On June 2, 2018 Celldex Therapeutics, Inc. (NASDAQ:CLDX) today presented two programs at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, Celldex Therapeutics, JUN 2, 2018, View Source [SID1234527065]). Data from the Phase 1/2 study of Celldex’s varlilumab, a CD27 targeting investigational immune-activating antibody, and Bristol-Myers Squibb’s Opdivo (nivolumab), an anti-PD1 immunotherapy, for patients with ovarian cancer and colorectal cancer, were presented in an oral session by Rachel E. Sanborn, M.D., Co-director of the Providence Thoracic Oncology Program and Phase 1 Clinical Trials Program, at the Earle A. Chiles Research Institute, Providence Cancer Institute, in Portland, Ore. In addition, an overview of the Phase 2 study of the anti-ErbB3 antibody CDX-3379 in combination with Erbitux in advanced head and neck squamous cell cancer was presented in a "clinical trials in progress" poster session.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"The data presented today continue to support that varlilumab holds considerable potential as an immune activator," said Dr. Sanborn. "This was particularly noteworthy in ovarian cancer where the combination with the anti-PD1 monoclonal antibody, Opdivo, turned "immune-cold" tumors "hot," which in turn correlated with improved clinical outcomes, including improved response rate and progression-free survival in these patients."

"Moving forward, we believe more work needs to be done to identify synergistic combinations and patient populations that have the best chance of responding to varlilumab treatment," said Tibor Keler, Ph.D., Executive Vice President and Chief Scientific Officer of Celldex Therapeutics. "We are continuing to explore these opportunities through inclusion in our ongoing Phase 1 study of CDX-1140, our CD40 agonist antibody, and several investigator-initiated studies."

"We also continue to enroll patients into our ongoing Phase 2 study of CDX-3379 in combination with Erbitux in patients with HPV negative, Erbitux-resistant, advanced head and neck squamous cell carcinoma. We look forward to completing enrollment to the first stage of this study in the third quarter of 2018 and are exploring other potential opportunities in indications where ErbB3 is believed to play a role," concluded Dr. Keler.

ASCO Highlights

Varlilumab

Varlilumab was featured in an oral presentation that highlighted the ongoing Phase 2 study of varlilumab in combination with Opdivo. The Phase 1/2 study includes cohorts in ovarian cancer, colorectal cancer, head and neck squamous cell carcinoma, renal cell carcinoma and glioblastoma, with data from ovarian cancer (n=66) and colorectal cancer (n=42) patients included in the presentation today. The majority of patients enrolled in the study had baseline tumors that were mostly "cold" (PD-L1 negative or low, and low tumor-infiltrating lymphocyte [TIL] levels) with low expectation of responding to checkpoint inhibition therapy. The combination was well tolerated at all varlilumab dose levels tested.

Results in Ovarian Cancer Experience: n=66, 8 patients in Phase 1; 58 patients in Phase 2; median of three prior lines of therapy; 91% had Stage IV disease; 66% with PD-L1 negative tumors; multiple varlilumab dosing regimens evaluated. Detailed information by dosing cohort is included in the presentation and is available on the Celldex website.

Overall response rate: 14% (n=9) across 64 response-evaluable patients (7 confirmed, 2 unconfirmed)
Response rate by PD-L1 status:
PD-L1 positive: 20% (n=4 of 20; 3 confirmed, 1 unconfirmed)
PD-L1 negative: 14% (n=5 of 37; 4 confirmed, 1 unconfirmed)
Disease control rate (DCR), defined as best response of stable disease or better for greater than or equal to three months, was 38% (n=24 of 64). As of the cut-off for analysis, five patients continued on treatment.
For patients with tumor samples available, most patients experienced increases in tumor expression of PD-L1 (n=14 of 23; 61%) and CD8+ TIL levels (n=14 of 24; 58%). These increases were associated with improved clinical outcome, including improved progression-free survival (PFS) and response rate.

Results in Colorectal Cancer Experience: n=42; 21 patients in Phase 1; 21 patients in Phase 2; median of four prior lines of therapy; 100% had Stage IV disease; 87% had PD-L1 negative tumors; one patient was MSI-high and 21 patients were MSI-low/mismatch repair (MMR) proficient; MSI status for the remaining 20 patients was unknown.

