On May 5, 2017 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that the European Commission has approved KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL) who have failed autologous stem cell transplant (ASCT) and brentuximab vedotin (BV), or who are transplant-ineligible and have failed BV (Press release, Merck & Co, MAY 5, 2017, View Source [SID1234518858]). The approval allows marketing of KEYTRUDA in all 28 EU member states plus Iceland, Lichtenstein and Norway, at the approved dose of 200 mg every three weeks until disease progression or unacceptable toxicity.

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"Today’s approval brings an important new treatment option to patients in Europe with classical Hodgkin lymphoma who have not responded to existing therapies," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "This milestone underscores our commitment to evaluating KEYTRUDA in diseases with unmet need facing the hematology community."

"For patients with classical Hodgkin lymphoma who have not been successfully treated with prior therapies – many of whom are young and have a poor prognosis – there are limited options and treating the disease poses significant challenges," said Pier Luigi Zinzani, M.D., Ph.D., associate professor of hematology, Institute of Hematology "L. e A. Seràgnoli," University of Bologna. "With this approval, we will now be able to provide these patients with a much-needed new treatment option."

Data Supporting the Approval

The approval was based on data in 241 patients from the KEYNOTE-087 and KEYNOTE-013 trials. These multicenter, open-label studies evaluated patients with cHL who failed ASCT and BV, who were ineligible for ASCT because they were unable to achieve a complete or partial remission after salvage chemotherapy and failed BV, or who failed ASCT and did not receive BV. Both studies included patients regardless of PD-L1 expression. Patients with active, non-infectious pneumonitis, an allogeneic transplant within the past five years (or more than five years but with graft-versus-host-disease [GVHD]), active autoimmune disease or a medical condition that required immunosuppression were ineligible for either trial. The major efficacy outcome measures, overall response rate (ORR) and complete remission rate (CRR), were assessed by blinded independent central review according to the 2007 revised International Working Group (IWG) criteria. Secondary efficacy outcome measures were duration of response, progression-free survival, and overall survival.

In KEYNOTE-087, 210 patients received KEYTRUDA (pembrolizumab) at a dose of 200 mg every three weeks until unacceptable toxicity or documented disease progression. Eighty-one percent of patients were refractory to at least one prior therapy, including 35 percent who were refractory to first-line therapy. Additionally, 61 percent of patients had undergone prior ASCT, 38 percent were transplant ineligible; 17 percent had no prior BV use and 36 percent of patients had prior radiation therapy. Efficacy analysis showed an ORR of 69 percent (95% CI: 62.3, 75.2) with a CRR of 22 percent and a partial remission rate (PRR) of 47 percent. The median follow-up time was 10.1 months. Among the 145 responding patients, the median duration of response was 11.1 months (range 0.0+ to 11.1), with 76 percent of responding patients having responses of six months or longer.

In KEYNOTE-013, 31 patients received KEYTRUDA at a dose of 10 mg/kg every two weeks until unacceptable toxicity or documented disease progression. Eighty-seven percent of patients were refractory to at least one prior therapy, including 39 percent who were refractory to first-line therapy. Seventy-four percent of patients had undergone prior ASCT, 26 percent were transplant ineligible, and 42 percent of patients had prior radiation therapy. Efficacy analysis showed an ORR of 58 percent (95% CI: 39.1, 75.5) with a CRR of 19 percent and a PRR of 39 percent. The median follow-up time was 28.7 months. Among the 18 responding patients, the median duration of response was not reached (range 0.0+ to 26.1+), with 80 percent of patients with a response of six months or longer and 70 percent of patients with a response of 12 months or longer.

The safety analysis supporting the European approval of KEYTRUDA (pembrolizumab) was based on 3,194 patients with advanced melanoma, NSCLC or cHL across four doses (2 mg/kg every three weeks, 200 mg every three weeks, or 10 mg/kg every two or three weeks) in clinical studies. The most common adverse reactions (greater than 10%) with KEYTRUDA were fatigue (22%), pruritus (15%), rash (13%), diarrhea (12%) and nausea (10%). The majority of adverse reactions reported were of Grade 1 or 2 severity. The most serious adverse reactions were immune-related adverse reactions and severe infusion-related reactions.

