On January 17, 2021Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and genetically defined diseases, today reported a full analysis of the final data, including mature overall survival (OS) results, from its global Phase 3 ClarIDHy trial of TIBSOVO (ivosidenib tablets) in patients with previously treated isocitrate dehydrogenase 1 (IDH1) mutated cholangiocarcinoma (Press release, Agios Pharmaceuticals, JAN 17, 2021, View Source [SID1234574070]). Data from the study were featured in an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (ASCO-GI), which is being held virtually January 15-17, 2021.

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The final analysis showed an improvement in the secondary endpoint of OS favoring patients randomized to TIBSOVO compared to those randomized to placebo; however, statistical significance was not reached. The median OS for patients randomized to TIBSOVO was 10.3 months compared to 7.5 months for patients randomized to placebo (hazard ratio [HR]=0.79; 95% CI [0.56–1.12], 1-sided p=0.093). The protocol specified that patients randomized to placebo could cross over to TIBSOVO at the time of disease progression, and a high proportion of patients in the placebo arm (70.5%) crossed over to TIBSOVO. The results of a pre-specified analysis to adjust for crossover, based on the rank-preserving structural failure time (RPSFT) model, showed a median OS for patients in the placebo arm of 5.1 months (HR=0.49, 95% CI 0.34–0.70, 1-sided p<0.0001). The safety profile observed in the study was consistent with previously published data. As previously announced, the study demonstrated a statistically significant improvement in the primary endpoint of progression-free survival (PFS) by independent radiology review.

"The progression-free survival and overall survival data from the ClarIDHy Phase 3 study, coupled with a tolerable safety profile and supportive patient-reported quality-of-life data, demonstrate that TIBSOVO has the potential to be a clinically meaningful treatment option for patients with previously treated IDH1-mutant cholangiocarcinoma, an aggressive cancer with limited effective treatment options," said Andrew Zhu, M.D., Ph.D., director emeritus of liver cancer research at Massachusetts General Hospital, director of Jiahui International Cancer Center and professor of medicine at Harvard Medical School. "Treatment with TIBSOVO resulted in a consistent trend in improved overall survival, despite the high rate of crossover from the placebo arm, and this improvement was further supported by the pre-specified statistical analysis to adjust for the crossover effect. I look forward to the potential of having a new treatment option for my patients with this devastating disease."

"We are extremely pleased with the results of the ClarIDHy Phase 3 study, the first and only randomized Phase 3 trial for IDH1-mutant advanced cholangiocarcinoma, and believe TIBSOVO has demonstrated compelling results for patients facing a grim prognosis who currently have few treatment options," said Chris Bowden, M.D., chief medical officer at Agios. "We will collaborate closely with regulators to advance this potential new oral, non-cytotoxic, targeted treatment option, and we look forward to filing for U.S. approval later this quarter."

ClarIDHy Phase 3 Trial
The ClarIDHy trial is a global, randomized Phase 3 trial in previously treated IDH1-mutant cholangiocarcinoma patients who have documented disease progression following one or two systemic therapies in the advanced setting. Patients were randomized 2:1 to receive either single-agent TIBSOVO 500 mg once daily or placebo with crossover to TIBSOVO permitted at the time of documented radiographic progression per RECIST 1.1. The primary endpoint of the ClarIDHy trial is progression-free survival (PFS) as evaluated by independent radiology review. Secondary endpoints include investigator-evaluated PFS, safety and tolerability, overall response rate, OS, duration of response, pharmacokinetics, pharmacodynamics and quality of life assessments.

As of the May 31, 2020 data cutoff, 187 patients were randomized, with 126 patients in the TIBSOVO arm and 61 patients in the placebo arm. Forty-three patients randomized to placebo (70.5%) crossed over to open-label TIBSOVO upon radiographic disease progression and unblinding.

