On October 22, 2018 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a clinical stage targeted oncology company, reported the presentation of updated data from its ongoing Phase 2 clinical trial of sitravatinib in combination with OPDIVO (nivolumab) in non-small cell lung cancer (NSCLC) patients with documented progression on prior immune checkpoint inhibitor therapy (Press release, Mirati, OCT 22, 2018, View Source [SID1234530038]). The data were presented today in a Proffered Paper Session (oral presentation) at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress in Munich, Germany.

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Highlights from the Proffered Paper Sessions (Oral Presentations) at ESMO (Free ESMO Whitepaper) 2018

An ongoing Phase 2 study is evaluating the efficacy and safety of sitravatinib in combination with OPDIVO (nivolumab), an anti-PD-1 immune checkpoint inhibitor, in patients with NSCLC who have experienced documented disease progression following prior treatment with an immune checkpoint inhibitor. As of the data cutoff date of August 27, 2018:

56 patients were evaluable for response with at least one radiographic scan. Patients had a median of two lines of previous therapy.
45/56 of evaluable patients demonstrated tumor reductions.
18/56 of evaluable patients demonstrated tumor reductions of greater than 30%.
16/56 of evaluable patients achieved a Partial Response (PR) or Complete Response (CR).
9 confirmed PRs or CRs.
2 unconfirmed PRs or CRs that remain on trial awaiting confirmation.
5 unconfirmed PRs or CRs that will not be confirmed.
26/56 evaluable patients remained on treatment at the time of data cut-off including 8 responding patients.
A preliminary Kaplan-Meier estimate of median duration of response was greater than 9 months.
6 responding patients have been treated for more than 6 months.
2 responding patients have been treated for more than 12 months.
The combination has been well-tolerated and most adverse events (AEs) were Grade 1 or 2.
"To date, the combination of sitravatinib and nivolumab has demonstrated a significant number of durable responses in patients with advanced NSCLC who experienced disease progression following prior checkpoint inhibitor therapy, which is one of the most challenging clinical scenarios that we currently face for this patient population," said Ticiana Leal, M.D., Assistant Professor of Medicine, Thoracic Oncology Program Leader at the University of Wisconsin. "The results of the study are encouraging as it continues to show a clinical benefit for these patients and has a favorable safety profile."

Sitravatinib Registration Plans

The Company also provided an update on the regulatory pathway for sitravatinib in checkpoint refractory NSCLC patients following a successful end of phase 2 meeting with the U.S. Food and Drug Administration (FDA). Based on guidance received from the FDA, Mirati plans to initiate a Phase 3 randomized clinical trial in second line patients comparing the combination of sitravatinib plus a checkpoint inhibitor to docetaxel in patients whose tumors have progressed on prior checkpoint inhibitor therapy.

The trial will include an interim analysis of overall response rate (ORR) as a surrogate endpoint to serve as the basis for potential Subpart H accelerated approval. This interim analysis and the use of a docetaxel control arm follows clear guidance from the FDA.
The primary endpoint of the final analysis for the Phase 3 clinical trial will be overall survival.
The trial will enroll patients with NSCLC whose tumors have progressed following treatment with a checkpoint inhibitor and platinum-based chemotherapy.
Patients will be randomized for treatment with either the combination of sitravatinib with a checkpoint inhibitor or single-agent docetaxel.
The Company plans to initiate the pivotal Phase 3 in the first half of 2019. Ultimately, the Company expects this trial to enable a new drug application (NDA) for the treatment of NSCLC patients whose tumors have progressed following treatment with a platinum containing regimen and a checkpoint inhibitor.
"There are limited treatment options for NSCLC patients whose tumors progress following checkpoint inhibitor therapy," said Charles M. Baum, M.D., Ph.D., President and Chief Executive Officer, Mirati Therapeutics, Inc. "Based on the data from our ongoing Phase 2 clinical trial we believe that the planned Phase 3 clinical trial will demonstrate a greater response rate and overall survival compared with the historical clinical outcomes for late stage NSCLC patients treated with single-agent docetaxel, where response rates range from 7-11%. The combination of sitravatinib and nivolumab has continued to show it is well tolerated with manageable side effects. We remain encouraged by the frequency and duration of the responses observed to date in this patient population with limited treatment options where responses would not be expected from re-treatment with a checkpoint inhibitor alone."

