submits the complete application. The program aims to explore a more efficient review process to help ensure treatments are available for patients as soon as possible. Selection into the RTOR program does not guarantee or influence approvability of the application.

"This submission marks an important step in providing a potential treatment option for patients with metastatic castration-sensitive prostate cancer, regardless of prior treatment or the extent of their disease," said Craig Tendler, M.D., Vice President, Oncology Clinical Development and Medical Affairs, Janssen Research & Development, LLC. "We look forward to closely collaborating with the FDA through the efficient Real-Time Oncology Review pilot program with the goal of bringing ERLEADA to an earlier population of patients with metastatic prostate cancer as soon as possible."

About the TITAN Study1
TITAN (NCT02489318) is a Phase 3 randomized, placebo-controlled, double-blind study in patients with mCSPC regardless of extent of disease, and prior treatment with docetaxel or treatment of localized disease. More than 1,050 patients with mCSPC were randomized to receive either ERLEADA plus androgen deprivation therapy (ADT), or placebo plus ADT. The TITAN study included mCSPC patients with both low and high-volume disease, those who were newly diagnosed or those who have received prior definitive local therapy, or prior treatment with up to six cycles of docetaxel. Participants were treated until disease progression or the occurrence of unacceptable treatment related toxicity, or end of treatment. The dual primary endpoints of the study are OS and rPFS. Secondary endpoints include time to chemotherapy, time to pain progression, time to chronic opioid use and time to skeletal related event.1 For additional study information, visit ClinicalTrials.gov.

About ERLEADA
ERLEADA (apalutamide) is an androgen receptor (AR) inhibitor indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC). It became the first treatment to receive FDA approval for this disease state on February 14, 2018.2 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer include apalutamide as a treatment option for patients with non-metastatic (M0) CRPC with a category 1 recommendation for those with a PSA doubling time ≤10 months*.3 Additionally, the American Urological Association (AUA) Guidelines for Castration-Resistant Prostate Cancer (CRPC) were updated to include apalutamide (ERLEADA) with continued ADT as a treatment option that clinicians should offer to patients with asymptomatic nmCRPC. It is included as one of the options clinicians should offer to patients with nmCRPC who are at high-risk for developing metastatic disease (Standard; Evidence Level Grade A)**.4

*Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer V.2.2019. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed April 23, 2019. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use, or application, and disclaims any responsibility for their application or use in any way.

**Standard: Directive statement that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be taken based on Grade A or B evidence.

**Evidence Level: A designation indicating the certainty of the results as high, moderate, or low (A, B, or C, respectively) based on AUA nomenclature and methodology.

About Metastatic Castration-Sensitive Prostate Cancer
Metastatic prostate cancer is cancer that has spread to another part of the body.5 Metastatic castration-sensitive prostate cancer (mCSPC), refers to prostate cancer that still responds to androgen deprivation therapy (ADT).5 Patients with mCSPC tend to have a poor prognosis, with a median OS of less than five years, underscoring the need for new treatment options.6,7,8

ERLEADA IMPORTANT SAFETY INFORMATION2

CONTRAINDICATIONS

Pregnancy — ERLEADA (apalutamide) can cause fetal harm and potential loss of pregnancy.

WARNINGS AND PRECAUTIONS

Falls and Fractures — In a randomized study (SPARTAN), falls and fractures occurred in 16% and 12% of patients treated with ERLEADA compared to 9% and 7% treated with placebo, respectively. Falls were not associated with loss of consciousness or seizure. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone targeted agents.

Seizure — In a randomized study (SPARTAN), 2 patients (0.2%) treated with ERLEADA experienced a seizure. Permanently discontinue ERLEADA in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with ERLEADA. Advise patients of the risk of developing a seizure while receiving ERLEADA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others.

ADVERSE REACTIONS

Adverse Reactions — The most common adverse reactions (≥10%) were fatigue, hypertension, rash, diarrhea, nausea, weight decreased, arthralgia, fall, hot flush, decreased appetite, fracture, and peripheral edema.