Updated Efficacy Data
Efficacy data as of the data cutoff showed:

The median OS for patients in the TIBSOVO arm was 10.3 months compared to 7.5 months for patients in the placebo arm (HR=0.79; 95% CI [0.56–1.12], 1-sided p=0.093).
After adjusting for crossover from placebo to TIBSOVO using the pre-specified analysis of rank-preserving structural failure time (RPSFT), the median OS for patients in the placebo arm was 5.1 months (HR=0.49; 95% CI [0.34–0.70], 1-sided p<0.0001).
The 6-month survival rate for patients in the TIBSOVO arm was 69 percent compared to 57 percent of patients in the placebo arm, not adjusted for crossover.
The 12-month survival rate for patients in the TIBSOVO arm was 43 percent compared to 36 percent for patients in the placebo arm, not adjusted for crossover.
Treatment with TIBSOVO preserved patients’ physical functioning from baseline, as assessed by the EORTC QLQ-C30 questionnaire, whereas patients in the placebo arm experienced decline from baseline at cycle 2, day 1 (2-sided p=0.002) and cycle 3, day 1 (2-sided p=0.004).
Treatment with TIBSOVO improved patients’ pain at cycle 2, day 1 compared to placebo, as assessed by the EORTC QLQ-BIL21 questionnaire (2-sided p=0.039); no difference was observed at cycle 3, day 1.
Neither arm was favored on other pre-specified quality-of-life subscales (QLQ-C30 Appetite Loss and QLQ-BIL21 Pain and Eating).
Updated Safety Data

Grade 3 or above treatment-emergent adverse events (TEAE) were reported in 53 percent of total TIBSOVO patients, which includes patients originally randomized to TIBSOVO and those who crossed over from placebo to TIBSOVO, compared to 37.3 percent of patients on placebo, with the most common being ascites (9.0% total TIBSOVO vs. 6.8% placebo), anemia (7.2% total TIBSOVO vs. 0% placebo) and increased blood bilirubin (5.4% total TIBSOVO vs. 1.7% placebo).
TEAEs leading to discontinuation were more common with placebo compared with total TIBSOVO (8.5% vs. 6.6%).
TEAEs leading to dose reductions (3.0% vs. 0%) and interruptions (30.1% vs. 18.6%) were more common with total TIBSOVO compared with placebo.
The most common TEAEs of any grade for total TIBSOVO were nausea (38.0%), diarrhea (33.1%) and fatigue (28.9%).
Previously Reported Data
Data from the study were previously presented at the European Society for Medical Oncology Congress (ESMO) (Free ESMO Whitepaper), held in September 2019 in Barcelona, Spain, and published in The Lancet Oncology on May 13, 2020. Results from the trial demonstrated a statistically significant improvement in the primary endpoint of PFS among patients randomized to TIBSOVO compared with placebo patients (HR=0.37; 95% CI [0.25–0.54], p<0.0001), with a median PFS of 2.7 months in the TIBSOVO arm versus a median PFS of 1.4 months in the placebo arm. The estimated PFS rate was 32 percent at six months and 22 percent at 12 months for patients randomized to TIBSOVO, while no patients randomized to placebo were free from progression or death beyond six months as of the data cut-off.

Based on these data, the National Comprehensive Cancer Network (NCCN) guidelines, the French National Treatment Guidelines for Biliary Cancer and the Italian Clinical Practice Guidelines on Cholangiocarcinoma were updated to recommend treatment with TIBSOVO for patients with advanced previously treated IDH1-mutant cholangiocarcinoma.

Agios plans to submit a supplemental new drug application for TIBSOVO in previously treated IDH1-mutant cholangiocarcinoma in the first quarter of 2021.

TIBSOVO is not approved in any country for the treatment of patients with previously treated advanced IDH1-mutant cholangiocarcinoma.

About Cholangiocarcinoma
Cholangiocarcinoma is a rare cancer of the bile ducts within and outside of the liver. Cases that occur within the liver are known as intrahepatic cholangiocarcinoma (IHCC) and those that occur outside the liver are considered extrahepatic. IDH1 mutations occur in approximately 10% of cholangiocarcinoma cases. Current treatment options for localized disease include surgery, radiation and/or other ablative treatments. There are no approved systemic therapies for IDH1-mutated cholangiocarcinoma and limited chemotherapy options are available in the advanced setting. Gemcitabine-based chemotherapy is often recommended for newly diagnosed advanced or metastatic disease.

About TIBSOVO (ivosidenib)
TIBSOVO is indicated for the treatment of acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test in:

Adult patients with newly-diagnosed AML who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.
Adult patients with relapsed or refractory AML.
IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME

Patients treated with TIBSOVO have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.

WARNINGS AND PRECAUTIONS

Differentiation Syndrome: See Boxed WARNING. In the clinical trial, 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased. Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. Of the 34 patients with relapsed or refractory AML who experienced differentiation syndrome, 27 (79%) patients recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis.