One patient with PD-L1 negative, MSI-high disease experienced a confirmed partial response in the Phase 2 study portion and continues on treatment. Of note, a patient with PD-L1 negative disease, initially considered MMR proficient as determined by standard screening laboratory analysis, achieved a near complete response in the Phase 1 portion of the study, which now continues at 35 months. As part of this study, an additional molecular analysis was conducted on this patient’s tumor. The tumor had a high mutational burden and mutations in genes regulating DNA repair, which together likely contributed to the response. DCR was 20% (8/41).
CDX-3379

CDX-3379 was featured in a "clinical trials in progress" poster presentation, available on the Celldex website, that highlighted the ongoing Phase 2 study of CDX-3379, a human monoclonal antibody designed to block the activity of ErbB3 (HER3), in combination with Erbitux in patients with human papillomavirus (HPV) negative, Erbitux-resistant, advanced head and neck squamous cell carcinoma. The proposed mechanism of action for CDX-3379 sets it apart from other drugs in development in this class due to its ability to block both ligand-independent and ligand-dependent ErbB3 signaling by binding to a unique epitope. It has a favorable pharmacologic profile, including a longer half-life and slower clearance relative to other drug candidates in this class. The multicenter, open-label, Simon two-stage design study is expected to enroll approximately 27 patients (Stage 1=13; Stage 2=14). The primary objective of the study is objective response rate. Secondary objectives include assessments of clinical benefit response, duration of response, progression-free survival and overall survival, and safety and pharmacokinetics associated with the combination. Four clinical trial sites are currently open to enrollment, and Celldex is targeting to complete enrollment to the first stage of the study by the end of the third quarter of 2018. The Company continues to explore potential other opportunities in additional indications where ErbB3 is believed to play a role.

On June 2, 2018 New Novartis data from two long-term Treatment-free Remission (TFR) studies in patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase (CP) reported that it will be presented during the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (Press release, Novartis, JUN 2, 2018, View Source [SID1234527100]). Results from the open-label Phase II trials, ENESTop and ENESTfreedom, show sustained TFR in patients treated with both front-line and second-line Tasigna (nilotinib) therapy. The 144-week trials evaluate the potential to maintain molecular response (MR) after stopping therapy in eligible adult patients with Ph+ CML-CP.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Treatment-free Remission is a new treatment goal in CML," said François-Xavier Mahon, Cancer Center of Bordeaux, Institut Bergonié and lead investigator of ENESTop. "Clinical studies like ENESTop and ENESTfreedom offer evidence that when a Ph+ CML-CP patient achieves a deep molecular response with Tasigna, along with other eligibility criteria, s/he can attempt TFR and have a nearly 50% chance of remaining treatment-free long-term. These results confirm an exciting opportunity for eligible patients – the opportunity to reduce time on drug for a chronic leukemia."

Data from ENESTop, presented today in an oral session (Abstract #7003) show that approximately half (48.4%; CI 95%, 39.4%-57.5%) of patients with Ph+ CML-CP who are eligible to stop second-line Tasigna therapy maintained disease remission over a prolonged period of time in the absence of treatment at 144 weeks of follow up, almost 3 years[1]. Patients in this trial took Tasigna following a switch from Glivec (imatinib)*. ENESTop data also show that of the patients who restarted Tasigna due to loss of major molecular response (MMR=BCR-ABL/ABL <=0.1% IS), during the study period, nearly all (97.1%) regained MMR and 95.8% regained MR4.5 (BCR-ABL1 IS =< 0.0032%)[1]. Study authors stress that frequent scheduled and compliant monitoring is necessary to assess for loss of response. Results of ENESTop at 144-weeks are consistent with previously reported data at both 96- and 48-weeks.

A second long-term clinical trial, ENESTfreedom, is also part of the ASCO (Free ASCO Whitepaper) Scientific Program this week. The authors will report on TFR results at 144 weeks in patients who started front-line CML therapy with Tasigna. Results from ENESTfreedom will be shared with ASCO (Free ASCO Whitepaper) attendees on Monday, June 4 (Abstract #7063). In this trial, researchers found that almost half (46.8%; CI 95%: 39.6%-54.2%) of Ph+ CML-CP patients eligible to stop Tasigna treatment remained in MMR following treatment discontinuation[2].

"Novartis continues to redefine treatment options for Ph+ CML patients," said Samit Hirawat, MD, Head of Novartis Oncology Global Drug Development. "The importance of achieving deep and sustained responses with Tasigna has been demonstrated in our TFR clinical program, which is the largest among all oncology companies. These long-term trials deliver on our commitment to the patient community to continue to look for more and better solutions for CML."

An update on the Phase III clinical trial design for Novartis’ investigational BCR-ABL1 inhibitor, asciminib, will also be presented as part of the ASCO (Free ASCO Whitepaper) Scientific Program (Abstract #TPS7081).

Novartis Commitment to CML
Novartis’ ongoing research in Ph+ CML has helped transform the disease from a fatal leukemia to a chronic condition in most patients. The company maintains an unwavering commitment to scientific innovation and access to care for patients worldwide. As an organization committed to patients, Novartis continues to reimagine CML by pursuing ambitious goals with courage, passion and commitment for the global CML community.