Investor Call and Webcast Information

After the oral presentation, Mirati will host a live conference call and webcast, led by Dr. Charles Baum, on Monday, October 22, 2018, at 2:00 p.m. CEST/8:00 a.m. EDT/5:00 a.m. PDT. The live call can be accessed by dialing (866) 324-3683 (toll free) or (509) 844-0959 (international) and then using passcode 3890724. A telephone replay will be made available by dialing (855) 859-2056 (toll free) or (404) 537-3406 (international) using conference replay ID 3890724.

The call will also be webcast live through the "Investors" section of the Mirati corporate website at View Source A replay of the webcast will be available on the Mirati website shortly after the conclusion of the event.

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 who have experienced documented disease progression following 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 enrolling patients whose tumors harbor specific mutations in the CBL kinase. 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.

On October 22, 2018 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of KEYTRUDA, Merck’s anti-PD-1 therapy, as adjuvant therapy in the treatment of patients with melanoma with lymph node involvement who have undergone complete surgical resection (Press release, Merck & Co, OCT 22, 2018, View Source [SID1234530037]). This recommendation is based on data that demonstrated a significant improvement in recurrence-free survival (RFS) for KEYTRUDA in the pivotal Phase 3 EORTC1325/KEYNOTE-054 trial, which was conducted in collaboration with the European Organisation for Research and Treatment of Cancer (EORTC). These data were presented for the first time at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018 and published in The New England Journal of Medicine. The CHMP’s recommendation will now be reviewed by the European Commission for marketing authorization in the European Union (EU). A final decision is expected in the fourth quarter of 2018.

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"There is a growing need for innovative therapies that can help reduce the risk of recurrence following surgery in patients with stage III melanoma," said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. "Today’s news reflects the collaborative efforts of Merck and EORTC to improve the way we treat melanoma earlier in the treatment paradigm. We look forward to working with European regulatory authorities to bring KEYTRUDA to these patients in the adjuvant setting."

About EORTC

European Organisation for Research and Treatment of Cancer (EORTC) conducts clinical research in cancer, defining new standards of practice for better treatment and care of cancer patients. EORTC network comprises more than 5,500 multidisciplinary collaborators in more than 930 hospitals and institutions in 27 countries. Through translational and clinical research, EORTC offers an integrated approach to therapeutic strategies, drug evaluation programs, outcomes research and quality of life. For more information, visit www.eortc.org.

About Melanoma in Europe

Melanoma is the most serious form of skin cancer and is characterized by the uncontrolled growth of pigment-producing cells. Worldwide, the incidence of melanoma has been increasing over the past four decades in many populations, and it is estimated that in 2018 there will be more than 287,000 new melanoma cases and over 60,000 people will die from the disease. In Europe, the five-year survival rate for advanced or metastatic melanoma (stage IV) is estimated to be about five to 22 percent.

About Merck’s Commitment to Melanoma

Merck’s long-term commitment to melanoma includes a broad clinical development program studying KEYTRUDA as monotherapy and in combination with other novel mechanisms. The program, which is comprised of more than 4,500 patients across 10 Merck-sponsored clinical studies, is evaluating KEYTRUDA across most settings and stages of the disease.

About KEYTRUDA (pembrolizumab) Injection, 100mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 850 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

KEYTRUDA (pembrolizumab) Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous NSCLC, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, as a single agent, is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for pemetrexed and carboplatin or cisplatin, as appropriate.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for the treatment of patients with PMBCL who require urgent cytoreductive therapy.

In adults with PMBCL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with PMBCL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is also indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In children with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity or up to 24 months in patients without disease progression.