If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt TIBSOVO until signs and symptoms are no longer severe.

QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. One patient developed ventricular fibrillation attributed to TIBSOVO. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, or electrolyte abnormalities, or in those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary.

Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.

Guillain-Barré Syndrome: Guillain-Barré syndrome occurred in <1% (2/258) of AML patients treated with TIBSOVO in the clinical study. Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome.

ADVERSE REACTIONS

The most common adverse reactions including laboratory abnormalities (≥20%) were hemoglobin decreased (60%), fatigue (43%), arthralgia (39%), calcium decreased (39%), sodium decreased (39%), leukocytosis (38%), diarrhea (37%), magnesium decreased (36%), edema (34%), nausea (33%), dyspnea (32%), uric acid increased (32%), potassium decreased (32%), alkaline phosphatase increased (30%), mucositis (28%), aspartate aminotransferase increased (27%), phosphatase decreased (25%), electrocardiogram QT prolonged (24%), rash (24%), creatinine increased (24%), cough (23%), decreased appetite (22%), myalgia (21%), constipation (20%), and pyrexia (20%).
In patients with newly diagnosed AML, the most frequently reported Grade ≥3 adverse reactions (≥5%) were fatigue (14%), differentiation syndrome (11%), electrocardiogram QT prolonged (11%), diarrhea (7%), nausea (7%), and leukocytosis (7%). Serious adverse reactions (≥5%) were differentiation syndrome (18%), electrocardiogram QT prolonged (7%), and fatigue (7%). There was one case of posterior reversible encephalopathy syndrome (PRES).
In patients with relapsed or refractory AML, the most frequently reported Grade ≥3 adverse reactions (≥5%) were differentiation syndrome (13%), electrocardiogram QT prolonged (10%), dyspnea (9%), leukocytosis (8%), and tumor lysis syndrome (6%). Serious adverse reactions (≥5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%). There was one case of progressive multifocal leukoencephalopathy (PML).
DRUG INTERACTIONS

Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation.
Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO.
Sensitive CYP3A4 Substrates: Avoid concomitant use with TIBSOVO.

QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation.

LACTATION

Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with TIBSOVO and for at least 1 month after the last dose.

On January 16, 2021 Servier reported that updated results from the exploratory phase II TASCO1 study evaluating LONSURF (trifluridine/tipiracil) + bevacizumab and capecitabine + bevacizumab (C-B) in a first-line setting for patients with unresectable metastatic colorectal cancer (mCRC) who are non-eligible for intensive therapy (Press release, Servier, JAN 16, 2021, View Source [SID1234574072]).1 The data were announced today during an oral presentation at the 2021 ASCO (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (ASCO-GI). Patients with mCRC who are not eligible for chemotherapy face a large unmet need, with fewer treatment options available to them and lower survival rates.

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Colorectal cancer (CRC) makes up 9.7% of total global cancer cases, with almost 1.4 million new cases of CRC each year.2 In Europe, CRC is the second most common cause of death due to cancer, and those with a metastatic disease have a 5-year survival rate of just 11%.3

"For patients with metastatic colorectal cancer, those non-eligible for standard combination therapy have few options left and we are continuously searching for new ways to give these patients more hope," said Professor Eric Van Cutsem, Leuven, Belgium "The data from TASCO1 are very encouraging and provide evidence that trifluridine/tipiracil + bevacizumab is a beneficial treatment combination for these patients."

In the exploratory phase II TASCO1 study, 153 patients were randomized and followed until September 1, 2020.1 The updated results showed that the median overall survival (OS) was 22.3 months with LONSURF + bevacizumab, whereas it was 17.6 months with C-B. This data translates into an improved median OS of 4.6 months with LONSURF + bevacizumab when compared with C-B (HR, 0.78; 95% CI, 0.55, 1.10). The survival probability at 18 months with LONSURF + bevacizumab was 0.62 (95% CI, 0.50, 0.72) and 0.47 (95% CI, 0.35, 0.57) with C-B.1 It should be noted that this was an exploratory, non-comparative study.

"We are very pleased with the updated results from the phase II TASCO1 study and we are continuing with our research into this promising combination in multiple mCRC settings. These data support all efforts that went into the confirmatory phase III SOLSTICE study. The results are expected in 2021," said Patrick Therasse, M.D., Ph. D., Head of Servier Late Stage and Life Cycle Management Oncology, "Patients with mCRC who are not eligible for intensive chemotherapy have limited options and further clinical trials for additional treatments are highly anticipated by the clinical and patient communities alike."