Laboratory Abnormalities — All Grades (Grade 3-4)

Hematology — anemia ERLEADA 70% (0.4%), placebo 64% (0.5%); leukopenia ERLEADA 47% (0.3%), placebo 29% (0%); lymphopenia ERLEADA 41% (2%), placebo 21% (2%)
Chemistry — hypercholesterolemia ERLEADA 76% (0.1%), placebo 46% (0%); hyperglycemia ERLEADA 70% (2%), placebo 59% (1%); hypertriglyceridemia ERLEADA 67% (2%), placebo 49% (0.8%); hyperkalemia ERLEADA 32% (2%), placebo 22% (0.5%)
Rash — Rash was most commonly described as macular or maculo-papular. Adverse reactions were 24% with ERLEADA versus 6% with placebo. Grade 3 rashes (defined as covering > 30% body surface area [BSA]) were reported with ERLEADA treatment (5%) versus placebo (0.3%).

The onset of rash occurred at a median of 82 days. Rash resolved in 81% of patients within a median of 60 days (range: 2 to 709 days) from onset of rash. Four percent of patients treated with ERLEADA received systemic corticosteroids. Rash recurred in approximately half of patients who were re-challenged with ERLEADA.

Hypothyroidism was reported for 8% of patients treated with ERLEADA and 2% of patients treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. Elevated TSH occurred in 25% of patients treated with ERLEADA and 7% of patients treated with placebo. The median onset was day 113. There were no Grade 3 or 4 adverse reactions. Thyroid replacement therapy, when clinically indicated, should be initiated or dose-adjusted.

DRUG INTERACTIONS

Effect of Other Drugs on ERLEADA — Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties. No initial dose adjustment is necessary; however, reduce the ERLEADA dose based on tolerability [see Dosage and Administration (2.2)].

Effect of ERLEADA on Other Drugs — ERLEADA is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. Concomitant use of ERLEADA with medications that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is recommended when possible or evaluate for loss of activity if medication is continued. Concomitant administration of ERLEADA with medications that are substrates of UDP-glucuronosyl transferase (UGT) can result in decreased exposure. Use caution if substrates of UGT must be co-administered with ERLEADA and evaluate for loss of activity.

P-gp, BCRP or OATP1B1 substrates — Apalutamide is a weak inducer of P-glycoprotein (P- gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. Concomitant use of ERLEADA with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP or OATP1B1 must be co-administered with ERLEADA and evaluate for loss of activity if medication is continued.

On April 29, 2019 I-Mab Biopharma (I-Mab), a China-based clinical stage biopharmaceutical company exclusively focused on the development of innovative biologics in immuno-oncology and autoimmune diseases, and MorphoSys AG (FSE: MOR; Prime Standard Segment, MDAX & TecDAX;NASDAQ: MOR), reported that the first patient has been dosed in a phase 3 randomized and multi-center clinical study in Taiwan to evaluate MorphoSys’s investigational human CD38 antibody TJ202/MOR202 in combination with lenalidomide in patients with relapsed or refractory multiple myeloma (Press release, I-Mab Biopharma, APR 29, 2019, View Source [SID1234535448]). I-Mab has the exclusive rights for development and commercialization of TJ202/MOR202 in mainland China, Taiwan, Hong Kong and Macao.

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"The initiation of our first phase 3 trial represents another important milestone in advancing TJ202/MOR202 towards registration with the hope of providing more therapeutic options for MM patients globally. With planned enrollment of 291 patients, this will be a broad trial of this second most common blood cancer worldwide," said Dr. Joan Shen, M.D., Head of R&D at I-Mab. "In parallel with our pivotal phase 2 trial of TJ202/MOR202 in combination with dexamethasone, the phase 3 study will further assess the efficacy of TJ202/MOR202 as a potential second line treatment in MM."