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%), and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue for Grade 4 colitis.

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in patients with HNSCC occurring in 15% (28/192) of patients. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency), thyroid function (prior to and periodically during treatment), and hyperglycemia. For hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or 4 hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials and postmarketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 developed graft-versus-host disease (GVHD) (one fatal case) and 2 developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (one fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor–blocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

Increased Mortality in Patients with Multiple Myeloma

In clinical trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled clinical trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those ≥1% included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (≥20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

Lactation

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

Pediatric Use

There is limited experience in pediatric patients. In a study in 40 pediatric patients with advanced melanoma, lymphoma, or PD-L1–positive advanced, relapsed, or refractory solid tumors, the safety profile was similar to that seen in adults treated with KEYTRUDA. Toxicities that occurred at a higher rate (≥15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%), and hyponatremia (18%).

On October 22, 2018 CytomX Therapeutics, Inc. (Nasdaq:CTMX) a clinical-stage oncology-focused biopharmaceutical company pioneering a novel class of investigational antibody therapeutics based on its Probody therapeutic technology platform, today presented clinical results from two arms of the PROCLAIM (PRObody CLinical Assessment In Man) module, PROCLAIM-072 (Press release, CytomX Therapeutics, OCT 22, 2018, View Source [SID1234530036]). PROCLAIM-072 is an ongoing Phase 1/2 trial evaluating CX-072, a Probody therapeutic targeting PD-L1, as monotherapy and in combination with Yervoy (ipilimumab) or Zelboraf (vemurafenib) in patients with advanced, unresectable solid tumors. Data from the CX-072 monotherapy arm and ipilimumab combination arm were presented today in two posters at the 2018 Annual Meeting of the European Society of Clinical Oncology (ESMO) (Free ESMO Whitepaper) in Munich, Germany. The data presented at ESMO (Free ESMO Whitepaper) were based on an August 3, 2018 data cutoff, reflecting an approximately three-month difference from the data cutoff for the presentations made at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in June.

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"Our data presented today continue to support our thesis that CX-072 has potential to be a new and differentiated combination partner for anti-cancer therapy. CX-072 has demonstrated activity both as monotherapy and in combination with ipilimumab and is generally well tolerated in both regimens," said Sean McCarthy D.Phil., president and chief executive officer of CytomX Therapeutics. "We are advancing monotherapy CX-072 towards registrational studies and continuing to explore the full potential of the CX-072/ipilimumab combination. With the clinical data reported today, and at ASCO (Free ASCO Whitepaper), the Probody platform is declaring its potential to deliver multiple opportunities to make a meaningful difference for cancer patients."

Poster 435 – Preliminary Results of PROCLAIM-072: The First-In-Human, Dose-Finding Trial of PD-L1 Probody Therapeutic CX-072 as Monotherapy in Patients with Advanced Solid Tumors

Presenter: Valentina Boni, M.D., Ph.D., Clinical Researcher, START Madrid and Associate Professor, University CEU San Pablo in Madrid, Spain

The primary objectives of Parts A and A2 of this first-in-human, dose-escalation, monotherapy arm are to assess safety and tolerability, including determination of the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of CX-072 as monotherapy. Patients in Part A received escalating doses of CX-072 from 0.03 mg/kg to 30 mg/kg. Patients in Part A2 received escalating doses of CX-072 from 0.3 mg/kg to 10 mg/kg and had mandatory biopsies of PD-L1 positive solid tumors. At the time of the August 3, 2018 data cutoff, Parts A and A2 had enrolled 46 patients, with 11 patients still receiving treatment. Treatment duration for patients in Part A2 was limited at higher doses. Enrollment in Part A is complete and Part A2 is ongoing with patient follow-up ongoing.