About ENESTop
ENESTop (Evaluating Nilotinib Efficacy and Safety Trial) is an open label Phase II study involving 163 Ph+ CML patients, conducted at 63 sites across 18 countries. The trial evaluated stopping treatment in 126 adults with Ph+ CML-CP receiving Tasigna for at least three years, after patients had achieved and sustained deep molecular response (DMR) for one year with Tasigna following Glivec. The study is ongoing with planned follow-up to evaluate the ability of patients to sustain remission for longer durations upon discontinuation of Tasigna.

Findings from ENESTop at 144-weeks found that 48.4% (CI 95%, 39.4%-57.5%) of 126 patients were able to remain in TFR at 144 weeks[1]. In the study, 58 patients with confirmed loss of MR4 (n=24; BCR-ABL1 IS =< 0.01%) or loss of MMR (n=34) restarted Tasigna by the cut-off date[1]. Of the 34 patients who restarted treatment with Tasigna due to loss of MMR, 91.2% regained MR4.5 (n=31; BCR-ABL1 IS =< 0.0032%)[1]. Of the 24 patients with loss of MR4 who restarted Tasigna, 95.8% (n=23) regained MR4.5,[1]. No new major safety findings were observed in ENESTop in patients treated with Tasigna beyond those in the known safety profile of Tasigna[1]. Among patients who remained in the TFR phase of the trial for more than 96 weeks (n=68), 10.3%, 51.5%, 19.1%, and 11.8% experienced any-grade musculoskeletal pain-related adverse events in the consolidation phase and first, second, and third 48-week phases of TFR, respectively[1].

About ENESTfreedom
ENESTfreedom (Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Following REsponsE in De nOvo CML-CP Patients) is an open label Phase II study involving 215 Ph+ CML patients in the chronic phase, conducted at 132 sites across 19 countries. ENESTfreedom evaluated stopping treatment in 190 adults with Ph+ CML-CP receiving Tasigna for at least three years, after the patients had achieved a response of MR4.5 with Tasigna and a sustained DMR for one year as a first-line treatment. The study is ongoing with planned follow-up to evaluate the ability of patients to sustain remission for longer durations following discontinuation of Tasigna.

Findings from ENESTfreedom at 144-weeks found that 46.8% of 190 eligible CML patients (CI 95%: 39.6%-54.2%) remained in MMR following discontinuation of Tasigna[2]. Of the 91 patients who restarted treatment with Tasigna due to loss of MMR by the cut-off date, 98.9% (n=90) and 92.3% (n=84) were able to regain MMR and MR4.5, respectively[2]. No new major safety findings were observed in ENESTfreedom in patients treated with Tasigna beyond those in the known safety profile of Tasigna[2]. Among patients who remained in TFR for more than 96 weeks (n=94), any-grade musculoskeletal pain-related AEs were 16.0%, 40.4%, 9.6% and 4.3% in the consolidation phase and first, second and third 48-week phases of TFR, respectively[2].

About Tasigna
Tasigna (nilotinib) is approved in more than 130 countries for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML) in chronic phase and with chronic and accelerated phase Ph+ CML resistant or intolerant to at least one prior therapy, including Glivec (imatinib). Tasigna is also approved for the treatment of pediatric patients with newly diagnosed Ph+ CML in the chronic phase and with resistance or intolerance to prior TKI therapy.

IMPORTANT SAFETY INFORMATION for TASIGNA (nilotinib) Capsules
Use with caution in patients with uncontrolled or significant cardiac disease and in patients who have or may develop prolongation of QTc. Low levels of potassium or magnesium must be corrected prior to Tasigna administration. Monitor closely for an effect on the QTc interval. Baseline ECG is recommended prior to initiating therapy and as clinically indicated. Cases of sudden death have been reported in clinical studies in patients with significant risk factors. Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors. Avoid food 2 hours before and 1 hour after taking dose.

Reactivation of hepatitis B can occur in patients who are chronic carriers of this virus after receiving TKI treatment.

Use with caution in patients with liver impairment, with a history of pancreatitis and with total gastrectomy. Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not use Tasigna. Tasigna may cause fetal harm in pregnant women. If pregnancy is planned during the treatment-free remission phase, the patient must be informed of a potential need to re-initiate treatment with Tasigna during pregnancy. Women should not breastfeed while taking Tasigna and for 2 weeks after the last dose.

Cases of cardiovascular events included ischemic heart disease-related events, peripheral arterial occlusive disease, and ischemic cerebrovascular events have been reported. Serious cases of hemorrhage from various sites including gastrointestinal were reported in patients receiving Tasigna. Grade 3 or 4 fluid retention including pleural effusion, pericardial effusion, ascites and pulmonary edema have been reported. Cases of tumor lysis syndrome have been reported in Tasigna-treated patients who were resistant or intolerant to prior CML therapy.

