On June 19, 2015 Eli Lilly reported that The Lancet Oncology has published results of the Phase III REACH trial that evaluated CYRAMZA (ramucirumab) as a second-line treatment for people with hepatocellular carcinoma (HCC), also known as liver cancer (Press release, Eli Lilly, JUN 19, 2015, View Source [SID:1234505463]). Schedule your 30 min Free 1stOncology Demo! While the REACH trial’s primary endpoint of overall survival favored the CYRAMZA arm, it was not statistically significant. However, encouraging single-agent CYRAMZA activity was observed, with meaningful improvements in key secondary endpoints as well as within certain patient subgroups.
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The global, randomized, double-blind REACH trial compared ramucirumab plus best supportive care to placebo plus best supportive care as a second-line treatment in patients with HCC after being treated with sorafenib in the first-line setting. Median overall survival (OS) was 9.2 months on the ramucirumab arm compared to 7.6 months on the placebo arm (HR 0.866; 95% CI: 0.717-1.046; p=0.1391). While the median OS was not statistically significant, a prespecified subgroup of patients with an elevated baseline of alpha-fetoprotein (AFP) ≥400 ng/mL showed a greater survival improvement with ramucirumab treatment. Median OS in this subgroup of patients was 7.8 months in the ramucirumab arm compared to 4.2 months in the placebo arm (HR 0.674; 95% CI 0.508-0.895; p=0.0059).
"Advanced liver cancer carries a poor prognosis with limited treatment options. Several phase III studies to date have not been able to demonstrate improved survival in the second-line setting following sorafenib failure," said Andrew X. Zhu, M.D., director of Liver Cancer Research at Massachusetts General Hospital Cancer Center and principal investigator of the REACH trial. "Further analyses from the REACH study have identified AFP as a potential marker for selecting patients with advanced hepatocellular carcinoma who may benefit from ramucirumab treatment."
The REACH study analyses presented at the Gastrointestinal Cancers Symposium earlier this year concluded that a greater reduction in the risk of death in patients with progressively higher baseline AFP values warrants further investigation. Based on these findings, Lilly will soon begin enrollment in REACH-2, a new Phase III trial to evaluate the benefit of ramucirumab treatment in advanced liver cancer patients with an elevated baseline AFP (ClinicalTrials.gov identifier: NCT02435433).
"Globally, a high unmet need exists in second-line hepatocellular carcinoma, and currently there are no therapies approved in the U.S., EU or Japan to treat patients in this setting," said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology. "We are encouraged by the efficacy seen overall in the REACH study, especially in specific subpopulations, and we hope to confirm those results with the new CYRAMZA Phase III trial."
The safety data in the REACH study were consistent with results from previous single-agent ramucirumab studies and the safety information included in the U.S. Prescribing Information for ramucirumab. The most common (≥5% incidence) clinical grade ≥3 adverse events occurring more frequently in patients on the ramucirumab arm compared to the control arm were hypertension (12% vs. 4%), asthenia (fatigue) (5% vs. 2%), and malignant neoplasm progression (6% vs. 4%). The safety profile of ramucirumab in patients with elevated baseline AFP > 400 ng/mL was consistent with that observed in the overall safety population.
Ramucirumab has been granted Orphan Drug Designation for treatment of hepatocellular carcinoma in the U.S. and EU. Orphan drug status is given – in the U.S. by the FDA’s Office of Orphan Products Development (OOPD) and in the EU by the European Commission – to medicines that have demonstrated promise for the treatment of rare diseases.
About the REACH Trial
REACH is a global, randomized, double-blind Phase III study of ramucirumab plus best supportive care compared to placebo plus best supportive care as a second-line treatment in patients with hepatocellular carcinoma who have been previously treated with sorafenib in the first-line setting. Initiated in 2010, the study enrolled 565 patients across 27 countries; as defined in the trial protocol, the primary analyses are focused on patients with a Child-Pugh score of < 7 (Child-Pugh Class A only). The primary endpoint (also referred to as the major efficacy outcome measure) of the REACH trial was overall survival and key secondary endpoints (also referred to as the supportive efficacy outcome measures) include: progression-free survival; overall response rate; time to progression; and safety.