#ENDS#

About TASCO1

TASCO1 is an open-label, randomized, non-comparative Phase II study evaluating LONSURF + bevacizumab and capecitabine plus bevacizumab in patients with previously untreated metastatic colorectal cancer who are non-eligible for intensive therapy. From April 2016 to March 2017, 153 patients were randomized and followed until end-of-study on September 1, 2020. The primary endpoint was progression-free survival, and the key secondary endpoint was overall survival.

For more information on TASCO1, please visit www.ClinicalTrials.gov (View Source). The ClinicalTrials.gov Identifier is NCT02743221.

About SOLSTICE

SOLSTICE is an open-label, randomized, multicentre Phase III trial in 854 unresectable metastatic colorectal cancer patients who are not candidates for, or do not require, intensive therapy. Patients were randomized 1:1 to receive first-line LONSURF + bevacizumab versus capecitabine + bevacizumab. The primary objective is to demonstrate superior progression-free survival with LONSURF + bevacizumab over capecitabine + bevacizumab. The first patient was enrolled in March 2019. Results are expected in 2021.

For more information on SOLSTICE, please visit www.ClinicalTrials.gov (View Source). The ClinicalTrials.gov Identifier is NCT03869892.

About Metastatic Colorectal Cancer (mCRC)

Colorectal cancer is the third most common cancer worldwide with approximately 1.8 million new diagnoses in 2018. Each year there are over 880,000 deaths, making it the second biggest cancer killer worldwide (after lung cancer).3

For those with metastatic disease (where the cancer has spread from the primary site), the average 5-year survival is approximately 11%.4 Standard chemotherapy regimens for advanced mCRC include fluoropyrimidines, oxaliplatin, irinotecan or targeted treatments, such as those that target vascular endothelial growth factors (VEGF) or endothelial growth factor receptors (EGFR).

Over the last decade, clinical outcomes for patients with mCRC have improved considerably due to the advent of novel treatment agents, predictive biomarkers, and a more strategic approach to the delivery of systemic therapies. Currently, the median overall survival for patients with mCRC being treated both in phase III trials and in large observational series or registries is 30 months – more than double that of 20 years ago.5,6,7

About LONSURF8

LONSURF consists of a thymidine-based nucleoside analog, trifluridine, and the thymidine phosphorylase (TP) inhibitor, tipiracil, which increases trifluridine exposure by inhibiting its metabolism by TP. Trifluridine is incorporated into DNA, resulting in DNA dysfunction and inhibition of cell proliferation.

In the EU, LONSURF is indicated as monotherapy for the treatment of adult patients with metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, anti- VEGF agents, and anti-EGFR agents. LONSURF is also indicated as monotherapy for the treatment of adult patients with metastatic gastric cancer (mGC), including adenocarcinoma of the gastroesophageal junction (mGEJC), who have been previously treated with at least two prior systemic treatment regimens for advanced disease.

As of November 2020, LONSURF has been approved in 91 countries for the treatment of advanced mCRC and in 56 countries for the treatment of advanced mGC/mGEJC.

LONSURF was discovered and developed by Taiho Pharmaceutical. In June 2015, Taiho Pharmaceutical and Servier entered into an exclusive license agreement for the co-development and commercialization of LONSURF in Europe and other countries outside of the United States, Canada, Mexico, and Asia.

On January 16, 2021 GlaxoSmithKline (GSK) plc reported that updated data from GARNET cohort F evaluating dostarlimab in mismatch repair-deficient (dMMR) non-endometrial advanced solid cancers being presented today at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (ASCO GI) (Press release, GlaxoSmithKline, JAN 16, 2021, View Source [SID1234574071]). Study results (abstract #9) showed a 38.7% objective response rate (ORR) (N=106, 95% CI; 29.4–48.6) in patients with dMMR advanced solid cancers who received dostarlimab, an investigational anti-programmed death-1 (PD-1) monoclonal antibody. Additionally, after a median follow-up of 12.4 months, the median duration of response (DoR) had not yet been reached, and responses were durable across tumour types.

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Dr Axel Hoos, Senior Vice President and Head of Oncology R&D, GSK said: "We are committed to finding new approaches to improve outcomes for patients with difficult to treat cancers who have limited treatment options today. These new results from the ongoing GARNET study demonstrate the potential for dostarlimab to help a broad range of patients with solid tumours that have a deficiency in DNA mismatch repair."