Under I-Mab’s fast-to-market development strategy, the phase 3 study, if successful, could lead to a biologics license application (BLA) in Greater China. The randomized, open-label, parallel-controlled, multicenter study will be conducted in mainland China and Taiwan to evaluate the efficacy and safety of the combination of TJ202/MOR202 plus lenalidomide (LEN) and dexamethasone (DEX) versus the combination of LEN and DEX in patients with relapsed or refractory MM who received at least one prior line of treatment. The primary endpoint is to evaluate the progression-free survival (PFS) comparing the efficacy of TJ202/MOR202 plus LEN/DEX versus LEN/DEX.

The dosing of the first patient triggers a milestone payment of USD 3 million to MorphoSys.

"We are delighted that our partner I-Mab has started a phase 3 trial of TJ202/MOR202 in combination with lenalidomide in Asia in addition to the ongoing phase 2 trial of MOR202 in combination with dexamethasone. We see a high medical need for the treatment of patients with multiple myeloma in the Chinese region and look forward to supporting I-Mab in developing this investigational compound for these patients," said Dr. Malte Peters, Chief Development Officer of MorphoSys AG.

With MorphoSys’s support through a licensing agreement in November 2017, I-Mab is currently leading the clinical development of TJ202/MOR202 in Greater China, including mainland China, Hong Kong, Macao and Taiwan. In addition to Taiwan, I-Mab has filed an investigational new drug (IND) application to China’s National Medical Products Administration in August 2018. Previously on March 20, 2019, I-Mab and MorphoSys announced the first patient dosing of TJ202/MOR202 in a phase 2 multi-center clinical study in Taiwan in patients with relapsed or refractory multiple myeloma.

About TJ202/MOR202
TJ202/MOR202 is an investigational human monoclonal antibody derived from MorphoSys’s HuCAL antibody technology. The antibody is directed against CD38 on the surface of multiple myeloma cells, which has been characterized as one of the most strongly and uniformly expressed antigens on the surface of malignant plasma cells. According to its suggested mode of action, the antibody recruits cells of the body’s immune system to kill the tumor through antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). The antibody does not involve complement dependent cytotoxicity, or CDC, an additional immune mechanism involved in tumor cell killing. Scientific research suggest that an anti-CD38 antibody may have therapeutic potential also in other cancers as well as autoimmune diseases. Based on an exclusive regional licensing agreement signed in late 2017, I-Mab owns the exclusive rights for development and commercialization of TJ202/MOR202 in mainland China, Taiwan, Hong Kong and Macao.

On April 29, 2019 Medicure Inc. ("Medicure" or the "Company") (TSXV:MPH, OTC:MCUJF), a pharmaceutical company, reported its results from operations for the quarter and year ended December 31, 2018 (Press release, Medicure, APR 29, 2019, View Source [SID1234535447]).

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Year Ended December 31, 2018 Highlights:

Recorded total net revenue from the sale of products of $29.1 million during the year ended December 31, 2018 compared to $27.1 million for the year ended December 31, 2017;
Recorded total net revenue from the sale of AGGRASTAT of $28.5 million during the year ended December 31, 2018 compared to $27.1 million for the year ended December 31, 2017;
Net income for the year ended December 31, 2018 was $3.9 million, compared to net income of $43.4 million for the year ended December 31, 2017, which includes the gain on the sale of the Apicore business which occurred in October 2017;
Adjusted earnings before interest, taxes, depreciation and amortization (EBITDA)1 for the year ended December 31, 2018 was $0.2 million compared to adjusted EBITDA of $4.8 million for the year ended December 31, 2017 and
Diversified product portfolio with US FDA ANDA approval of Sodium Nitroprusside and acquisition of US marketing rights to ZYPITAMAGTM.
Financial Results

Net revenues for the year ended December 31, 2018 were $29.1 million compared to $27.1 million for the year ended December 31, 2017. Net revenues from AGGRASTAT for the year ended December 31, 2018 were $28.5 million compared to $27.1 million for the year ended December 31, 2017. Additionally, ZYPITAMAGTM, which was launched commercially by the Company in 2018, contributed $0.7 million of net revenues for the year ended December 31, 2018.