In pediatric patients the long-term effects of prolonged treatment with Tasigna is unknown.

Eligible patients who are confirmed to express the typical BCR-ABL transcripts, e13a2/b2a2 or e14a2/b3a2, can be considered for treatment discontinuation. Frequent monitoring of BCR-ABL transcript levels in patients eligible for treatment discontinuation must be performed with a quantitative diagnostic test validated to measure molecular response levels with a sensitivity of at least MR4.5 (BCR-ABL/ABL <=0.0032% IS). BCR-ABL transcript levels must be assessed prior to and during treatment discontinuation. Loss of major molecular response (MMR=BCR-ABL/ABL <=0.1% IS) or confirmed loss of MR4 (two consecutive measures separated by at least 4 weeks showing loss of MR4 (MR4=BCR-ABL/ABL <=0.01% IS) will trigger treatment re-initiation within 4 weeks of when loss of remission is known to have occurred. It is crucial to perform frequent monitoring of BCR-ABL transcript levels and complete blood count with differential in order to detect possible loss of remission. For patients who fail to achieve MMR after three months of treatment re-initiation, BCR-ABL kinase domain mutation testing should be performed.

Musculoskeletal pain, myalgia, pain in extremity, arthralgia, bone pain and spinal pain may occur upon discontinuing treatment with Tasigna within the framework of attempting treatment-free remission.

The most frequent Grade 3 or 4 adverse events are hematological (neutropenia, thrombocytopenia, anemia) which are generally reversible and usually managed by withholding Tasigna temporarily or dose reduction. Chemistry panels, including electrolytes, lipid profile, liver enzymes, and glucose should be checked prior to therapy and periodically. Tasigna can cause increases in serum lipase. The most frequent non-hematologic adverse events were rash, pruritus, nausea, fatigue, headache, alopecia, myalgia, constipation and diarrhea.

About asciminib
Asciminib (ABL001) is an investigational compound. Efficacy and safety have not been established. There is no guarantee this compound will become commercially available.

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "expect," "anticipate," "look forward," "believe," "committed," "investigational," "pipeline," "launch," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political and economic conditions; safety, quality or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

On June 1, 2018 Cambrex Corporation (NYSE: CBM), a leading manufacturer of small molecule innovator and generic Active Pharmaceutical Ingredients (APIs), reported that Steven Klosk, President and Chief Executive Officer, will present at the Jefferies 2018 Global Healthcare Conference on June 7, 2018 at 9:30 a.m. EDT in New York City (Press release, Cambrex, JUN 1, 2018, View Source [SID1234527035]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The live audio webcast and slide presentation can be accessed from the Cambrex website at www.cambrex.com in the Investors section under "Webcasts & Presentations", and a replay will be available for 90 days after the live event concludes

On June 1, 2018 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that long-term phase 1 safety and efficacy data for DS-8201, an investigational HER2-targeting antibody drug conjugate (ADC), in 241 heavily pretreated patients with HER2-expressing breast, gastric and other solid cancers who received recommended expansion doses of 5.4 mg/kg or 6.4 mg/kg, will be presented today during an Oral Abstract Session at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL (Abstract 2501; 2:57 – 3:09 PM CDT) (Press release, Daiichi Sankyo, JUN 1, 2018, View Source [SID1234527018]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Updated preliminary results in a subgroup analysis of 34 patients with heavily pretreated HER2-low-expressing metastatic breast cancer (defined as IHC 2+/ISH- or IHC 1+/ISH- tumors) showed that DS-8201 demonstrated a confirmed overall response rate of 50.0 percent (17/34 patients) and a disease control rate of 85.3 percent (29/34 patients). Preliminary estimates of median duration of response have reached 11 months (95 percent CI: NA) and median progression-free survival has reached 12.9 months (95 percent CI: NA). A total of 14 patients (41.2 percent) were continuing to receive treatment at the time of data cutoff, which was April 18, 2018.

"HER2-targeted treatments historically have not been effective in treating metastatic breast cancer with low levels of HER2 expression," said Hiroji Iwata, MD, PhD, Vice Director and Chief of Breast Oncology at Aichi Cancer Center Hospital, Nagoya, Japan. "While these results of DS-8201 in the HER2-low-expressing subgroup need to be further confirmed in a larger clinical setting, the preliminary data are intriguing in that we may need to begin rethinking how we approach HER2 as a cell surface target for precision medicine treatment in metastatic breast cancer."