Cohort F of the GARNET trial enrolled patients with dMMR non-endometrial solid cancers, the majority of which were gastrointestinal, with highest prevalence in colorectal, gastric and small intestinal cancers among other solid cancers of which the majority of patients (n=81) had been treated with 2 or more prior lines of systemic therapy. Patients received 500 mg of dostarlimab every three weeks for four doses and 1,000 mg of dostarlimab every six weeks thereafter for up to two years, or until disease progression or discontinuation. The primary objectives of the study were confirmed ORR and DoR, as assessed against RECIST v 1.1 by blinded independent central review.

Objective response rates were consistent across patients with colorectal (n=69) and non-colorectal cancers (n=37), including small intestine, gastric, pancreatic, ovarian, liver and other types of solid cancers. In patients with colorectal cancer, the ORR was 36.2% (95% CI; 25.0–48.7) and in patients with non-colorectal cancer the ORR was 43.2% (95% CI; 27.1–60.5). 8% of patients in cohort F achieved a complete response.

Dr Thierry André, Professor of Medical Oncology, Sorbonne University and Saint-Antoine Hospital in Paris said: "The patients who participated in GARNET cohort F had mismatch repair-deficient solid cancers with progressive disease on standard therapy and few available treatment options. This data shows that dostarlimab may become an important new treatment option that provides durable responses for these patients."

Dostarlimab was well tolerated with a low discontinuation rate (3.5%) due to treatment-related adverse events (TRAEs) among patients who received one or more doses of dostarlimab and were evaluable for safety (n=144). The most commonly reported TRAEs were asthenia (13%), diarrhoea (13%), pruritis (13%), arthralgia (9%), and fatigue (9%). Grade 3 or greater TRAEs occurred in 8% of patients. No deaths associated with dostarlimab were reported in the study.

A Biologics License Application and Marketing Authorisation Application for dostarlimab are currently under review by the US Food and Drug Administration and the European Medicines Agency, respectively, for the treatment of patients with recurrent or advanced dMMR/microsatellite instability high (MSI-H) endometrial cancer who have progressed on or after platinum-based chemotherapy. Dostarlimab is not currently approved for use anywhere in the world.

About GARNET

The ongoing phase I GARNET trial is evaluating dostarlimab as monotherapy in patients with advanced solid tumours. Part 2B of the study includes five expansion cohorts: dMMR/MSI-H endometrial cancer (cohort A1), mismatch repair proficient/microsatellite stable (MMRp/MSS) endometrial cancer (cohort A2), non-small cell lung cancer (cohort E), dMMR/MSI-H non-endometrial cancer or POLE-mut solid tumour basket cohort (cohort F), and platinum-resistant ovarian cancer without BRCA mutations (cohort G). GARNET is ongoing and enrolling patients.[i]

About Dostarlimab

Dostarlimab is a humanised PD-1 monoclonal antibody that binds with high affinity to the PD-1 receptor and blocks its interaction with the ligands PD-L1 and PD-L2.[ii] In addition to GARNET, dostarlimab is being investigated in other registrational enabling studies, including the phase 3 RUBY study for patients with recurrent or primary advanced endometrial cancer in combination with standard of care (SOC) chemotherapy[iii] and the phase 3 FIRST study of platinum-based therapy with dostarlimab and niraparib versus SOC platinum-based therapy as first-line treatment of stage III or IV non-mucinous epithelial ovarian cancer. Dostarlimab is also being evaluated in combination with other therapeutic agents for patients with advanced solid tumours or metastatic cancer.

Dostarlimab was discovered by AnaptysBio and TESARO, Inc. under a Collaboration and Exclusive License Agreement signed in March 2014. The collaboration has resulted in three monospecific antibody drugs that have progressed into the clinic. These are: dostarlimab (GSK4057190), a PD-1 antagonist; cobolimab, (GSK4069889), a TIM-3 antagonist; and GSK4074386, a LAG-3 antagonist. GSK is responsible for the ongoing research, development, commercialisation, and manufacture of each of these products under the Agreement.

GSK in Oncology

GSK is focused on maximising patient survival through transformational medicines. GSK’s pipeline is focused on immuno-oncology, cell therapy, cancer epigenetics and synthetic lethality. Our goal is to achieve a sustainable flow of new treatments based on a diversified portfolio of investigational medicines utilising modalities such as small molecules, antibodies, antibody drug conjugates and cells, either alone or in combination.