Net revenues from AGGRASTAT for the three months ended December 31, 2018 were $8.2 million compared to $5.0 million for the three months ended December 31, 2017.

The Company continues to experience an increase in patient market share held by AGGRASTAT and an increase in the number of new hospital customers using the product leading to the highest hospital demand for AGGRASTAT in the Company’s history, which is partially offset by increased price competition as a result of increased generic competitors, which resulted in lower discounted prices for AGGRASTAT throughout 2018. An increased volume of AGGRASTAT sold and a weaker Canadian dollar compared to its US counterpart resulted in the revenue increases experienced in 2018.

Medicure continues to focus on expanding the customer base for AGGRASTAT and growing the sales of ZYPITAMAGTM (pitavastatin). Diversification of revenues remains an important aspect of the Company’s focus with the Company signing a marketing agreement for ReDSTM in January 2019 and the expected launch of Sodium Nitroprusside in mid-2019.

Adjusted EBITDA for the year ended December 31, 2018 was $0.2 million compared to $4.8 million for the year ended December 31, 2017. The decrease in adjusted EBITDA for the year is the result of the higher selling, general and administration expenses caused by the incurrence of additional costs relating to the commercial organization due to the launch of ZYPITAMAGTM and higher research and development expenses related to the Company’s product development pipeline. Adjusted EBITDA for the three months ended December 31, 2018 was negative $2.0 million compared to negative $0.6 million for the three months ended December 31, 2017.

Net income for the year ended December 31, 2018 was $3.9 million or $0.25 per share. This compares to net income of $43.4 million or $2.78 per share for the year ended December 31, 2017, which includes income of $11.5 million or $0.74 per share from continuing operations and income from discontinued operations of $31.9 million or $2.04 per share. Discontinued operations includes the operations of Apicore and the gain on the sale of the Apicore business.

Net income for the three months ended December 31, 2018 was $1.5 million or $0.10 per share, compared to net income of $51.4 million or $2.81 per share for the three months ended December 31, 2017, primarily relating to the gain on the sale of the Apicore business.

At December 31, 2018, the Company had unrestricted cash and short-term investments totaling $71.9 million compared to $5.3 million as of December 31, 2017. The increase in cash is due to the proceeds received from the sale of the Apicore business in October 2017, which were received in 2018. Cash flows from operating activities for the year ended December 31, 2018 totaled $0.7 million.

All amounts referenced herein are in Canadian dollars unless otherwise noted.

Notes

(1) The Company defines EBITDA as "earnings before interest, taxes, depreciation, amortization and other income or expense" and Adjusted EBITDA as "EBITDA adjusted for non-cash and non-recurring items". The terms "EBITDA" and "Adjusted EBITDA", as it relates to the quarters and years ended December 31, 2018 and 2017 results prepared using International Financial Reporting Standards ("IFRS"), do not have any standardized meaning according to IFRS. It is therefore unlikely to be comparable to similar measures presented by other companies.

Conference Call Info:

Topic: Medicure’s Fiscal Year End 2018 Results

Call date: Tuesday, April 30, 2019

Time: 7:30 AM Central Time (8:30 AM Eastern Time)

Canada toll-free: 1 (888) 465-5079 Canada toll: 1 (416) 216-4169

United States toll-free: 1 (888) 545-0687

Passcode: 8925377#

Webcast: This conference call will be webcast live over the internet and can be accessed from the Medicure investor relations page at the following link: View Source

You may request international country-specific access information by e-mailing the Company in advance. Management will accept and answer questions related to the financial results and operations during the question-and-answer period at the end of the conference call. A recording of the call will be available following the event at the Company’s website.