About Hodgkin Lymphoma

Hodgkin lymphoma is a type of lymphoma that develops in the white blood cells, called lymphocytes, which are part of the immune system. Hodgkin lymphoma can start almost anywhere – most often in lymph nodes in the upper part of the body, with the most common sites being in the chest, neck or under the arms. Worldwide, there were approximately 66,000 new cases of Hodgkin lymphoma and 25,500 people died from the disease in 2012. Classical Hodgkin lymphoma accounts for about 95 percent of all cases of Hodgkin lymphoma in developed countries.

About KEYTRUDA (pembrolizumab)

KEYTRUDA is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA 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.

KEYTRUDA is administered as an intravenous infusion over 30 minutes every three weeks for the approved indications. KEYTRUDA for injection is supplied in a 100 mg single-dose vial.

KEYTRUDA Indications and Dosing in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a dose of 2 mg/kg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA (pembrolizumab) 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 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.

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.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, 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 KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. 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 KEYTRUDA for Grade 4 colitis.

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. 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.

KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

KEYTRUDA can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

KEYTRUDA (pembrolizumab) can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

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

KEYTRUDA can cause other clinically important immune-mediated adverse reactions. 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%), exfoliative dermatitis, bullous pemphigoid, rash (1.4%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma. In addition, myelitis and myocarditis were reported in other clinical trials, including cHL, and postmarketing use.

Solid organ transplant rejection has been reported in postmarketing use of KEYTRUDA. Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with KEYTRUDA vs the risk of possible organ rejection in these patients.

KEYTRUDA can cause severe or life-threatening infusion-related reactions, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for signs and symptoms of infusion-related reactions, including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA (pembrolizumab).

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after being treated with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after treatment with KEYTRUDA on any trial, 6 patients (26%) developed graft-versus-host-disease (GVHD), one of which was fatal, and 2 patients (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning, one of which was fatal. 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. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT. Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.

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.

KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL and treatment was interrupted due to adverse reactions in 26% of patients. Fifteen percent (15%) of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 16% of patients. The most frequent serious adverse reactions (>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 (occurring in ≥20% of patients) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

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.

There is limited experience in pediatric patients. In a study of 40 pediatric patients with advanced melanoma, PD-L1–positive advanced, relapsed, or refractory solid tumors or lymphoma, patients were treated with KEYTRUDA for a median of 43 days (range 1 to 414 days), with 24 patients (60%) receiving treatment for 42 days or more. The safety profile in pediatric patients was similar to that seen in adults treated with KEYTRUDA (pembrolizumab). 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 May 5, 2017 ImmunoGen, Inc. (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported recent highlights and reported financial results for the quarter ended March 31, 2017 (Press release, ImmunoGen, MAY 5, 2017, View Source [SID1234518855]).

"We have started 2017 with significant progress towards our strategic priorities of advancing our portfolio, supporting our partners, and driving continued innovation in ADCs," said Mark Enyedy, ImmunoGen’s president and chief executive officer. "Following enrollment of our first patient in FORWARD I in January, we have since expanded the study to include additional centers in North America and Europe, and expect to activate more than 100 sites in these geographies before the end of the year. We presented data at the SGO Annual Meeting supporting our patient selection strategy for FORWARD I and delivered nine presentations at the AACR (Free AACR Whitepaper) Annual Meeting highlighting novel ADCs and enhancements to our platform technologies. For the remainder of the year, we look forward to a number of additional milestones, including sharing new efficacy and safety data for mirvetuximab soravtansine at ASCO (Free ASCO Whitepaper) and filing an IND for our CD123-targeting ADC, IMGN632, in the third quarter."

Recent Highlights

Proprietary Portfolio

Treated the first patient in FORWARD I and expanded the study to more than 40 sites in North America and Europe;
Presented expanded Phase 1 data from the biopsy cohort for mirvetuximab soravtansine at the Society for Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer demonstrating that archival tumor tissue can reliably identify patients with folate receptor alpha (FRα)-positive platinum-resistant ovarian cancer and supporting the patient selection strategy for FORWARD I; and
Delivered nine presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting demonstrating improvements to ImmunoGen’s payload and linker technologies and highlighting data with novel ADCs directed to a range of tumor targets.
Partner Programs

Bayer completed enrollment in a registration-enabling Phase 2 study for anetumab ravtansine in mesothelioma; and
Takeda initiated preclinical development with the first ADC using ImmunoGen’s IGN platform directed to a solid tumor.
ASCO Presentations

ImmunoGen will report data on mirvetuximab soravtansine in poster presentations at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on June 3, 2017:

Gynecologic Cancer: General Poster Session
Location: Hall A
Saturday, June 3, 2017, 1:15 p.m. – 4:45 p.m. CDT