1stOncology covers the latest development on more than 560 bispecific antibodies (also including ADCs and adoptive cell therapies) and over 85 different combination therapy trials of these in oncology. These emerging therapies are showing exciting results through the many designs and strategies that are currently being developed to fight cancer. 1stOncology will help you to explore the engineering finesse employed in the development of these therapies, as well as the ongoing results from the clinic.

Moreover, 1stOncology provides unique insights to novel targeting strategies among the more than one thousand targets of biotherapeutics in cancer drug development. In 1stOncology you can easily explore the strategies for intracellular and membrane-bound targets, delivery and activation approaches, mitigating off-target effects etc.

Hence, 1stOncology is a valuable tool to evaluate developing biotherapeutics such as bispecific antibodies and more for new indications and targets. Sign up for your free 30 minutes consultation below.

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On January 15, 2021 The Janssen Pharmaceutical Companies of Johnson & Johnson reported the U.S. Food and Drug Administration (FDA) approval of DARZALEX FASPRO (daratumumab and hyaluronidase-fihj), a subcutaneous formulation of daratumumab, in combination with bortezomib, cyclophosphamide and dexamethasone (D-VCd) for the treatment of adult patients with newly diagnosed light chain (AL) amyloidosis[1] (Press release, Johnson & Johnson, JAN 15, 2021, View Source [SID1234634705]). DARZALEX FASPRO is the first and only FDA-approved treatment for patients with this blood cell disorder that is associated with the production of an abnormal protein, which leads to the deterioration of vital organs, most notably the heart, kidneys and liver.[2],[3] This indication is approved under accelerated approval and is based on the hematologic complete response rate (hemCR) measure. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. DARZALEX FASPRO is not indicated and is not recommended for the treatment of patients with light chain (AL) amyloidosis who have NYHA Class IIIB or Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials.

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"Today’s milestone is an important step for patients diagnosed with this rare disease," said Isabelle Lousada, Founder and CEO, Amyloidosis Research Consortium. "Sadly, most patients with AL amyloidosis are diagnosed more than one year after their initial symptoms present, at a time when they may already be experiencing organ deterioration or failure.[4] I believe this approval will increase awareness of and education around this life-threatening disease and offer new hope for people with AL amyloidosis and their caregivers."

The FDA approval is based on positive results from the Phase 3 ANDROMEDA study, which were recently presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2020 Annual Meeting. The study evaluated DARZALEX FASPRO in combination with VCd, compared with VCd alone, a common treatment regimen used in adult patients with newly diagnosed AL amyloidosis.[5] Patients receiving treatment with DARZALEX FASPRO experienced a hemCR more than triple that of patients receiving VCd alone (42 percent for D-VCd and 13 percent for VCd; P<0.0001).1

"There is an urgent need for awareness and treatment options to help in the fight against this serious blood cell disorder," said Raymond L. Comenzo, M.D., Director, John C. Davis Myeloma and Amyloid Program, Tufts Medical Center, and ANDROMEDA study investigator. "Achieving hematologic complete response is an important treatment goal, and today’s approval based on this clinical endpoint will provide doctors and the larger medical community with a new option to treat newly diagnosed patients."

Approximately 4,500 people in the U.S. develop this rare disease each year.[6] AL amyloidosis is a life-threatening blood cell disorder that occurs when blood plasma cells in the bone marrow produce amyloid deposits, which build up in vital organs and eventually cause organ deterioration.3 The disease can affect different organs in different people, but the most frequently affected organs are the heart, kidneys, liver, spleen, gastrointestinal tract and nervous system.2,3 About one-third of patients visit five or more doctors before receiving a diagnosis, and 72 percent are diagnosed more than one year after they first experience symptoms.3,4 Patients often have a poor prognosis due to the delay in diagnosis of AL amyloidosis, which frequently presents with non-specific symptoms that can mimic other, more common conditions.[7] As many as 30 percent of patients with AL amyloidosis die within the first year after diagnosis.[8]

"DARZALEX FASPRO, as the first and only FDA-approved treatment for newly diagnosed AL amyloidosis, marks a significant advance for a disease with high unmet medical need," said Jessica Vermeulen, M.D., Ph.D., Global Medical Head/Clinical Leader, Hematology & Oncology, Janssen Research & Development, LLC. "Today’s approval underscores our commitment to deliver innovative therapies for patients with plasma cell diseases."