Monotherapy Well Tolerated

The maximum tolerated dose (MTD) was not reached. As of an August 3, 2018 data cutoff, results were consistent with previous analyses. The administration of monotherapy CX-072 was generally well tolerated with the majority of treatment-related adverse events (TRAEs) Grade 1/2. Of the 46 treated patients, 5 (11%) reported Grade 3/4 TRAEs and 3 (7%) reported treatment-related serious adverse events (SAEs). Immune-related adverse events (irAE) were reported in 3 (7%) of patients.

Monotherapy Clinical Activity

As of an August 3, 2018 data cutoff, results showed that among 38 evaluable patients who received CX-072, objective responses by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were observed in 3 (8%) patients, all treated at a dose of > 3 mg/kg: PD-L1 negative triple negative breast cancer (confirmed partial response (cPR); 10 mg/kg), thymic cancer (unconfirmed partial response (uPR); 3 mg/kg), and cervical cancer (uPR; 10 mg/kg). Stable disease was observed in 15 (39%) of patients for an overall disease control rate of 47%. For the 18 patients who received CX-072 ≥3 mg/kg, objective responses were observed in 3/18 (17%) and the disease control rate was 61%. Decreased target lesions were observed in 38% (14/37) of all evaluable patients with measurable disease at baseline and in 59% (10/17) of the subset of patients who received > 3 mg/kg of CX-072.

Poster 436 – Preliminary Interim Results of the First-In-Human, Dose-Finding PROCLAIM-072 Trial Evaluating the PD-L1 Probody Therapeutic CX-072 in Combination with Ipilimumab in Patients with Advanced Solid Tumors

Presenter: Ruth Plummer, M.D., Northern Institute for Cancer Research, Newcastle University

The primary objectives of this ongoing arm of the study are to assess safety and tolerability, and to determine the MTD and DLT of CX-072 when administered in a concomitant combination schedule with ipilimumab. At the August 3, 2018 data cutoff, the study had enrolled 20 immunotherapy naïve patients who had received an average of 3 prior anti-cancer treatments in a variety of tumor types for which no anti-PD-1 or PD-L1 agents were available for their disease. Patients received the combination ipilimumab (3 mg/kg or greater) and CX-072 (escalating doses of 0.3 mg/kg to 10 mg/kg) every three weeks for four cycles followed by monotherapy CX-072 every two weeks.

Combination with Ipilimumab Well Tolerated

As of the August 3, 2018 data cutoff date, the MTD had not yet been reached and was generally well tolerated with no new safety signals observed beyond those expected for each component of the CX-072 plus ipilimumab combination. The full dose of 3 mg/kg of ipilimumab in combination with CX-072 10 mg/kg was well tolerated. The majority of TRAEs were Grade 1/2. Of the 20 treated patients, 4 (20%) reported a Grade 3/4 TRAE, a rate similar to that reported previously for 3 mg/kg ipilimumab monotherapy1. These events included: Grade 3 colitis (n=1), Grade 3 dyspnea/Grade 3 pneumonitis (n=1), Grade 3 headache/Grade 3 hyponatremia (n=1), and Grade 3 amylase/Grade 4 lipase (n=1). Grade 3/4 irAEs were reported in 2/20 (10%) patients, 0% (0/11) at doses of >3 mg/kg CX-072 with 3 mg/kg of ipilimumab. The study is still ongoing with enrollment and dose escalation continuing.

1 Larkin J, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015;373: 23–34.

Ipilimumab Combination Clinical Activity

As of an August 3, 2018 data cutoff, results also showed that among 14 evaluable patients who received ipilimumab (3 mg/kg) combined with CX-072 (0.3 to 10 mg/kg), 3 (21%) achieved objective responses by RECIST v1.1, including patients with: anal cancer (confirmed complete response (cCR); 0.3 mg/kg CX-072), testicular cancer (confirmed partial response (cPR); 1 mg/kg CX-072) and cancer of unknown primary (cPR; 3 mg/kg CX-072). Stable disease was observed in 3 additional patients for a disease control rate of 43%. As of the data cutoff, all 3 of the responders remained on treatment with durations of response of 7.4, 5.3, and 3.2 months, respectively.