In an updated preliminary subgroup analysis in 99 efficacy evaluable patients with HER2-positive metastatic breast cancer pretreated with ado-trastuzumab emtansine (T-DM1) (as well as trastuzumab and pertuzumab in the majority of cases), DS-8201 demonstrated a confirmed overall response rate of 54.5 percent (54/99 patients) and a disease control rate of 93.9 percent (93/99 patients). Median duration of response and median progression-free survival have not yet been reached. Out of 111 patients with HER2-positive metastatic breast cancer who received at least one dose of DS-8201, 65 (55.1 percent) were continuing to receive treatment at the time of data cut off.

Updated overall safety data across all subgroups of the phase 1 study were reported. The most common adverse events (>30 percent, any Grade), included nausea (68.9 percent), decreased appetite (55.6 percent), alopecia (36.1 percent), vomiting (34.9 percent) and anemia (32.0 percent). Grade 3 adverse events occurring in ≥10 percent of patients included decreased neutrophil count (15.4 percent), anemia (14.9 percent), decreased white blood cell count (12.4 percent) and decreased platelet count (10.4 percent). Twenty-three patients (9.5 percent) discontinued treatment due to adverse events, which included ten (10) Grade 5 adverse events: pneumonitis (4), disease progression (2), interstitial lung disease (ILD) (1), ileus (1), pneumonia aspiration (1) and pneumonia (1). All reported or suspected cases of ILD or pneumonitis currently are under review by an independent ILD adjudication committee.

"These updated results further support our broad and comprehensive development program underway exploring the potential of DS-8201 in HER2-low-expressing breast cancer, which represents about half of all breast cancers, as well as in HER2-positive metastatic breast cancer, where unmet treatment needs remain," said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. "Our pivotal phase 2 trial in HER2-positive metastatic breast cancer is underway, and we are planning phase 3 trials in HER2-low-expressing and HER2-positive metastatic breast cancer in order to determine whether the smart delivery of chemotherapy with DS-8201 may be an effective treatment option against breast tumors that express varying levels of HER2 as a cell surface antigen. A similar biological paradigm is being tested in our other ongoing phase 2 studies of DS-8201 in gastric and colorectal cancer."

HER2-Expressing Gastric Cancer and Other Solid Cancer Subgroup Analyses

Updated preliminary results of two additional subgroup analyses were reported in addition to the two breast cancer subgroups. In the subgroup of 44 patients with HER2-expressing (defined as IHC 3+ or IHC 2+/

ISH-) gastric cancer or gastroesophageal junction adenocarcinoma previously treated with trastuzumab and chemotherapy, DS-8201 demonstrated a confirmed overall response rate of 43.2 percent (19/44 patients) and a disease control rate of 79.5 percent (35/44 patients). Preliminary estimates of median duration of response has reached 7.0 months (95 percent CI: NA) and median progression-free survival has reached 5.6 months (95 percent CI: 3.0, 8.3).

In an updated preliminaryanalysis in 31 evaluable patients with other HER2-expressing solid tumors such as colorectal and non-small cell lung cancer, DS-8201 demonstrated a confirmed overall response rate of 38.7 percent (12/31 patients) and a disease control rate of 83.9 percent (26/31 patients). Preliminary estimates of median duration of response has reached 12.9 months (95 percent CI: 2.8, 12.9) and median progression-free survival has reached 12.1 months (95% CI: 2.7, 14.1).

Unmet Need in HER2-Expressing Breast and Gastric Cancer

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

Several unmet needs remain today in HER2-expressing metastatic breast cancer. Many HER2-positive tumors advance to the point where no currently approved HER2-targeting treatment continues to control the disease, and there is no current standard of care for HER2-positive tumors after treatment with trastuzumab, pertuzumab and T-DM1.4 Additionally, there are no anti-HER2 therapies indicated for HER2 low-expressing tumors (IHC 2+/FISH- or IHC 1+).

HER2-expressing gastric cancer also is an area of unmet medical need as advances in the treatment of the disease have been limited, largely due to its genetic complexity and heterogeneity.5 Currently, there are no approved HER2-targeting therapy options for patients with HER2-positive advanced gastric cancer after treatment with trastuzumab.

About the DS-8201 Phase 1 Study

The open-label, two-part phase 1 study is currently evaluating DS-8201 in patients with advanced/unresectable or metastatic solid tumors that are refractory or intolerant to standard treatment, or for whom no standard treatment is available. The primary objective of the dose escalation phase of the study was to assess the safety and tolerability of DS-8201 and determine the maximum tolerated dose. Data from this part of the study were published in the Lancet Oncology.6

In the dose expansion part of the phase 1 study, DS-8201 is given to patients with HER2-positive advanced or metastatic breast cancer and gastric cancer, HER2-low-expressing breast cancer and other HER2-expressing or mutant solid tumors. Patient enrollment in the two breast cancer cohorts and the HER2-expressing solid tumors cohort is ongoing in the U.S. and Japan. For more information about the study, please visit ClinicalTrials.gov.