TFS to acquire US pharmaceutical partners to capture downstream revenues from product sales
On June 18, 2016 TFS Corporation Limited ("TFS", "Company", ASX: TFC), the world’s largest owner and manager of commercial Indian sandalwood plantations, reported it has entered into share purchase agreements to acquire US-based pharmaceutical partners ViroXis Corporation ("ViroXis") and Santalis Pharmaceuticals ("Santalis", together "the Acquisitions") (Press release, TFS, JUN 18, 2015, View Source [SID1234517229]).
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TFS Chief Executive Officer Frank Wilson said, "The Acquisitions will extend TFS’s soil to oil strategy by expanding the Company’s vertically integrated business model. TFS will benefit from direct ownership of the pharmaceutical companies which exclusively develop and sell products containing TFS-grown and processed Indian sandalwood oil to the high-value pharmaceutical sector."
"While TFS previously benefited from pharmaceutical product development through oil sales, with these Acquisitions we will also capture all of the future product earnings, including product royalties and licence fees, generated by ViroXis and Santalis, thereby significantly enhancing our own earnings," Mr Wilson said.
"We have been directly involved over the last five years in successfully building the first mover advantage established by ViroXis and Santalis. These transactions will allow us to work even closer with the product development teams and accelerate the establishment of a range of sandalwood-based dermatological products. With increased control of the formulation we also expect to generate additional revenue from our oil sales."
Santalis has already licensed a range of dermatological products that contain TFS-grown Indian sandalwood oil to Nestle-owned Galderma, a global dermatological company. The acne product Benzac Acne Solutions, which is the first to have been commercialised by Santalis, successfully debuted on US shelves earlier this year and is already available in around 25,000 stores through major US retail chains. Following these Acquisitions, each sale of the Benzac Acne Solutions range will directly generate royalty revenues for TFS in addition to existing oil sales.
"Over time we expect a series of products containing TFS’s Indian sandalwood oil to be distributed by pharmaceutical companies to worldwide markets," Mr Wilson said.
Transaction summary
Subject to certain conditions to completion, TFS will pay minimum consideration of US$23.4 million for the issued shares in ViroXis and Santalis it does not already own (100% and 50% respectively), payable by US$1.5 million in cash and US$21.9 million in TFS shares.
The scrip component of the minimum consideration will involve the issuance of around 15.3 million TFS shares at a price of AU$1.85 per share. TFS anticipates issuing around 12.6 million shares in July 2015 and the remaining 2.7 million shares in the period between 10 September 2015 and 31 July 2016. Around 9.1 million of the 12.6 million shares expected to be issued in July 2015 will be subject to lock up provisions (which range between six and thirty months).
The shares issued pursuant to the Acquisitions will be made utilising the Company’s available placement capacity under ASX listing rule 7.1.
The total maximum consideration payable by TFS consists of fixed minimum payments of US$23.4 million and contingent payments over time of up to US$221.5 million. The contingent consideration only becomes payable when the acquired companies achieve significant operating and commercial milestones (from the launch or approval of new pharmaceutical products containing Indian sandalwood oil) and significant operating cash inflows.
The structure of the Acquisitions is designed to ensure that the founders of ViroXis and Santalis, who will continue to operate the businesses, are closely aligned to the ongoing and long-term success of the companies and their products. Both founders will sign new employment contracts on completion.
"Total consideration is directly linked to ViroXis and Santalis successfully developing and selling additional pharmaceutical products to the healthcare market, as has been achieved with the Benzac range. We have structured the transaction with minimal upfront cash outlay, flexibility with cash and scrip payments, incentives to generate additional revenue and profit, and lock-up provisions, to provide maximum value to TFS shareholders," Mr Wilson said.
Since 2010, ViroXis and Santalis have invested over US$17 million in the development and commercialisation of pharmaceutical products containing Indian sandalwood oil.
The Acquisitions do not impact TFS’s previous guidance for FY15 of NPAT of at least $90 million. After absorbing transaction costs, TFS continues to expect cash EBITDA to increase year-on-year by approximately 10%. On a stand-alone basis, and excluding any benefit from higher Indian sandalwood oil sales, the Acquisitions are expected to be EPS dilutive in FY16.
Further details on the key terms of the transactions are provided in Appendix One.
Background on ViroXis and Santalis
ViroXis is a bio-pharmaceutical company focused on developing and commercialising innovative, proprietary, botanical pharmaceuticals derived from sandalwood oil, exclusively for viral conditions. ViroXis was cofounded by its Chief Executive Officer Ian Clements, who has more than 20 years of experience in the pharmaceutical and biotechnology industries.
