On January 27, 2016 Boehringer Ingelheim reported the results of the LUX-Lung 7 trial. Superiority in progression-free survival and time to treatment failure was demonstrated with second-generation EGFR-directed therapy afatinib, versus first-generation gefitinib in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) with common EGFR mutations (del19 or L858R)(Press release, Boehringer Ingelheim, JAN 27, 2016, View Source [SID:1234508865]).1

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The Phase IIb trial met two of its co-primary endpoints of progression-free survival (PFS) by independent review and time to treatment failure (a measure of time between start, and discontinuation of treatment for any reason).1 The LUX-Lung 7 trial results will be presented today at the 14th Annual British Thoracic Oncology Group (BTOG) Conference in Dublin, Ireland. Data for the third co-primary endpoint, overall survival (OS), are not yet mature and will be presented in the future.

Results from the LUX-Lung 7 trial showed that afatinib significantly reduced the risk of lung cancer progression by 27% versus gefitinib.1 The improvement in PFS became more pronounced over time, with a significantly higher proportion of patients alive and progression-free at 18 months (27% vs 15%) and 24 months (18% vs 8%), showing a greater long-term benefit to using afatinib versus gefitinib.1 In addition to superior PFS, patients on afatinib had a significantly longer time on treatment: risk of treatment failure reduced by 27%, versus gefitinib.1 Significantly more patients had an objective tumour response (a clinically meaningful decrease in tumour size) with afatinib when compared to gefitinib (70% vs 56%), with a median duration of response of 10.1 months and 8.4 months, respectively.1 The improvement in PFS with afatinib was consistent across most pre-defined clinical subgroups, including gender, age, race and EGFR mutation type.1

LUX-Lung 7 lead investigator Professor Keunchil Park, director of Innovative Cancer Medicine Institute (ICMI) at Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea commented, "LUX-Lung 7 is the first global trial directly comparing two EGFR-directed therapies and the results demonstrate the benefits of second-generation inhibitor afatinib, compared to first-generation drug, gefitinib, in first-line therapy. These results provide important guidance on the choice of first-line treatment for patients with EGFR mutation-positive lung cancer."

Adverse events (AEs) observed in the LUX-Lung 7 trial were consistent with the known safety profiles of both treatments. Treatment with both afatinib and gefitinib was generally tolerable, leading to an equally low rate of treatment-related discontinuation in both arms (6.3%).1 The overall frequency of serious AEs was similar for both (afatinib: 44.4% vs gefitinib: 37.1%); the most common grade ≥3 related AEs with afatinib were: diarrhea (12.5%) and rash/acne (9.4%), and with gefitinib: aspartate aminotransferase (AST)/alanine aminotransferase (ALT) increase (8.8%) and rash/acne (3.1%).1 Drug-related interstitial lung disease was reported for four patients on gefitinib and no patients on afatinib.1

"LUX-Lung 7 is the second positive head-to-head trial of afatinib versus first-generation EGFR TKIs in lung cancer, showing that first- and second-generation EGFR targeted agents are not the same," said Dr Mehdi Shahidi, Medical Head, Solid Tumour Oncology, Boehringer Ingelheim. "Interestingly, the progression-free survival difference observed in the LUX-Lung 7 trial became more prominent over time so that by 24 months the rate of patients who were free of cancer growth was more than doubled with afatinib."

About the LUX-Lung 7 trial
LUX-Lung 7 is the first global, head-to-head trial comparing second- and first-generation EGFR-directed therapies (afatinib and gefitinib respectively) for patients with EGFR mutation-positive NSCLC who received no prior treatment. The Phase IIb trial included 319 patients with advanced stage NSCLC harbouring common EGFR mutations (del19 or L858R). The trial’s co-primary endpoints were PFS by independent review, time to treatment failure and OS; and the secondary endpoints included objective response rate, disease control rate, tumour shrinkage, patient-reported outcomes and safety.

Results: compared to gefitinib, afatinib significantly improved:

PFS (HR=0.73; 95% CI, 0.57‒0.95; p=0.0165; median: 11.0 months [afatinib] versus 10.9 months [gefitinib])
Time to treatment failure (HR=0.73; 95% CI, 0.58‒0.92; p=0.0073; median: 13.7 months [afatinib] versus 11.5 months [gefitinib])
Objective Response Rate (70% vs 56%, p=0.0083)