About DS-8201

DS-8201 is the lead product in the investigational ADC Franchise of the Daiichi Sankyo Cancer Enterprise. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Designed using Daiichi Sankyo’s proprietary ADC technology, DS-8201 is a smart chemotherapy comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. It is designed to target and deliver chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.

DS-8201 is currently in pivotal phase 2 clinical development for HER2-positive unresectable and/or metastatic breast cancer resistant or refractory to T-DM1 (DESTINY-Breast01) in North America, Europe and Asia; pivotal phase 2 development for HER2-positive advanced gastric cancer resistant or refractory to trastuzumab (DESTINY-Gastric01) in Japan and South Korea; phase 2 development for HER2-expressing advanced colorectal cancer in North America, Europe and Japan; phase 2 development for unresectable and/or metastatic non-squamous HER2-overexpressing or HER2-mutated non-small cell lung cancer (NSCLC) in North America, Europe and Japan; and phase 1 development for other HER2-expressing advanced/unresectable or metastatic solid tumors in the U.S. and Japan.

DS-8201 has been granted Breakthrough Therapy designation for the treatment of patients with HER2-positive, locally advanced or metastatic breast cancer who have been treated with trastuzumab and pertuzumab and have disease progression after ado-trastuzumab emtansine (T-DM1), and Fast Track designation for the treatment of HER2-positive unresectable and/or metastatic breast cancer in patients who have progressed after prior treatment with HER2-targeted therapies including T-DM1 by the U.S. Food and Drug Administration (FDA). DS-8201 has also been granted SAKIGAKE Designation by the Japan Ministry of Health, Labour and Welfare (MHLW) for the treatment of HER2-positive advanced gastric or gastroesophageal junction cancer.

DS-8201 is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.

On June 1, 2018 Celgene Corporation (NASDAQ:CELG) reported results from the OPTIMISMM study, a phase III, randomized, open-label, international clinical study of the investigational combination regimen of POMALYST (pomalidomide), bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (RRMM) who had received at least one prior treatment including lenalidomide (Press release, Celgene, JUN 1, 2018, View Source [SID1234527036]). The results were presented at the 54th Annual American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Scientific Sessions (ASCO) (Free ASCO Whitepaper) in Chicago, Illinois on June 1-5, 2018.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

OPTIMISMM evaluated the efficacy and safety of POMALYST/IMNOVID (pomalidomide) plus bortezomib and low-dose dexamethasone (PVd) versus bortezomib and low-dose dexamethasone (Vd) in patients with early RRMM (1-3 prior lines of therapy). It is the only phase III trial to report results with a triplet combination in patients who have all received prior lenalidomide therapy. With lenalidomide becoming a standard of care, this represents a patient population for which there is a growing unmet medical need.

An analysis of the results found that the treatment with PVd resulted in significantly improved progression-free survival (PFS) and an earlier, deeper, more durable response in these patients compared to Vd treatment. The study, which included a high percentage of patients refractory to lenalidomide (71% in the PVd arm, 69% in the Vd arm), met its primary endpoint of PFS. Those receiving PVd achieved a statistically significant longer PFS than those in the Vd treatment arm (11.20 months vs. 7.10 months, respectively [P= < .0001, HR 0.61; 95% CI: (0.49-0.77)]), reducing the risk of disease progression or death by 39% in the PVd arm. The PFS benefit was observed in the following subgroups of patients: LEN-refractory, LEN-nonrefractory, prior PI exposure or high-risk cytogenetics. Overall response rate (ORR), one of the study’s secondary endpoints, was also significantly higher in the PVd treatment arm, compared to those receiving Vd (82.2% vs. 50.0%, p < 0.001). Additionally, time to treatment response was longer in the PVd arm (0.9 months PVd vs. 1.4 months Vd), complete response was higher in the PVd arm (15.7% PVd vs. 4.0% Vd) and those receiving PVd experienced a longer duration of response than those in the Vd arm (13.7 months PVd vs. 10.9 months Vd.)

In an exploratory sub-group analysis, patients who had received one prior line of therapy reported longer PFS (20.73 months in PVd arm (n=40) vs. 11.63 months in Vd arm (n=41)) and ORR (90.1% in PVd arm vs. 54.8% in Vd arm) with a 46% reduction in the risk of disease progression or death in the PVd treatment arm compared with Vd. Other secondary endpoints included overall survival and safety.