Probody Pharmacokinetics

Results from a preliminary single-dose pharmacokinetic analysis of single-agent CX-072 suggest that, as designed, CX-072 circulates predominantly as the intact masked prodrug across all dose levels with 96% intact at 30 mg/kg. Further, CX-072 is only minimally influenced by target mediated drug disposition at low doses, suggesting that masking is effective in blocking interaction with PD-L1 in the periphery.

CX-072 Monotherapy and Ipilimumab Combination Expansion Arms

Based upon the results from the Part A CX-072 monotherapy arm presented at ASCO (Free ASCO Whitepaper) in June, in the second quarter, the Company began dosing patients in Part D, the expansion arm examining CX-072 as monotherapy at 10 mg/kg in 8 undisclosed tumor types. The Company has the potential to move one or more of these indications into a registrational trial with the goal of advancing towards commercialization. The Company expects initial Part D clinical data in 2019.

The Company is currently dosing patients in the Part B CX-072 combination with ipilimumab arm at 6 mg/kg of ipilimumab. The Company plans to initiate expansion modules with this combination in the first half of 2019 at doses and indications to be determined.

Conference Call and Webcast

CytomX will host a conference call and live webcast with slides today, Monday, October 22, 2018, beginning at 2:30 p.m. CEST/ 8:30 a.m. EDT to discuss these data presentations and review the next steps for the programs. This event can be accessed in three ways:

From the CytomX website: View Source Please access the website 15 minutes prior to the start of the call to download and install any necessary audio software.

By telephone: Participants can access the call by dialing 1-877-809-6037 (United States) or 1- 615-247-0221 (International) referencing Conference ID 1275596.

By replay: A replay of the webcast will be located under the Investor Relations section of CytomX’s website approximately two hours after the conclusion of the live call and will be available for 30 days following the call.
About PROCLAIM

PROCLAIM (Probody Clinical Assessment In Man) is an international umbrella program designed to evaluate CytomX’s Probody therapeutics. The first module is the PROCLAIM-CX-072 clinical program, an open-label, dose-finding Phase 1/2 trial evaluating CX-072 as monotherapy and in combination with Yervoy (ipilimumab) or Zelboraf (vemurafenib) in patients with metastatic or locally advanced unresectable solid tumors or lymphomas. CytomX aims to achieve three goals as part of the PROCLAIM-072 clinical trial:

Tolerability: Demonstrate that CX-072 is well tolerated in patients and potentially improves safety, particularly in the combination setting.
Anti-cancer activity: Demonstrate initial evidence of CX-072’s anti-cancer activity as monotherapy and in combination.
Translational program and Probody platform proof-of-concept: Explore mechanistic aspects of Probody activity in patients as observed in preclinical models.

On October 22, 2018 SELLAS Life Sciences Group, Inc. (Nasdaq:SLS) ("SELLAS" or the "Company"), a clinical-stage biopharmaceutical company focused on the development of novel cancer immunotherapies for a broad range of cancer indications, reported data from the prospective, randomized, single-blinded, controlled Phase 2b independent investigator-sponsored clinical trial of the combination of nelipepimut-S (NeuVax, NPS) +/- trastuzumab (Herceptin) targeting HER2 low-expressing breast cancer patient cohorts (Press release, Sellas Life Sciences, OCT 22, 2018, View Source [SID1234530035]). The data were presented in an oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Annual Meeting, being held in Munich, Germany.

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"These data presented at ESMO (Free ESMO Whitepaper) today highlight the therapeutic potential of NPS for patients with early-stage triple negative breast cancer (TNBC), who currently face limited and ineffective treatment options in the adjuvant setting," said Dr. Angelos Stergiou, MD, ScD h.c., President and Chief Executive Officer of SELLAS. "The combination of NPS and trastuzumab demonstrated a clinically meaningful and statistically significant difference in the cohort of patients with TNBC with a 75.2% reduction in risk of relapse or death at 26 months. Importantly, following review of the final data that were also assessed by the independent Data Safety Monitoring Board (DSMB) on October 15, 2018, there was an incremental further improvement of clinical benefit to patients now observed in comparison with the data from the interim analysis completed more than six months ago."