Title: Mirvetuximab soravtansine (IMGN853), a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in platinum-resistant epithelial ovarian cancer (EOC) patients (pts): Activity and safety analyses in phase I pooled expansion cohorts. (Abstract No.: 5547, Poster Board No.: 369)
Title: Safety findings from FORWARD II: A phase 1b study evaluating the folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC) mirvetuximab soravtansine (IMGN853) in combination with bevacizumab, carboplatin, pegylated liposomal doxorubicin (PLD), or pembrolizumab in patients (pts) with ovarian cancer. (Abstract No.: 5553, Poster Board No.: 375)
Title: FORWARD I (GOG 3011): A randomized phase 3 study to evaluate the safety and efficacy of mirvetuximab soravtansine (IMGN853) versus chemotherapy in adults with folate receptor alpha (FRα)-positive, platinum-resistant epithelial ovarian cancer (EOC), primary peritoneal cancer, or primary fallopian tube cancer. (Abstract No.: TPS5607, Poster Board No.: 425b)
Additional Upcoming Events

ImmunoGen expects to present initial Phase 1 data for IMGN779, a CD33-targeting ADC, for the treatment of acute myeloid leukemia in mid-2017. These will be the first clinical data reported with an ADC using ImmunoGen’s DNA-alkylating payload.
The Company anticipates filing an investigational new drug (IND) application in the third quarter of 2017 to support clinical testing with IMGN632, a CD123-targeting ADC integrating a more potent DNA-alkylating payload intended to treat a range of hematological malignancies.
ImmunoGen also anticipates advancing the first development candidate under its collaboration with CytomX into preclinical development in 2017.
Financial Results

Revenues for the quarter ended March 31, 2017 were $28.5 million, compared to $19.7 million for the quarter ended March 31, 2016. License and milestone fees for the first quarter of 2017 included $6 million in partner milestone payments and $12.7 million in amortization of a non-cash fee related to the Company’s license agreement with CytomX, compared with $10 million from partner milestone payments in the same quarter in 2016. Revenues in the first quarter of 2017 included $7.6 million in non-cash royalty revenues, compared with $7.4 million in non-cash royalty revenues for the same quarter in 2016. Revenues for the first quarter of 2017 also included $1.5 million of research and development (R&D) support fees and $0.7 million of clinical materials revenue, compared with $1.1 million and $1.2 million, respectively, for the same quarter in 2016.

Operating expenses for the first quarter of 2017 were $41.4 million, compared to $47.3 million for the same quarter in 2016. Operating expenses in the first quarter of 2017 include R&D expenses of $32.9 million, compared to $36.1 million for the same quarter in 2016. This change is primarily due to a workforce reduction resulting from the strategic review in September 2016, as well as decreased costs associated with manufacturing clinical materials on behalf of ImmunoGen’s partners. Partially offsetting these decreases, clinical trial costs increased in the first quarter of 2017 driven primarily by studies of mirvetuximab soravtansine. Operating expenses include general and administrative expenses of $8.1 million in the first quarter of 2017, compared to $11.2 million in the same quarter in 2016. This decrease is primarily due to a non-cash stock compensation charge in the first quarter of 2016 resulting from the CEO transition, as well as decreased personnel expenses in the first quarter of 2017.

ImmunoGen reported a net loss of $17.3 million, or $0.20 per basic and diluted share, for the first quarter of 2017 compared to a net loss of $31.9 million, or $0.37 per basic and diluted share, for the same quarter last year.

ImmunoGen had approximately $126.6 million in cash and cash equivalents as of March 31, 2017, compared with $160.0 million as of December 31, 2016, and had $100.0 million of convertible debt outstanding in each period. Cash used in operations was $33.0 million for the first quarter of 2017, compared with $26.1 million for the first quarter of 2016. Capital expenditures were $0.4 million and $3.5 million for the quarters ended March 31, 2017 and 2016, respectively.

Financial Guidance

ImmunoGen’s financial guidance for 2017 remains unchanged from that issued in February 2017. ImmunoGen expects:

Revenues between $70 million and $75 million, which includes $28 million of expected upfront and milestone fees from partners;
Operating expenses between $175 million and $180 million; and
Cash and cash equivalents at December 31, 2017 between $35 million and $40 million.
ImmunoGen expects that its current cash plus expected cash revenues from partners and collaborators will enable the Company to fund operations into the second quarter of 2018.