Santalis is focused on developing and commercialising sandalwood products targeting all possible conditions outside of viral skin diseases (dermatological conditions such as acne, eczema, psoriasis, redness and sensitive skin). Santalis was founded in 2010 and is a 50-50 joint venture with TFS. Santalis is led by Chief Executive Officer Paul Castella, who co-founded Santalis with Mr Clements and was also a co-founder of ViroXis. Dr Castella has a Ph.D. in molecular biology and has founded and managed numerous biotechnology companies with a successful record of product development, regulatory approval and commercialisation.
ViroXis CEO Ian Clements said: "I am delighted we have reached this agreement with TFS, with their ongoing support enabling us to extend and accelerate development of products using Indian sandalwood oil to treat viral skin infections, such as common skin warts and Molluscum contagiosum."
Santalis CEO Paul Castella added: "We have achieved great success to date through our landmark agreements with Galderma and we will be able to build on this by working even more closely with TFS in developing and marketing our pipeline of dermatological products containing Indian sandalwood oil. Santalis successfully developed the Benzac acne products, which have now launched across the US, and is well advanced with numerous other products, including for eczema."
Further details on ViroXis and Santalis are provided in Appendix Two.
APPENDIX ONE
TRANSACTION DETAILS
Transaction details The minimum purchase price is US$23.4 million (ViroXis: US$18.4 million, Santalis: US$5.0 million).
The maximum purchase price over time is US$244.9 million (ViroXis: US$154.9 million, Santalis: US$90.0 million) if all milestones, base earn out thresholds and incentive and final earn out thresholds are met through to the eight year anniversary of completion.
The contingent consideration has been structured as follows:
Minimum purchase price
The fixed minimum purchase price for ViroXis is US$18.4 million, comprising cash of US$1.5 million and stock of US$16.9 million.
The fixed minimum purchase price for Santalis is US$5.0 million comprised fully of stock.
The TFS shares will be issued at AU$1.85 per share, being the volume weighted average price for TFS shares for the 30 trading days to 17 June 2015.
In relation to the fixed minimum purchase price, a total of 15.3 million shares is expected to be issued within the following time-frames and be subject to the following lock up periods: Stock issued in July 2015 and subject to no lock up period: 3.5 million Stock issued in July 2015 and subject to lock up period of between 6 and 30 months: 9.1 million Stock issued between September 2015 and July 2016 and subject to no lock up period: 2.7 million
Milestone payments
The purchase price for ViroXis will increase by a maximum of US$26.0 million if the following milestones are achieved within certain periods in up to five years after completion:
1. US$2.0 million on the launch of an over-the-counter ("OTC") product
2. US$4.0 million on the enrolment of the first patient in a Phase 3 FDA trial for a skin indication
3. US$4.0 million on the enrolment of the first patient in a Phase 3 FDA trial for a second skin indication
4. US$8.0 million on FDA approval of a prescription product for a skin indication
5. US$8.0 million on FDA approval of a prescription product for a second skin indication
The purchase price for Santalis will increase by a maximum of US$20.0 million if the following milestones are achieved in the five years after completion:
1. US$5.0 million on the launch of a new OTC product
2. US$2.5 million on the enrolment of the first patient in a Phase 3 FDA trial for a skin indication
3. US$2.5 million on the enrolment of the first patient in a Phase 3 FDA trial for a second skin indication 4. US$5.0 million on FDA approval of a prescription product for a skin indication
5. US$5.0 million on FDA approval of a prescription product for a second skin indication
If FDA approval of a prescription product (milestones 4 and 5 above) is granted between five and eight years post completion, then 50% of the relevant milestone payment will be payable.
All milestone payments are payable in stock and/ or cash, at TFS’s election and in such proportions as TFS determines.
Base earn out payments
The purchase price for ViroXis will increase by a maximum of US$50.0 million based on the level of aggregate net cash flow ("NCF") generated by the business in the five years post completion. The base earn out payment thresholds are:
No earn out payment Less than US$4.3 million US$5.0 million NCF equal to or greater than US$4.3 million and less than US$8.6 million US$15.0 million NCF equal to or greater than US$8.6 million and less than US$12.8 million US$35.0 million NCF equal to or greater than US$12.8 million and less than US$17.1 million US$50.0 million NCF equal to or greater than US$17.1 million
The purchase price for Santalis will increase by a maximum of US$31.0 million based on the level of aggregate net cash flow ("NCF") generated by the business in the five years post completion. The base earn out payment thresholds are:
No earn out payment Less than US$2.5 million US$5.0 million NCF equal to or greater than US$2.5 million and less than US$5.0 million US$10.0 million NCF equal to or greater than US$5.0 million and less than US$7.4 million US$20.0 million NCF equal to or greater than US$7.4 million and less than US$9.9 million US$31.0 million NCF equal to or greater than US$9.9 million
All base earn out payments are payable in stock and/ or cash, at TFS’s election and in such proportions as TFS determines.