The key data from today’s presentation, based on the final analysis, are shown below, including the summary table and the Kaplan-Meier (K-M) survival curve showing specifically the TNBC cohort:

Safety: Most treatment-emergent adverse events (TEAEs) were of mild or moderate (G1/2) severity (local: 98%; systemic: 93%). The majority of G3 systemic TEAEs were unrelated to NPS. Treatment-related adverse events consisted of manageable local injection site reactions, skin induration, pruritus, and fatigue.

Efficacy:
Outcomes Summary (comparison between the 2-arms of the study, i.e., Active: NPS + TZ, and Control: TZ alone):

Notably, the patient demographics and baseline disease characteristics were well balanced between the two arms, both in the intention-to-treat (ITT) and TNBC populations.

Elizabeth A. Mittendorf, M.D., Ph.D., Rob and Karen Hale Distinguished Chair in Surgical Oncology, Director of Research, Breast Surgical Oncology Brigham and Women’s Hospital, Director, Breast Immuno-Oncology Program Dana-Farber/Brigham and Women’s Cancer Center, and the Principal Investigator of the Phase 2b study commented: "It is encouraging to see that the final analysis of the NPS +/- trastuzumab Phase 2b trial for the TNBC cohort not only confirms the previously reported positive data, presented in full today, but also provides evidence for a significant clinically positive outcome with the combination. In many early stage TNBC patients, the benefit of initial treatment with neoadjuvant chemotherapy is incomplete, leaving room for improvement, especially in the adjuvant or maintenance setting. To date, targeted therapies have not proven effective for TNBC. Putting HER2 in the crosshairs of an immunotherapeutic combination, in this case NPS plus trastuzumab in triple-negative (HER2 IHC 1+/2+; hormone receptor negative) breast cancer patients, makes sense biologically considering preexisting activated cellular immunity in most patients with these tumors and the pharmacodynamic synergy between these two agents."

Dr. Stergiou further stated, "We look forward to continuing our discussions with U.S. and European regulatory agencies on the most optimal and expeditious development path for NPS in TNBC. To that end, we will be meeting with the FDA in December. We are also engaging in ongoing discussions with potential partners. I would like to thank all patients who participated in this NPS study, and their families and outstanding physicians, as well as our team at SELLAS and our supportive stockholders. As October is breast cancer awareness month, one could not have thought of a better timing to present this data, consistent with our mission to develop potentially life-saving drugs for patients in need."

Herceptin is a registered trademark of Genentech, Inc. and is not a trademark of SELLAS. The manufacturer of this brand is not affiliated with and does not endorse SELLAS or its products.

Conference Call

SELLAS will host a conference call on Monday, October 22, 2018 at 8:00 a.m. ET to discuss these data. To participate in the conference call, please dial (866) 416-7995 (domestic) or +1 (409) 217-8225 (international) and refer to conference ID 5571389. A live webcast of the call can be accessed under "Events & Presentations" in the Investors section of the Company’s website at www.sellaslifesciences.com.

An archived webcast recording will be available on the SELLAS website beginning approximately two hours after the call.

About ESMO (Free ESMO Whitepaper)

The European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) is Europe’s leading non-profit medical oncology organization. ESMO (Free ESMO Whitepaper) is a membership-based society, comprising of 500 expert committee members and 18,000 oncology professionals. ESMO (Free ESMO Whitepaper) organizes a large number of meetings to provide its members and the community with the resources they need and also plays a major role in public policy and European affairs. The ESMO (Free ESMO Whitepaper) 2018 Annual Meeting represents a multi-professional platform for oncology education and exchange, and for immense international visibility for scientific research, and will be held under the tagline "Securing access to optimal cancer care."