On April 29, 2019 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) and AstraZeneca reported the publication of two manuscripts in The Lancet Oncology reporting long-term phase 1 safety and efficacy results of [fam-] trastuzumab deruxtecan (DS-8201) (Press release, Daiichi Sankyo, APR 29, 2019, https://www.prnewswire.com/news-releases/daiichi-sankyo-announces-two-lancet-oncology-publications-of-phase-1-dose-expansion-results-of-fam–trastuzumab-deruxtecan-in-her2-positive-metastatic-breast-and-gastric-cancer-300840146.html [SID1234535446]). The investigational HER2 targeting antibody drug conjugate (ADC) was evaluated in heavily pretreated patients with HER2 positive metastatic breast cancer and gastric cancer.

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HER2 Positive Breast Cancer Results
The first manuscript reports efficacy results for 115 patients who received at least one dose of [fam-] trastuzumab deruxtecan, of which 111 were evaluable for confirmed response. These patients with HER2 positive metastatic breast cancer previously treated with ado-trastuzumab emtansine (T-DM1) received [fam-] trastuzumab deruxtecan at a recommended expansion dose of 5.4 or 6.4 mg/kg in the dose escalation or dose expansion parts of the phase 1 study. Patients enrolled in this part of the study had a median of seven prior anticancer regimens, including T-DM1 and trastuzumab, and in 86 percent of cases, pertuzumab.

A confirmed objective response rate of 59.5 percent [95 percent CI: 49.7-68.7] and a disease control rate of 93.7 percent [95 percent CI: 87.4-97.4] was observed with [fam-] trastuzumab deruxtecan. Median duration of response was 20.7 months (range 0.0-21.8), median progression-free survival was 22.1 months (range 0.8-27.9), and median overall survival has not yet been reached in the study. Fifty-five (48 percent) patients remain on treatment with [fam-] trastuzumab deruxtecan, as of data cut-off on August 10, 2018.

"For patients with HER2 positive metastatic breast cancer that progresses after trastuzumab, pertuzumab, and T-DM1, optimal treatment is not clearly defined and choices may be limited," said Kenji Tamura, MD, PhD, Department of Breast and Medical Oncology National Cancer Center Hospital, Tokyo, Japan, and lead author on the study. "These results demonstrate preliminary clinically meaningful response rates with an impressive duration of response, supporting further development and suggesting a potential role for [fam-] trastuzumab deruxtecan as a HER2 targeted therapy option in this setting."

Safety results for 115 patients with HER2 positive metastatic breast cancer, who received at least one dose of [fam-] trastuzumab deruxtecan 5.4 or 6.4 mg/kg in part one or part two of the study also were reported. The most common adverse events (≥30 percent, any grade) included nausea, decreased appetite, vomiting, alopecia, fatigue, anemia, diarrhea, and constipation. Fifty (50.0) percent of patients experienced an adverse event grade ≥3, and 19.0 percent had a serious adverse event, including two previously reported cases of grade 5 drug-related pneumonitis. Any reported cases of interstitial lung disease (ILD)/pneumonitis in the [fam-] trastuzumab deruxtecan clinical development program are evaluated by an independent adjudication committee, and a formal monitoring and management program is in place with ongoing analyses to help optimally characterize the risk. A presentation of ILD risk characterization at the San Antonio Breast Cancer Symposium in December 2018 in patients with metastatic breast cancer treated at the recommended dose of 5.4 mg/kg showed an overall incidence of 5.6 percent, with the majority of cases being grades 1 and 2, and 1.1 percent grade 3 and above, including one (1) case of grade 5 (Poster # P6-17-06).1

Summary of Results

Total evaluablei

(n=114)

Confirmed Objective Response Rate (ORR)ii, iii

(95% CI)

59.5%

(49.7-68.7)