Incentive earn out payments
The purchase price for ViroXis will increase by an incentive earn out payment equal to 20% of the NCF in excess of US$10.0 million for each of the three years ending on the six, seven and eight year anniversaries of completion. The incentive earn out payment is capped at US$60.7 million.
The purchase price for Santalis will increase by an incentive earn out payment equal to 20% of the NCF in excess of US$10.0 million for each of the three years ending on the six, seven and eight year anniversaries of completion. The incentive earn out payment is capped at US$37.5 million.
All incentive earn out payments are payable in stock and/ or cash, at TFS’s election and in such proportions as TFS determines.
Final earn out payments
The purchase price for ViroXis will increase by a final earn out payment equal to 20% of the amount, if any, that aggregate NCF for the 8 year period after completion exceeds US$111.9 million, subject to the maximum purchase price cap for all purchase payments of US$154.9 million.
The purchase price for Santalis will increase by a final earn out payment equal to 20% of the amount, if any, that aggregate NCF for the 8 year period after completion exceeds US$111.7 million, subject to the maximum purchase price cap for all payments of US$90.0 million.
All final payments are payable in stock or cash, at TFS’s election and in such proportions as TFS determines.
Put and call mechanism: Santalis In accordance with the terms of the Santalis share purchase agreement, Mr Clements and Dr Castella will initially retain some of their Santalis shares following completion of the Acquisitions (which is expected to be in July 2015).
There are put and call options in place between TFS and Mr Clements and Dr Castella which are exercisable prior to 31 July 2016. These options require TFS to acquire the retained shares on the same terms as TFS acquired the balance of the shares at completion and TFS expects to exercise its call option within this timeframe.
Additional requirements
Further to the purchase prices, TFS will provide minimum funding support to ViroXis and Santalis for product development and other costs. The costs to TFS will be US$2.5 million per year for five years for each of ViroXis and Santalis (total of US$25 million over 5 years).
8-K – Current report
On June 18, 2015 TG Therapeutics reported updated clinical results from its Phase 2 study of TG-1101 (ublituximab), the Company’s novel glycoengineered anti-CD20 monoclonal antibody, in combination with ibrutinib, the oral BTK inhibitor (Filing, 8-K, TG Therapeutics, JUN 18, 2015, View Source [SID:1234505460]). The updated results from the Phase 2 study were delivered in an oral presentation by Dr. John Burke, Rocky Mountain Cancer Associates/US Oncology, Aurora, CO during the 13th International Congress on Malignant Lymphoma (ICML), being held from June 17 – June 20, 2015 in Lugano, Switzerland.
OVERVIEW OF THE UPDATED RESULTS PRESENTED ON TG-1101 + IBRUTINIB
Today’s presentation included data from 44 patients with relapsed and/or refractory CLL treated with TG-1101 in combination with ibrutinib at the labeled dose of 420 mg. Forty patients were evaluable for efficacy, of which 50% (20 patients) were considered "High-Risk", defined as the presence of a 17p del, 11q del and/or p53 mutation, the same criteria which is being used for the current Phase 3 GENUINE study.
Dr. Jeff Sharman, Medical Director of Hematology Research for the US Oncology Network, and Study Chair for both the Phase 2 and the Phase 3 GENUINE Study stated: "The updated Phase 2 data continues to demonstrate that adding ublituximab to ibrutinib can induce not only significant response rates for high-risk CLL patients, but has the potential to impact depth of response, with higher CR and MRD negative rates observed compared to historical data with ibrutinib monotherapy. The Phase 3 study is now up and running, and we look forward to a strong collaboration with all investigators, as this is a very attractive protocol for patients with high-risk CLL."