"In the early relapse setting, there remains a need for a deeper understanding of potential treatment options, and in particular for patients who have received prior lenalidomide-based therapy. These are the first phase III clinical findings to report a significant and clinically meaningful progression-free survival improvement in patients who have previously received lenalidomide, a majority of whom are lenalidomide refractory," said Paul Richardson, MD, Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute.

The most common Grade 3/4 treatment-emergent adverse events (TEAE) were neutropenia (PVd: 42% vs. Vd: 9%), infections (PVd: 31% vs. Vd: 18%) and thrombocytopenia (PVd: 27% vs. Vd: 29%.) Rates of grade 3 or 4 deep vein thrombosis in the PVd vs. Vd arms were 0.7% vs. 0.4% and rates of grade 3 or 4 pulmonary embolism in PVd vs. Vd were 4.0% vs. 0.4%. No events were fatal. SPMs occurred in 3.2% (2.7 per 100 person years) of patients treated with PVd and 1.5% (1.2 per 100 person years) of patients treated with Vd. The most common reason for treatment discontinuation was progressive disease.

"The results of the OPTIMISMM trial continue to bolster the growing body of research into combination regimens based on the foundation of our IMiD therapies," said Nadim Ahmed, President of Hematology and Oncology for Celgene. "We are excited by the findings, as they illustrate the potential for a pomalidomide-based triplet regimen to be used earlier in the treatment course. The study also included patients who received PVd immediately following progression after lenalidomide treatment, a growing and clinically relevant patient population for which no phase III data were available until now."

Pomalyst plus dexamethasone in combination with bortezomib is not approved in any country for any use.

ABOUT OPTIMISMM

OPTIMISMM is the first phase III trial to compare the efficacy and safety of PVd vs. Vd as an early line of therapy in patients with RRMM (with 1-3 prior lines of therapy) and prior lenalidomide (LEN) exposure, including LEN-refractory patients. The study was a multi-center, international, open-label, randomized phase III clinical trial to compare the efficacy and safety of a POMALYST (lenalidomide), bortezomib and low-dose dexamethasone (PVd) treatment regimen to a bortezomib and low-dose dexamethasone (Vd) treatment regimen in patients with relapsed or refractory multiple myeloma.

This global study evaluated 559 patients with relapsed or refractory multiple myeloma who had received up to three prior lines of therapy, including two or more cycles of lenalidomide treatment, who had an ECOG score of PS ≤ 2. Prior treatment with bortezomib was allowed, except for patients whose disease progressed while on a regimen containing bortezomib 1.3 mg/m2 twice weekly dosing. Patients were stratified based on age (≤ 75 years old vs > 75 years old), number of prior antimyeloma regimens (1 vs. > 1), and β2-microglobulin levels ( < 3.5 mg/L vs ≥ 3.5 to ≤ 5.5 mg/L vs > 5.5 mg/L) at screening. The median age of the patients was 67 years in the PVd group and 68 years in the Vd group.

Patients were randomized 1:1 to receive PVd or Vd. In 21-day cycles, patients received POMALYST 4 mg/d on days 1-14 (PVd arm only); bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of cycles 1-8 and on days 1 and 8 of cycles 9 and beyond; and dexamethasone 20 mg/d (10 mg if aged > 75 years) on the days of and after receiving bortezomib treatment.

About POMALYST

Indication

POMALYST (pomalidomide) is a thalidomide analogue indicated, in combination with dexamethasone, for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Important Safety Information

WARNING: EMBRYO-FETAL TOXICITY and VENOUS AND ARTERIAL THROMBOEMBOLISM

Embryo-Fetal Toxicity
POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment.
Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment.
POMALYST is only available through a restricted distribution program called POMALYST REMS.

Venous and Arterial Thromboembolism
Deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke occur in patients with multiple myeloma treated with POMALYST. Prophylactic antithrombotic measures were employed in clinical trials. Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient’s underlying risk factors.