Disease Control Rate (DCR)ii, iv

(95% CI)

93.7%

(87.4-97.4)

Duration of Response (DOR)v

Median in months

(95% CI)vi

20.7

(0.0-21.8)vi

Progression Free Survival (PFS)

Median in months

(95% CI)vi

22.1

(0.8 – 27.9)vi

i The activity evaluable set included all patients who received at least one dose of trastuzumab deruxtecan at 5·4 mg/kg or 6·4 mg/kg and for whom both baseline and post-treatment activity data were available.

ii There were 111 patients who had two or more post baseline scans, had progressive disease, or discontinued treatment for any reason before second postbaseline scan and were considered evaluable for confirmed response.

iii Objective response was calculated as the proportion of patients showing complete response or partial response for a minimum of 5 weeks from the first dosing date.

iv Disease control was calculated as the proportion of patients demonstrating complete response, partial response, or stable disease for a minimum of 5 weeks from the first dosing date.

v Duration of response was measured from the time at which complete response or partial response criteria are first met until the first date of objectively documented progressive disease.

vi Censored observation indicated with plus (+).

HER2 Positive Gastric Cancer Results
The second manuscript reports results for 44 patients with HER2 positive advanced gastric or gastro-esophageal junction cancer previously treated with trastuzumab who received [fam-] trastuzumab deruxtecan at a recommended expansion dose of 5.4 or 6.4 mg/kg in the dose escalation or dose expansion parts of the study. These patients had a median of three prior anticancer regimens including trastuzumab.

A confirmed objective response rate of 43.2 percent [95 percent CI: 28.3, 59.0] and a disease control rate of 79.5 percent [95 percent CI: 64.7-90.2] were seen with [fam-] trastuzumab deruxtecan. The median duration of response was 7.0 months (range 4.4-16.6), median progression free survival was 5.6 months [95 percent CI: 3.0-8.3], and median overall survival was 12.8 months (range 1.4-25.4). Three (3) patients remain on treatment with [fam-] trastuzumab deruxtecan as of data cut-off on August 10, 2018.

"These results are encouraging given the limited options for patients with advanced HER2 positive gastric cancer that progresses after initial treatment regimens including trastuzumab," said lead study author Kohei Shitara, MD, National Cancer Center Hospital East, Chiba, Japan. "There are no other anti-HER2 therapies approved for gastric cancer beyond trastuzumab, and these data support further study of [fam-] trastuzumab deruxtecan in these patients."

Safety results for the 44 patients with HER2 positive gastric or gastro-esophageal junction cancer who received at least one dose of [fam-] trastuzumab deruxtecan 5.4 or 6.4 mg/kg in part one or part two of the study also were presented. The most common adverse events (≥30 percent, any grade) included nausea, decreased appetite, white blood cell count decrease, anemia, platelet count decrease, and constipation. Sixty-four (64.0) percent of patients experienced an adverse event grade ≥3, and 25.0 percent had a serious adverse event. There were two deaths due to TEAEs, (one due to pneumonia and one due to progression of disease), and neither were considered drug-related.

Summary of Results

Total evaluablevii

(n=44)

Confirmed Objective Response Rate (ORR)viii

(95% CI)

43.2%

(28.3-59.0)

Disease Control Rate (DCR)ix

(95% CI)

79.5%

(64.7-90.2)

Duration of Response (DOR)x

Median in months

(95% CI)xi

7.0

(4.4-16.6)xi

Progression Free Survival (PFS)

Median in months

(95% CI)xi

5.6

(3.0-8.3)xi

Overall Survival (OS)

Median in months

(95% CI)xi

12.8

(1.4-25.4)xi

vii The activity evaluable set included all patients who received at least one dose of trastuzumab deruxtecan at 5·4 mg/kg or 6·4 mg/kg and for whom both baseline and post-treatment activity data were available.

viii Objective response is calculated as the proportion of patients showing complete response or partial response for a minimum of 5 weeks from the first dosing date.

ix Disease control was calculated as the proportion of patients showing complete response, partial response, or stable disease for a minimum of 5 weeks from the first dosing date.

x Duration of response was measured from the time at which complete response or partial response criteria are first met until the first date of objectively documented progressive disease.

xi Censored observation indicated with plus (+).