Michael S. Weiss, the Company’s Executive Chairman and Interim CEO commented on the data, "We continue to be pleased with the performance of the combination of TG-1101 plus ibrutinib and continue to believe the combination represents a best-in-class treatment for patients with relapsed/refractory CLL, especially in patients with high-risk disease, which is generally known to be chemotherapy resistant. We expect, if approved, TG-1101 will be the first chemo-free combination approved with ibrutinib for patients with relapsed/refractory CLL. The data presented today gives us additional confidence that the outcome of our Phase 3 GENUINE Study will be successful and we will be able to offer patients a novel chemo-free treatment option. We greatly appreciate the dedication to the program from our Study Chair Dr. Jeff Sharman and all the participating sites and physicians across the country that are participating in this important clinical trial."
Safety and Tolerability of TG-1101 + ibrutinib
TG-1101 in combination with ibrutinib was well tolerated in the 44 CLL patients evaluable for safety, with day 1 infusion related reactions (IRR) being the most frequently reported adverse event (regardless of causality), the majority of which were Grade 1 or 2 in severity. Only 3 Grade 3 or 4 adverse events were observed in > 5% of patients: neutropenia (11%), anemia (11%), and IRR (7%). Adverse events were manageable with only 7% of CLL patients (3/44) discontinuing from the study due to an adverse event: 1 diarrhea (attributed to ibrutinib) and 2 non-related adverse events. Overall, aside from day 1 IRR, the addition of TG-1101 to ibrutinib did not appear to alter the safety and tolerability profile of ibrutinib monotherapy.
Clinical Activity of TG-1101 + ibrutinib
Of the 44 CLL patients treated, 40 were evaluable for response. The 4 patients who were not evaluable included 2 who discontinued due to an adverse event and 2 who withdrew consent, in each case, prior to a first efficacy assessment. Of the 20 CLL patients with previously treated high-risk disease, the patient population we are currently studying in our Phase 3 GENUINE study, 95% (19/20) achieved an objective response with 20% achieving MRD negativity and/or a CR or an unconfirmed CR (pending bone marrow confirmation) as per the iwCLL (Hallek 2008). Additionally, disease response improved for the high-risk CLL patients from a median 64% nodal reduction by month 3 to a median 85% nodal reduction by month 6.
Amongst all 40 CLL patients evaluable for efficacy, 88% (35/40) achieved an objective response per the iwCLL (Hallek 2008) criteria and 4 patients, or an additional 10%, achieved nodal reductions ranging from 20%-55%, without disease progression.
TG-1101 also appeared to abrogate ibrutinib related lymphocytosis with patients experiencing a median 75% reduction in their absolute lymphocyte count (ALC) by the end of month 3 following initiation of combination therapy and 70% of patients achieving normal ALC ranges (< 4,000/uL) by month 6.
ADDITIONAL ICML MEETING PRESENTATIONS
In addition to the TG-1101 + ibrutinib data, the following data, which was presented previously at ASCO (Free ASCO Whitepaper) and EHA (Free EHA Whitepaper), was presented at the 13th International Congress on Malignant Lymphoma (ICML) meeting:
· Single agent TGR-1202 in patients with relapsed or refractory CLL, NHL or other B-cell Malignancies: Oral Presentation (Owen A. O’Connor, MD, PhD)
· Combination of TG-1101 + TGR-1202 (the Company’s "1303" combination) in patients with relapsed/refractory NHL and high-risk CLL: Poster Presentation (Matt Lunning, DO)
· Chemo-free triplet combination of TG-1101 + TGR-1202 + ibrutinib in patients with B-cell malignancies: Oral Presentation (Loretta Nastoupil, MD)
A copy of all data presentations from the ICML Lugano meeting can be found at View Source
ABOUT THE GENUINE PHASE 3 TRIAL (TG-1101 + IBRUTINIB)
The Phase 3 trial, the "GENUINE" trial, evaluating TG-1101 (ublituximab) in combination with ibrutinib compared to ibrutinib alone for the treatment of patients with previously treated high-risk CLL is now open in over 120 centers across the US and is actively enrolling patients. The trial is being conducted under Special Protocol Assessment (SPA) which provides agreement that the Phase 3 trial design adequately addresses objectives that would support the regulatory submission for drug approval.
The GENUINE trial will enroll approximately 330 patients, with approximately the first two-thirds of the patients included in the ORR assessment. As per the SPA, the Company plans to use the ORR data from the trial as the basis for submission of a Biologics License Application (BLA) for accelerated approval for TG-1101. All patients will then be followed for progression free survival (PFS) assessment, which is designed to support full approval.