On October 22, 2018 GTx, Inc. (Nasdaq: GTXI) reported financial results for the third quarter ended September 30, 2018, and provided a corporate update (Press release, GTx, OCT 22, 2018, View Source [SID1234530034]).

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"During the quarter, we turned our focus to the ongoing selective androgen receptor degrader program and the potential of our novel selective androgen receptor degrader to treat castration-resistant prostate cancer. We expect to select the most appropriate development compounds by year-end, which we plan to take into IND-enabling studies next year," said Robert J. Wills, Ph.D., Executive Chairman of GTx. "Additionally, we are exploring other strategic options for the company with the goal of optimizing the full potential of our development pipeline."

Corporate Development Update

Selective Androgen Receptor Degrader (SARD): Prostate Cancer

The Company has an ongoing preclinical program to evaluate its novel selective androgen receptor degrader (SARD) technology in castration-resistant prostate cancer (CRPC). In some men with CRPC, current prostate cancer therapy is not effective or subject to emerging resistance. The Company believes that its SARDs may be first-in-class dual-interacting androgen receptor (AR) antagonists and degraders, and may therefore potentially treat CRPC in men who are non-responsive to current androgen targeted therapies. Going forward, the Company plans to:

Complete ongoing mechanistic preclinical studies by year-end or early in the first quarter of 2019;
Select the most appropriate SARD compounds to move forward with IND-enabling studies in 2019; and
Potentially advance one of its SARD compounds into a first-in-human clinical trial in 2020
Selective Androgen Receptor Modulator (SARM): Stress Urinary Incontinence (SUI), Breast Cancer

SUI: Enobosarm, a SARM, was evaluated in post-menopausal women with SUI compared to placebo. During the quarter, the Company announced that the ASTRID Trial, a Phase 2 double-blind, placebo-controlled clinical trial of orally-administered enobosarm (3 mg or 1 mg) in post-menopausal women with SUI, did not achieve statistical significance on the primary endpoint for the trial. Enobosarm was generally safe and well tolerated, and reported adverse events were minimal and similar across all treatment groups. The Company is conducting a comprehensive review of all the ASTRID data and is consulting with key experts to fully understand the study outcomes.

Advanced Breast Cancer: Enobosarm was also evaluated as a hormonal therapy for women with estrogen receptor positive (ER+) and androgen receptor positive (AR+) breast cancer in a Phase 2 clinical trial. The trial met the primary efficacy endpoint in the trial; there are three women in the study who continue to respond to treatment after almost two years on enobosarm (two have stable disease, one now has a partial response). Approximately one year ago, the Company determined that treatment paradigms had shifted to immunotherapies and/or combination therapies, and that it was no longer feasible for GTx to conduct further development of enobosarm in breast cancer.

Enobosarm has been evaluated in more than two dozen clinical trials enrolling over 2,200 subjects, in which approximately 1,500 subjects were treated with enobosarm at doses ranging from 0.1 mg to 100 mg. At all evaluated dose levels, enobosarm was observed to be generally safe and well tolerated.

Third Quarter 2018 Financial Results

As of September 30, 2018, cash and short-term investments were $38.1 million compared to $43.9 million at December 31, 2017.
Research and development expenses for the quarter ended September 30, 2018 were $7.5 million compared to $5.9 million for the same period of 2017.
General and administrative expenses for the quarter ended September 30, 2018 were $2.2 million compared to $2.6 million for the same period of 2017.
The net loss for the quarter ended September 30, 2018 was $9.4 million compared to a net loss of $8.5 million for the same period in 2017.
Net loss for the nine months ended September 30, 2018 was $33.0 million compared to a net loss of $21.2 million for the same period in 2017.
GTx had approximately 24.1 million shares of common stock outstanding as of September 30, 2018. Additionally, there are warrants outstanding to purchase approximately 5.3 million shares of GTx common stock at an exercise price of $8.50 per share and approximately 3.3 million shares of GTx common stock at an exercise price of $9.02.