The most common adverse reactions (≥20 percent) were upper respiratory tract infection, diarrhea, peripheral edema, constipation, fatigue, peripheral sensory neuropathy, nausea, insomnia, dyspnea and cough. Serious adverse reactions occurred in 43 percent of patients who received DARZALEX FASPRO in combination with VCd. Serious adverse reactions that occurred in at least 5 percent of patients in the D‑VCd arm were pneumonia (9 percent), cardiac failure (8 percent) and sepsis (5 percent). Fatal adverse reactions occurred in 11 percent of patients. Fatal adverse reactions that occurred in more than one patient included cardiac arrest (4 percent), sudden death (3 percent), cardiac failure (3 percent) and sepsis (1 percent).1

Among patients who received DARZALEX FASPRO in combination with VCd, 72 percent of patients had baseline cardiac involvement with Mayo Cardiac Stage I (3 percent), Stage II (46 percent) and Stage III (51 percent). Serious cardiac disorders occurred in 16 percent of patients (8 percent of patients with Mayo Cardiac Stage I and II and 28 percent of patients with Stage III). Serious cardiac disorders in more than 2 percent of patients included cardiac failure (8 percent), cardiac arrest (4 percent) and arrhythmia (4 percent). Fatal cardiac disorders occurred in 10 percent of patients (5 percent of patients with Mayo Cardiac Stage I and II and 19 percent of patients with Stage III) who received DARZALEX FASPRO in combination with VCd. Fatal cardiac disorders that occurred in more than one patient in the D-VCd arm included cardiac arrest (4 percent), sudden death (3 percent) and cardiac failure (3 percent).1

The FDA reviewed and approved this indication under the FDA Real-Time Oncology Review (RTOR) program, which allows data for certain applications to be reviewed before the applicant formally submits the complete application. The RTOR program aims to explore a more efficient and timely review process to help ensure treatments are available as soon as possible for patients. Selection into the RTOR program does not guarantee or influence approvability of the supplemental application. The submission was also reviewed under Project Orbis, an initiative of the FDA Oncology Center of Excellence, which provides a framework for concurrent submission and review of oncology medicine applications among international regulatory agencies.

About the ANDROMEDA Study1
ANDROMEDA (NCT03201965) is an ongoing Phase 3, randomized, open-label study investigating the safety and efficacy of DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) in combination with bortezomib, cyclophosphamide and dexamethasone (D-VCd), compared to VCd alone, for the treatment of adult patients with newly diagnosed light chain (AL) amyloidosis. The study includes 388 patients with newly diagnosed AL amyloidosis with measurable hematologic disease and one or more organs affected. The primary endpoint is overall complete hematologic response rate by intent-to-treat (ITT). Patients received DARZALEX FASPRO 1,800 mg/ 30,000 units administered subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity or a maximum of 2 years. Among patients who received D-VCd, 74 percent were exposed for 6 months or longer and 32 percent were exposed for greater than one year.

About DARZALEX FASPRO
In August 2012, Janssen Biotech, Inc. and Genmab A/S entered into a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialize daratumumab. DARZALEX FASPRO is the only CD38-directed antibody approved to be given subcutaneously to treat patients with multiple myeloma and now AL amyloidosis. DARZALEX FASPRO is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE drug delivery technology.

DARZALEX FASPRO is indicated for the treatment of adult patients with multiple myeloma:

in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant
in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy
in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant
in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy
as monotherapy, in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent
Access to DARZALEX FASPRO (daratumumab hyaluronidase-fihj)
Janssen offers comprehensive access and support information, resources and services to assist U.S. patients in gaining access to DARZALEX FASPRO through the Janssen CarePath Savings Program. Through the program, patients with commercial insurance plans will pay $5 per injection with a $20,000 maximum program benefit per calendar year. This program is not valid for patients using Medicare, Medicaid, or other government-funded programs to pay for their medications. Information on the enrollment process is available online at www.CarePathSavingsProgram.com/DARZALEX.

Full prescribing information will be available at www.DARZALEX.com.

DARZALEX FASPRO IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
DARZALEX FASPRO is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase or any of the components of the formulation.

WARNINGS AND PRECAUTIONS

Hypersensitivity and Other Administration Reactions1

Both systemic administration-related reactions, including severe or life-threatening reactions, and local injection-site reactions can occur with DARZALEX FASPRO.