Afatinib is approved in more than 60 countries for the first-line treatment of distinct types of EGFR mutation-positive NSCLC (under the brand names: GIOTRIF / GILOTRIF). Approval of afatinib in this indication was based on the primary endpoint of PFS from the LUX-Lung 3 clinical trial where afatinib significantly delayed tumour growth when compared to standard chemotherapy.2 In addition, afatinib is the first treatment to have shown an OS benefit for patients with specific types of EGFR mutation-positive NSCLC compared to chemotherapy.3 A significant OS benefit was demonstrated independently in the LUX-Lung 3 and 6 trials for patients with the most common EGFR mutation (exon 19 deletions; del19) compared to chemotherapy.3

On January 26, 2016 Medivation, Inc. (NASDAQ: MDVN) and Astellas Pharma US, LLC, a United States (U.S.) subsidiary of Tokyo-based Astellas Pharma Inc. (TSE: 4503), reported that results from the STRIVE trial (NCT01664923) of enzalutamide compared to bicalutamide in men with castration-resistant prostate cancer (CRPC) were published in the Journal of Clinical Oncology (Press release, Medivation, JAN 26, 2016, View Source [SID:1234508864]). The article, titled, "Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial," appears in the January 25, 2016 online issue and will be published in a future print issue of the journal.

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The study achieved its primary endpoint demonstrating a statistically significant increase in progression-free survival (PFS) for enzalutamide compared with bicalutamide (Hazard Ratio = 0.24; 95% Confidence Interval, 0.18-0.32; p < 0.0001). Median PFS was 19.4 months in the enzalutamide group compared with 5.7 months in the bicalutamide group.

The median time on treatment in the STRIVE trial was 14.7 months in the enzalutamide group versus 8.4 months in the bicalutamide group. Serious adverse events were reported in 29.4% of enzalutamide-treated patients and 28.3% of bicalutamide-treated patients. Grade 3 or higher cardiac adverse events were reported in 5.1% of enzalutamide-treated patients versus 4.0% of bicalutamide-treated patients. One seizure was reported in the trial in the enzalutamide-treated group and none in the bicalutamide-treated group. The most common side effects noted more frequently in the enzalutamide-treated versus bicalutamide-treated patients included fatigue, back pain, hot flush, fall, hypertension, dizziness, and decreased appetite, consistent with the known safety profile of enzalutamide.

The STRIVE study is the second of two head-to-head studies of enzalutamide versus bicalutamide, the first of which was TERRAIN, which was published in the January 13, 2016 online issue of Lancet Oncology.

About the STRIVE Trial
The Phase 2 STRIVE trial enrolled 396 castration-resistant prostate cancer patients in the U.S. The trial randomized 257 patients with metastatic prostate cancer and 139 patients with non-metastatic prostate cancer whose disease progressed despite treatment with a luteinizing hormone-releasing hormone (LHRH) analogue therapy or following surgical castration. The primary endpoint of the trial was PFS, defined as time from randomization to radiographic (bone or soft tissue) progression, prostate-specific antigen (PSA) progression (defined by Prostate Cancer Working Group 2 criteria), or death due to any cause, whichever occurs first. The trial was designed to evaluate enzalutamide at a dose of 160 mg taken once daily (n=198) versus bicalutamide at a dose of 50 mg taken once daily (n=198), the approved dose in combination with a LHRH analogue.

About XTANDI (enzalutamide) capsules
XTANDI is approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

Enzalutamide Mechanism of Action
Enzalutamide is an androgen receptor inhibitor that blocks multiple steps in the androgen receptor signaling pathway within the tumor cell. In preclinical studies, enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors, and inhibit androgen receptor nuclear translocation and interaction with DNA.

Important Safety Information
Contraindications XTANDI is not indicated for women and is contraindicated in women who are or may become pregnant. XTANDI can cause fetal harm when administered to a pregnant woman.

Warnings and Precautions
Seizure In Study 1, conducted in patients with metastatic castration-resistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of XTANDI patients and 0% of placebo patients. In Study 2, conducted in patients with chemotherapy-naive metastatic CRPC, seizure occurred in 0.1% of XTANDI patients and 0.1% of placebo patients. There is no clinical trial experience re- administering XTANDI to patients who experienced a seizure, and limited safety data are available in patients with predisposing factors for seizure. Study 1 excluded the use of concomitant medications that may lower threshold; Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity during which sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) In post approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Adverse Reactions
The most common adverse reactions (≥ 10%) reported from two combined clinical studies that occurred more commonly (≥ 2% over placebo) in XTANDI patients were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo.

In Study 1, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients. In Study 2, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups.

Lab Abnormalities: Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients (0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4).

Infections: In Study 1, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Falls (including fall-related injuries), occurred in 9% of XTANDI patients and 4% of placebo patients. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas.

Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of all patients.
Drug Interactions

Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI. Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI.

Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

For Full Prescribing Information for XTANDI (enzalutamide) capsules, please visit View Source

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1‐800‐FDA‐1088.

On January 26, 2016 ImmunoGen, Inc. (Nasdaq: IMGN), a biotechnology company that develops targeted anticancer therapeutics using its antibody-drug conjugate (ADC) technology, reported the Company earned a milestone payment with Bayer’s initiation of a global Phase 2 clinical study designed to support registration of anetumab ravtansine (BAY 94-9343) (Press release, ImmunoGen, JAN 26, 2016, View Source [SID:1234508863]). Anetumab ravtansine, a mesothelin-targeting ADC, is a potential new treatment for mesothelioma developed by Bayer using ImmunoGen’s ADC technology.

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"We are excited that Bayer has advanced anetumab ravtansine into a clinical study designed to support its registration," commented Daniel Junius, President and CEO. "There is a significant need for new therapies for mesothelioma, and ImmunoGen is committed to transforming the treatment of difficult cancers – both through our own product programs and through partnerships with other companies."

Bayer is developing anetumab ravtansine under a 2008 license agreement with ImmunoGen that granted the company exclusive rights to use ImmunoGen’s maytansinoid ADC technology to develop anticancer therapies targeting mesothelin. Bayer is responsible for the development, registration, and commercialization of anetumab ravtansine. ImmunoGen is entitled to receive milestone payments potentially totaling up to $170 million and royalties on commercial sales, if any.

On January 26, 2016 Heat Biologics, Inc. ("Heat") (Nasdaq:HTBX), an immuno-oncology company developing novel therapies that activate a patient’s immune system against cancer, reported that Taylor Schreiber, M.D. Ph.D., Heat’s Chief Scientific Officer, will discuss three-month interim data from the unblinded, monotherapy cohort of the company’s ongoing Phase 2 trial of HS-410 (vesigenurtacel-L) for the treatment of high risk, non-muscle invasive bladder cancer (NMIBC) at the Phacilitate Immunotherapy World Conference in Washington, D.C. on January 25-27, 2016 (Press release, Heat Biologics, JAN 26, 2016, View Source [SID:1234508862]). In the monotherapy arm of Heat’s Phase 2 trial, a series of weekly intradermal injections of HS-410 is being dosed as an alternative to intravesical standard of care, Bacillus Calmette-Guérin (BCG).

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Dr. Schreiber will report that to-date HS-410 has been well-tolerated, with no serious adverse events. Six out of seven patients in the 25-patient arm, who have reached the 3-month timepoint after treatment with HS-410 alone, remain recurrence free. One of those patients had carcinoma in situ (CIS) – the patient population believed to be least responsive to BCG – and that patient experienced complete response. Images of the bladder taken from treated patients showed changes that resemble lymphoid (T cell rich) structures that we have observed in biopsy samples, indicating that HS-410 is generating an immune response as expected.

"These interim data are consistent with previous results from our Phase 1 trial, demonstrating that intradermal injections of HS-410 lead to a localized immune response within the urinary bladder," said Dr. Schreiber. "The fact that these localized immune responses are now being seen in the absence of standard of care, BCG, indicates that the response is due to HS-410. If the monotherapy arm of the trial demonstrates a trend toward low recurrence rates in the absence of BCG, that may extend options for subsequent pivotal study designs, and may potentially provide bladder cancer patients with an alternative to repeated BCG catheterization procedures. We look forward to presenting additional data from this trial in the future."

Heat continues to enroll the anticipated 25 patients who will receive HS-410 monotherapy and expects to complete enrollment in the first half of 2016. The three other blinded, randomized, placebo-controlled arms in the Phase 2 trial evaluating HS-410 in combination with BCG are fully enrolled with a total of 75 patients. Heat anticipates reporting topline efficacy, immune-response and safety data from those arms in the fourth quarter of 2016.

About HS-410 (vesigenurtacel-L)

HS-410 is an investigational product candidate for NMIBC based on Heat’s proprietary ImPACT immunotherapy platform, designed to generate CD8+ "killer" T cells that attack cancer cells. HS-410 is currently being evaluated in an ongoing Phase 2, placebo-controlled, 100-patient NMIBC trial at multiple centers and has been granted U.S. FDA Fast Track Designation for the treatment of NMIBC.

About Bladder Cancer

According to the American Cancer Society, bladder cancer is the fifth most common cancer in the U.S., with approximately 75,000 new cases and 16,000 deaths in 2015. About 75% of the newly diagnosed patients have NMIBC. A key issue for bladder cancer is the high rate of recurrence, for which limited treatment options are available beyond complete bladder removal.