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Varian to Equip Inova With Integrated Technology for Radiotherapy, Radiosurgery, and Informatics
On June 18, 2015 Varian Medical Systems reported that it has entered into a multi-year agreement with Inova to be its exclusive supplier of advanced technology for image-guided, high-precision radiotherapy and radiosurgery (Press release, InfiMed, JUN 18, 2015, View Source [SID:1234505459]). Inova, a not-for-profit healthcare system operating five hospitals in Northern Virginia, will also install Varian software across its sites, as part of a long-term plan to create an integrated informatics system and to unify cancer care across its network.
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Under the agreement, Inova will acquire multiple Varian TrueBeam radiotherapy/ radiosurgery systems over nine years, with initial replacements at Inova’s Alexandria and Loudoun Hospitals. TrueBeam technology offers clinicians tremendous versatility in choosing and administering different types of radiation treatment for each patient as appropriate, from intensity-modulated radiotherapy to stereotactic radiosurgery. These treatments can be delivered with greater time efficiency—and hence cost effectiveness—than is possible with many other radiotherapy systems.
Inova will also expand its deployment of Varian’s ARIA information management and Eclipse treatment planning software, currently in use at two of the five sites, across the Inova network, and add Varian’s new InSightive software for data analytics.
"We have been managing radiation oncology departments at two of our sites using Varian software for some time," said says Gopal K. Bajaj, MD, Chairman and Medical Director of Radiation Oncology, Inova. "We will replace competitive solutions at the other sites in order to unify cancer care across the system. We like the fact that ARIA is a comprehensive system that consolidates all treatment data in a single database. It dovetails with our plans to integrate all of our cancer treatment services in support of better care coordination and closer collaboration among clinical team members."
Inova will also deploy Varian’s InSightive software for data analytics, which will enable clinicians and administrators to mine the enormous amount of data housed within the ARIA oncology information system database.
"ARIA is a robust practice management system and electronic medical record with a tremendous amount of information that Inova can mine and analyze to enhance the quality of care and the efficiency of its clinical operations," says Sukhveer Singh, vice president of Varian’s Oncology Continuum Solutions. "ARIA includes many interfaces for importing data from other hospital information systems, resulting in a very rich resource. InSightive Analytics provides access to this data, making it visible and useful."
"Our partnership with Varian will help as we create an integrated healthcare delivery system that uses knowledge-based approaches for the optimal benefit of patients," adds Donald Trump, MD, CEO of the Inova Dwight and Martha Schar Cancer Institute. "We will study the data from cancer patients across our network, including detailed information regarding patient characteristics as well from a detailed study of patients’ tumor tissue and their own genetic makeup, ultimately to analyze why different patients react differently to the same treatments. Varian’s ARIA and Insightive informatics will help us aggregate and analyze that data, and tease out actionable information for the benefit of our patients."
The total value of the multi-year agreement is estimated at $25 million inclusive of products and services, such as turnkey hardware and software support. Varian booked approximately $4 million of this amount during the third quarter of fiscal year 2015. The remainder of the order will be booked in accordance with the company’s policies over the term of the agreement.
Results From Phase 3 Trial Show Vectibix® (Panitumumab) Improves Overall Survival In Chemorefractory Wild-Type KRAS Metastatic Colorectal Cancer Versus Best Supportive Care
On June 18, 2015 Amgen reported that a Phase 3 study evaluating Vectibix (panitumumab) and best supportive care (BSC) met its primary endpoint, demonstrating a statistically significant improvement in overall survival (OS) in patients with chemorefractory wild-type KRAS (exon 2) metastatic colorectal cancer (mCRC) compared to those patients treated with BSC alone (Press release, Amgen, JUN 18, 2015, View Source [SID:1234505462]). Schedule your 30 min Free 1stOncology Demo! The Vectibix treatment arm further showed statistical significance for all key secondary endpoints including OS in patients with wild-type RAS (absence of mutations in exons 2, 3 and 4 of KRAS and NRAS) mCRC.
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In the Vectibix treatment arm, the observed adverse events were consistent with the known Vectibix safety profile.
Full results will be submitted to a future medical congress and for publication.
"Amgen has been at the forefront of researching personalized approaches to treating cancer, and the Vectibix clinical program continues to underscore the importance of identifying options for patients based on their cancer’s genetic makeup," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "These positive overall survival results for Vectibix reinforce the importance of KRAS and RAS biomarkers in making treatment decisions in metastatic colorectal cancer."