Systemic Reactions

In a pooled safety population of 683 patients with multiple myeloma (N=490) or light chain (AL) amyloidosis (N=193) who received DARZALEX FASPRO as monotherapy or in combination, 10% of patients experienced a systemic administration-related reaction (Grade 2: 3.5%, Grade 3: 1%). Systemic administration-related reactions occurred in 9% of patients with the first injection, 0.4% with the second injection, and cumulatively 1% with subsequent injections. The median time to onset was 3.2 hours (range: 9 minutes to 3.5 days). Of the 117 systemic administration-related reactions that occurred in 66 patients, 100 (85%) occurred on the day of DARZALEX FASPRO administration. Delayed systemic administration-related reactions have occurred in 1% of the patients.

Severe reactions included hypoxia, dyspnea, hypertension and tachycardia. Other signs and symptoms of systemic administration-related reactions may include respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction, pyrexia, chest pain, pruritis, chills, vomiting, nausea, and hypotension.

Pre-medicate patients with histamine-1 receptor antagonist, acetaminophen and corticosteroids. Monitor patients for systemic administration-related reactions, especially following the first and second injections. For anaphylactic reaction or life-threatening (Grade 4) administration-related reactions, immediately and permanently discontinue DARZALEX FASPRO. Consider administering corticosteroids and other medications after the administration of DARZALEX FASPRO depending on dosing regimen and medical history to minimize the risk of delayed (defined as occurring the day after administration) systemic administration-related reactions.

Local Reactions

In this pooled safety population, injection-site reactions occurred in 9% of patients, including Grade 2 reactions in 0.7%. The most frequent (>1%) injection-site reaction was injection site erythema. These local reactions occurred a median of 5 minutes (range: 0 minutes to 4.7 days) after starting administration of DARZALEX FASPRO. Monitor for local reactions and consider symptomatic management.

Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis1

Serious or fatal cardiac adverse reactions occurred in patients with light chain (AL) amyloidosis who received DARZALEX FASPRO in combination with bortezomib, cyclophosphamide and dexamethasone. Serious cardiac disorders occurred in 16% and fatal cardiac disorders occurred in 10% of patients. Patients with NYHA Class IIIA or Mayo Stage IIIA disease may be at greater risk. Patients with NYHA Class IIIB or IV disease were not studied. Monitor patients with cardiac involvement of light chain (AL) amyloidosis more frequently for cardiac adverse reactions and administer supportive care as appropriate.

Neutropenia1Daratumumab may increase neutropenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX FASPRO until recovery of neutrophils. In lower body weight patients receiving DARZALEX FASPRO, higher rates of Grade 3-4 neutropenia were observed.

Thrombocytopenia1Daratumumab may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Consider withholding DARZALEX FASPRO until recovery of platelets.

Embryo-Fetal Toxicity1Based on the mechanism of action, DARZALEX FASPRO can cause fetal harm when administered to a pregnant woman. DARZALEX FASPRO may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX FASPRO and for 3 months after the last dose.

The combination of DARZALEX FASPRO with lenalidomide is contraindicated in pregnant women, because lenalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide prescribing information on use during pregnancy.

Interference with Serological Testing1Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab administration. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type are not impacted.

Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX FASPRO. Type and screen patients prior to starting DARZALEX FASPRO.

Interference with Determination of Complete Response1Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some DARZALEX FASPRO-treated patients with IgG kappa myeloma protein.

ADVERSE REACTIONS1
The most common adverse reaction (≥20%) with DARZALEX FASPRO monotherapy is: upper respiratory tract infection. The most common adverse reactions with combination therapy
(≥20% for any combination) include fatigue, nausea, diarrhea, dyspnea, insomnia, pyrexia,
cough, muscle spasms, back pain, vomiting, upper respiratory tract infection, peripheral sensory
neuropathy, constipation, and pneumonia.

The most common adverse reactions (≥20%) in patients with light chain (AL) amyloidosis who received DARZALEX FASPRO are upper respiratory tract infection, diarrhea, peripheral edema, constipation, fatigue, peripheral sensory neuropathy, nausea, insomnia, dyspnea, and cough.

The most common hematology laboratory abnormalities (≥40%) with DARZALEX FASPROTM are decreased leukocytes, decreased lymphocytes, decreased neutrophils, decreased platelets, and decreased hemoglobin.