CONTRAINDICATIONS

Pregnancy: POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If POMALYST is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus.
WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity & Females of Reproductive Potential: See Boxed WARNINGS
Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 4 weeks after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm.
Blood Donation: Patients must not donate blood during treatment with POMALYST and for 4 weeks following discontinuation of POMALYST therapy because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST.
POMALYST REMS Program: See Boxed WARNINGS
Prescribers and pharmacies must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements; pharmacies must only dispense to patients who are authorized to receive POMALYST. Patients must sign a Patient-Physician Agreement Form and comply with REMS requirements; female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements.
Further information about the POMALYST REMS program is available at www.CelgeneRiskManagement.com or by telephone at 1-888-423-5436.
Venous and Arterial Thromboembolism: See Boxed WARNINGS. Patients with known risk factors, including prior thrombosis, may be at greater risk, and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient’s underlying risk factors.
Increased Mortality with Pembrolizumab: In clinical trials in patients with multiple myeloma, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.
Hematologic Toxicity: Neutropenia (46%) was the most frequently reported Grade 3/4 adverse reaction in patients taking POMALYST in clinical trials, followed by anemia and thrombocytopenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification.
Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with POMALYST. Elevated levels of alanine aminotransferase and bilirubin have also been observed in patients treated with POMALYST. Monitor liver function tests monthly. Stop POMALYST upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.
Severe Cutaneous Reactions Including Hypersensitivity Reactions: Angioedema and severe cutaneous reactions including Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. Discontinue POMALYST for angioedema, skin exfoliation, bullae, or any other severe cutaneous reactions such as SJS, TEN or DRESS, and do not resume therapy.
Dizziness and Confusional State: In patients taking POMALYST in clinical trials, 14% experienced dizziness (1% Grade 3 or 4) and 7% a confusional state (3% Grade 3 or 4). Instruct patients to avoid situations where dizziness or confusional state may be a problem and not to take other medications that may cause dizziness or confusional state without adequate medical advice.
Neuropathy: In patients taking POMALYST in clinical trials, 18% experienced neuropathy (2% Grade 3 in one trial) and 12% peripheral neuropathy.
Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.
Tumor Lysis Syndrome (TLS): TLS may occur in patients treated with POMALYST. Patients at risk are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
ADVERSE REACTIONS

The most common adverse reactions for POMALYST (≥30%) included fatigue and asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper-respiratory tract infections, back pain, and pyrexia.

In the phase III trial, nearly all patients treated with POMALYST + low-dose dex experienced at least one adverse reaction (99%). Adverse reactions (≥15% in the POMALYST + low-dose dex arm and ≥2% higher than control) included neutropenia (51.3%), fatigue and asthenia (46.7%), upper respiratory tract infection (31%), thrombocytopenia (29.7%), pyrexia (26.7%), dyspnea (25.3%), diarrhea (22%), constipation (21.7%), back pain (19.7%), cough (20%), pneumonia (19.3%), bone pain (18%), edema peripheral (17.3%), peripheral neuropathy (17.3%), muscle spasms (15.3%), and nausea (15%). Grade 3 or 4 adverse reactions (≥15% in the POMALYST + low-dose dex arm and ≥1% higher than control) included neutropenia (48.3%), thrombocytopenia (22%), and pneumonia (15.7%).

DRUG INTERACTIONS

Avoid concomitant use of POMALYST with strong inhibitors of CYP1A2. Consider alternative treatments. If a strong CYP1A2 inhibitor must be used, reduce POMALYST dose by 50%.

USE IN SPECIFIC POPULATIONS

Pregnancy: See Boxed WARNINGS. If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. There is a POMALYST pregnancy exposure registry that monitors pregnancy outcomes in females exposed to POMALYST during pregnancy as well as female partners of male patients who are exposed to POMALYST. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.
Lactation: There is no information regarding the presence of pomalidomide in human milk, the effects of POMALYST on the breastfed child, or the effects of POMALYST on milk production. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in a breastfed child from POMALYST, advise women not to breastfeed during treatment with POMALYST.
Pediatric Use: Safety and effectiveness have not been established in pediatric patients.
Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients > 65 years of age were more likely than patients ≤65 years of age to experience pneumonia.
Renal Impairment: Reduce POMALYST dose by 25% in patients with severe renal impairment requiring dialysis. Take dose of POMALYST following hemodialysis on hemodialysis days.
Hepatic Impairment: Reduce POMALYST dose by 25% in patients with mild to moderate hepatic impairment and 50% in patients with severe hepatic impairment.
Smoking Tobacco: Advise patients that smoking may reduce the efficacy of POMALYST. Cigarette smoking reduces the AUC of pomalidomide by 32% by CYP1A2 induction.
Please see full Prescribing Information, including Boxed WARNINGS.

About Celgene’s Immunomodulatory Drugs

Immunomodulatory Drugs (IMiDs) are Celgene’s proprietary small molecule, orally available compounds for the treatment of some blood cancers. IMiD agents are hypothesized to have multiple mechanisms of action. They have been found to increase activation and proliferation of T cells, and proliferation of the IL-2 protein and activity of CD8+ effector T cells. IMiD agents have also been found to affect the stimulation and expression of natural killer (NK) cells, working within the environment of the cell to stimulate the immune system to attack the cancer cells, as well as attack the cancer cells directly. In addition to immunomodulatory properties, IMiD agents are hypothesized to have tumoricidal and antiangiogenic activity. Celgene’s portfolio of IMiD agents have become a foundation of multiple myeloma research, with a growing number of studies exploring these compounds as combination partners across a range of settings of the disease.