"These long-term phase 1 results support our ongoing pivotal development program with [fam-] trastuzumab deruxtecan in HER2 positive metastatic breast and gastric cancers, where significant unmet treatment needs remain," said Gilles Gallant, BPharm, PhD, FOPQ, Vice President, DS-8201 Global Team Leader, Oncology Research and Development, Daiichi Sankyo. "Our pivotal phase 2 DESTINY-Breast01 study has completed enrollment and our phase 3 DESTINY-Breast02 and DESTINY-Breast03 trials are underway to further evaluate [fam-] trastuzumab deruxtecan in HER2 positive metastatic breast cancer. We also are enrolling patients with advanced HER2 positive gastric cancer previously treated with trastuzumab in the pivotal phase 2 DESTINY-Gastric01 study."

"These results reinforce our belief that [fam-] trastuzumab deruxtecan could become a transformative new medicine for the treatment of HER2 positive breast and gastric cancers," said Hesham Abdullah, Vice President, Head of Late-Stage Immuno-Oncology Development, Research and Development, Oncology, AstraZeneca. "The encouraging response rates and quality of the duration of response in this heavily pretreated and difficult-to-treat setting demonstrate the value this potential treatment can bring to patients with unmet medical needs."

About HER2
HER2 is a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells that is associated with aggressive disease and poorer prognosis.2,3 To be considered HER2 positive, tumor cancer cells are usually tested by one of two methods: immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH). IHC test results are reported as: 0, IHC 1+, IHC 2+, or IHC 3+. A finding of IHC 3+ is considered HER2 positive, and a finding of IHC 2+ is borderline and typically is confirmed by a positive FISH test.5

Unmet Need in HER2 Positive Breast and Gastric Cancer
Approximately one in five breast and gastric cancers (20 percent) are HER2 positive.4,5 Several unmet treatment needs remain today in HER2 positive metastatic breast cancer. Many HER2 positive breast cancers eventually advance to the point where no currently approved HER2 targeting therapy continues to control the disease;6 after treatment with trastuzumab, pertuzumab, and T-DM1, optimal treatment is less clearly defined and choices may be limited.7

HER2 expressing gastric cancer also is an area of unmet medical need, where treatment advances have been limited, largely due to the genetic complexity and heterogeneity of the disease.8 Currently, there are no approved HER2 targeting therapies for patients with HER2-positive advanced gastric cancer that progresses after treatment with a trastuzumab regimen.

About the [Fam-] Trastuzumab Deruxtecan Phase 1 Study
An open-label, two-part phase 1 study is currently evaluating [fam-] trastuzumab deruxtecan in patients with advanced/unresectable or metastatic solid tumors that are refractory or intolerant to standard treatment, or for whom no standard treatment is available. The primary objectives of the dose escalation part of the study were to assess the safety, tolerability, and activity of [fam-] trastuzumab deruxtecan and determine the recommended dose for expansion. These data were published in The Lancet Oncology.9

In the dose expansion part of the study, [fam-] trastuzumab deruxtecan is being evaluated at two recommended doses (5.4 mg/kg and 6.4 mg/kg) in five patient cohorts, including HER2 positive advanced or metastatic breast cancer and gastric cancer, HER2 low expressing breast cancer, and other HER2 expressing solid tumors. Enrollment for patients with HER2 positive breast cancer and HER2 positive gastric/gastro-esophageal cancer has completed. Overall, 292 patients have been enrolled into this phase 1 study of [fam-] trastuzumab deruxtecan. For more information about the study, visit ClinicalTrials.gov.