Colorectal cancer is the third most common cancer worldwide, with approximately 1.2 million cases occuring globally each year.1,2 In the U.S., colorectal cancer is the second leading cause of cancer-related deaths, with an estimated 132,700 new cases diagnosed in 2015.3,4 In Europe, colorectal cancer is the second most common cancer, with approximately 470,000 new cases each year.5
About Study ‘0007 (NCT01412957)
This Phase 3 global, multicenter, randomized, open-label study was designed to evaluate the survival benefit of Vectibix and best supportive care (BSC) compared to BSC alone in patients with chemorefractory wild-type KRAS (exon 2) metastatic colorectal cancer (mCRC). The primary endpoint was overall survival (OS). Key secondary endpoints included progression-free survival (PFS) in patients with wild-type KRAS mCRC, as well as OS and PFS in patients with wild-type RAS (absence of mutations in exons 2, 3 and 4 of KRAS and NRAS) mCRC.
Patients were randomized 1:1 to receive 6 mg/kg of Vectibix every 14 days and BSC, or BSC alone (as defined by the investigator).
About Vectibix (panitumumab)
Vectibix is the first fully human anti-EGFR antibody approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic colorectal cancer (mCRC). Vectibix was approved in the U.S. in September 2006 as a monotherapy for the treatment of patients with EGFR-expressing mCRC after disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy.
In May 2014, the FDA approved Vectibix for use in combination with FOLFOX, as first-line treatment in patients with wild-type KRAS (exon 2) mCRC. With this approval, Vectibix became the first-and-only biologic therapy indicated for use with FOLFOX, one of the most commonly used chemotherapy regimens, in the first-line treatment of mCRC for patients with wild-type KRAS mCRC.
Important U.S. Product Information
Vectibix is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use:
As first-line therapy in combination with FOLFOX
As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy
Limitation of Use: Vectibix is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown.
WARNING: DERMATOLOGIC TOXICITY
Dermatologic Toxicity: Dermatologic toxicities occurred in 90 percent of patients and were severe (NCI-CTC grade 3 or higher) in 15% of patients receiving Vectibix monotherapy.
In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures.
Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (e.g., Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix. concerning dermatologic toxicity are provided in the product labeling.
Vectibix is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as "RAS".
Retrospective subset analyses across several randomized clinical trials were conducted to investigate the role of RAS mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR related adverse reactions without clinical benefit from these agents.
Additionally, in Study 3, 272 patients with RAS-mutant mCRC tumors received Vectibix. in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis, OS was shorter (HR = 1.21, 95% CI 1.01-1.45) in patients with RAS-mutant mCRC who received Vectibix and FOLFOX versus FOLFOX alone.
Progressively decreasing serum magnesium levels leading to severe (Grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix treatment, periodically during Vectibix treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.
In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions.
Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix in combination with chemotherapy.
Fatal and non-fatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix therapy. Discontinue Vectibix therapy if ILD is confirmed.
In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix versus the risk of pulmonary complications must be carefully considered.
Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix.
Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix for acute or worsening keratitis.
In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions. NCI-CTC grade 3–4 adverse reactions occurring at a higher rate in Vectibix-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%; primarily occurring in patients with diarrhea), hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).
NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate in Vectibix-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix-treated patients.
As a result of the toxicities experienced, patients randomized to Vectibix, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy.
Advise patients of the need for adequate contraception in both males and females while receiving Vectibix and for 6 months after the last dose of Vectibix therapy. Vectibix may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.
Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix.
Women who become pregnant during Vectibix treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Women who are nursing during Vectibix treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.
In Study 1, the most common adverse reactions (> 20%) with Vectibix were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix arm were general physical health deterioration and intestinal obstruction.
In Study 3, the most commonly reported adverse reactions (> 20%) in patients with wild-type KRAS mCRC receiving Vectibix (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. Serious adverse reactions (> 2% difference between treatment arms) in Vectibix-treated patients with wild-type KRAS mCRC were diarrhea and dehydration.
To see the Vectibix Prescribing Information, including Boxed Warning visit www.vectibix.com.
In the EU, Vectibix is currently indicated for the treatment of adult patients with wild-type RAS mCRC:
in first-line in combination with FOLFOX and FOLFIRI.
in second-line in combination with FOLFIRI for patients who have received first-line fluoropyrimidine-based chemotherapy (excluding irinotecan).
as monotherapy after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.