About [Fam-] Trastuzumab Deruxtecan
[Fam-] trastuzumab deruxtecan (DS-8201; [fam-] trastuzumab deruxtecan in U.S. only; trastuzumab deruxtecan in other regions of world) is the lead product in the investigational ADC Franchise of the Daiichi Sankyo Cancer Enterprise and the most advanced program in AstraZeneca’s ADC Scientific platform.

ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, [fam-] trastuzumab deruxtecan is comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. It is designed to target and deliver chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy), compared to the way chemotherapy is commonly delivered.

A broad and comprehensive development program with [fam-] trastuzumab deruxtecan is underway in North America, Europe, and Asia, including five pivotal studies. [Fam-] trastuzumab deruxtecan is in pivotal phase 3 development in previously treated HER2 low expressing metastatic breast cancer versus investigator’s choice (DESTINY-Breast04); phase 3 development in HER2 positive metastatic breast cancer versus ado-trastuzumab emtansine (T-DM1) (DESTINY-Breast03); and phase 3 development in HER2 positive metastatic breast cancer versus investigator’s choice post T-DM1 (DESTINY-Breast02). [Fam-] trastuzumab deruxtecan also is in pivotal phase 2 development for HER2 positive metastatic breast cancer resistant or refractory to T-DM1 (DESTINY-Breast01); pivotal phase 2 development for HER2 positive advanced gastric cancer resistant or refractory to trastuzumab (DESTINY-Gastric01); phase 2 development for HER2 expressing advanced colorectal cancer; phase 2 development for non-squamous HER2 overexpressing or HER2 mutated metastatic NSCLC; and, phase 1 development in combination with nivolumab for HER2 expressing metastatic breast and bladder cancer.

[Fam-] trastuzumab deruxtecan has been granted Breakthrough Therapy designation for the treatment of patients with HER2 positive, locally advanced or metastatic breast cancer who have been treated with trastuzumab and pertuzumab and have disease progression after T-DM1, and Fast Track designation for the treatment of HER2 positive unresectable and/or metastatic breast cancer in patients who have progressed after prior treatment with HER2 targeted therapies, including T-DM1 by the U.S. Food and Drug Administration (FDA). [Fam-] trastuzumab deruxtecan has received SAKIGAKE Designation for the treatment of HER2 positive advanced gastric or gastroesophageal junction cancer by the Japan Ministry of Health, Labour and Welfare (MHLW).

[Fam-] trastuzumab deruxtecan is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.

About the Collaboration between Daiichi Sankyo and AstraZeneca
In March 2019, Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize [fam-] trastuzumab deruxtecan as a medicine worldwide, except in Japan where Daiichi Sankyo will maintain exclusive rights. Daiichi Sankyo will be solely responsible for manufacturing and supply.

About Daiichi Sankyo Cancer Enterprise
The mission of Daiichi Sankyo Cancer Enterprise is to leverage our world-class, innovative science and push beyond traditional thinking to create meaningful treatments for patients with cancer. We are dedicated to transforming science into value for patients, and this sense of obligation informs everything we do. Anchored by three pillars including our investigational Antibody Drug Conjugate Franchise, Acute Myeloid Leukemia Franchise and Breakthrough Science, we aim to deliver seven distinct new molecular entities over eight years during 2018 to 2025. Our powerful research engines include two laboratories for biologic/immuno-oncology and small molecules in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in Berkeley, CA. Compounds in pivotal stage development include: [fam-] trastuzumab deruxtecan, an antibody drug conjugate (ADC) for HER2 expressing breast, gastric and other cancers; quizartinib, an oral selective FLT3 inhibitor, for newly-diagnosed and relapsed/refractory FLT3-ITD acute myeloid leukemia (AML); and pexidartinib, an oral CSF1R inhibitor, for tenosynovial giant cell tumor (TGCT). For more information, please visit: www.DSCancerEnterprise.com.