On September 27, 2015 Roche (SIX: RO, ROG; OTCQX: RHHBY) treported early results from a pivotal phase II study, IMvigor 210, of the investigational cancer immunotherapy atezolizumab (anti-PDL1; MPDL3280A) in people with locally advanced or metastatic urothelial carcinoma (mUC) (Press release, Hoffmann-La Roche , SEP 27, 2015, View Source [SID:1234507567]). The study showed that atezolizumab shrank tumours (objective response rate, ORR) in 27 percent of people with mUC whose disease had medium and high levels of PD-L1 expression and worsened after initial treatment. Ninety-two percent of people who responded to atezolizumab continued to respond when the results were assessed. Median duration of response was not yet reached. Adverse events were consistent with those observed in previous studies.

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"These results may represent the first major treatment advancement in advanced bladder cancer in nearly 30 years," said Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development. "We are encouraged that responses to atezolizumab were ongoing in the large majority of people when the study results were assessed."

Roche is planning to submit these data to global health authorities and to the FDA under a Breakthrough Therapy Designation for the treatment of people whose metastatic bladder cancer expresses PD-L1. This designation is designed to expedite the development and review of medicines intended to treat serious diseases that may demonstrate substantial improvement over existing therapies.

About the IMvigor 210 study
These final results from cohort 2 of this study (minimum of 24 weeks’ follow-up) will be presented in an oral session presentation by Jonathan E. Rosenberg, MD, Memorial Sloan Kettering Cancer Center, USA (Abstract #21LBA) on Sunday, 27 September, 10:40 Central European Time (CET).

Atezolizumab in patients (pts) with locally-advanced or metastatic urothelial carcinoma (mUC): Results from a pivotal multicenter phase II study (IMvigor 210).

IMvigor 210 is an open-label, multicentre, single-arm phase II study that evaluated the safety and efficacy of atezolizumab in people with locally advanced or mUC, regardless of PD-L1 expression. People in the study were enrolled into one of two cohorts. Cohort 1 consisted of people who had received no prior therapies for locally advanced or mUC, but who were ineligible for first-line cisplatin-based therapy; results for this cohort are not yet mature. Cohort 2, for which results were announced today, included people whose disease had progressed during or following previous treatment with a platinum-based chemotherapy regimen. People received a 1200-mg intravenous dose of atezolizumab on day one of 21-day cycles until progressive disease (Cohort 1) or loss of clinical benefit (Cohort 2).

The primary endpoint of the study was ORR. Secondary endpoints included duration of response (DoR), overall survival (OS), progression-free survival (PFS) and safety. People were selected by histology, prior lines of therapy and PD-L1 expression on tumour-infiltrating immune cells (IC), using an investigational immunohistochemistry (IHC) test that is being developed by Roche Diagnostics.

On September 27, 2015 Hospira Japan Co., Ltd. reported that the company has received an approval for the additional dosage/administration of gastric cancer for "Paclitaxel I.V. infusion [Hospira]" by a new drug application (NDA) based on evidence in the public domain with the Ministry of Health, Labour and Welfare (MHLW) in Japan (Press release, Hospira, SEP 27, 2015, View Source;p=RssLanding&cat=news&id=2090640 [SID:1234507569]).

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[Product name]
1. Paclitaxel I.V. lnfusion 30mg/5mL [Hospira]
2. Paclitaxel I.V. lnfusion 100mg/16.7mL [Hospira]

[Therapeutic Category]
Anticancer drug

[Dosage /administration for gastric cancer]
The underlined text represents the additional dosage/administration.

Method A or E are used for gastric cancer.
Method A: Normally for adults 210 mg/m2 (body surface area) in terms of Paclitaxel is administered over 3 hours in a single infusion, with intervals of at least three weeks between doses. This forms one course, which is repeated.
Method E: Normally for adults 80 mg/m2 (body surface area) in terms of paclitaxel is administered over 1 hour in a single infusion, once per week for three successive weeks, followed by an interval of at least two weeks. This forms one course, which is repeated.
Doses may be suitably reduced having regard to the condition of the patient.

On the basis of the requirement of the additional dosage/administration for gastric cancer for originator, which includes Paclitaxel, the report was prepared by the "Review Committee on Unapproved Drugs and Indications with High Medical Needs." The decision was made based on the report at the meeting of the Second Committee on New Drugs, Pharmaceutical Affairs and Food Sedation Council, held on March 5, 2015, which confirmed that filing through the "NDA based on evidence in the public domain" was reasonable for this additional dosage/administration.

The MHLW notification related to "NDA based on evidence in the public domain" for generics recommends pharmaceutical companies work on filing for additional dosage/administration for generic at the same time as originators. Hospira Japan filed this additional dosage/administration for "Paclitaxel I.V. infusion 30mg/5mL [Hospira] " and "Paclitaxel I.V. infusion 100mg/16.7mL [Hospira] " by "NDA based on evidence in the public domain."

Hospira Japan is committed to contributing to healthcare in Japan by providing value-added products with its broad portfolio and meeting the expectations of patients and healthcare professionals.

On September 27, 2015 Ignyta, Inc. (Nasdaq: RXDX), a precision oncology biotechnology company, reported that updated interim results of its Phase 1 clinical trials of entrectinib, the company’s proprietary oral tyrosine kinase inhibitor targeting solid tumors that harbor activating alterations to NTRK1, NTRK2, NTRK3, ROS1 or ALK, were presented in an oral presentation session at the 2015 European Cancer Congress (ECC 2015) in Vienna, Austria (Press release, Ignyta, SEP 27, 2015, View Source [SID:1234507570]).

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"We continue to be excited by the data from our two Phase 1 clinical trials of entrectinib, particularly in patients who would meet the anticipated eligibility criteria for our planned Phase 2 clinical trials," said Pratik Multani, M.D., Chief Medical Officer of Ignyta. "Out of the 18 patients in the two studies who met these criteria, we observed 13 responses, for an overall response rate of 72% across multiple tumor histologies. In addition, based upon an increased dataset of 92 patients, we have been able to confirm entrectinib’s acceptable safety profile for further development at the recommended phase 2 dose (RP2D). We intend to use this clinical experience as the basis for STARTRK-2, our planned, potentially registration-enabling Phase 2 clinical trial of entrectinib."

The clinical trials included the ALKA-372-001 study and the STARTRK-1 study, which is the first of the "Studies of Tumor Alterations Responsive to Targeting Receptor Kinases". Both trials were designed to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose, as well as preliminary anti-cancer activity, of single agent entrectinib in patients with solid tumors with the relevant molecular alterations: NTRK1 (encoding TrkA), ROS1 or ALK for ALKA-372-001 and NTRK1/2/3 (encoding TrkA/TrkB/TrkC), ROS1 or ALK for STARTRK-1.

As of the August 15, 2015, data cut-off for the presentation, the findings showed:

A total of 92 patients with a range of solid tumors had been dosed across both clinical trials, with nine patients treated at or above the RP2D beyond six months and one patient beyond one year.

Entrectinib was well tolerated to date:
Across both studies, the most frequent (>10% incidence) treatment-related adverse events were fatigue, dysgeusia, paresthesia, nausea, and myalgia. Seven of these were Grade 3 in severity, consisting of fatigue (4 patients), cognitive impairment (2 patients), and diarrhea (1 patient). No Grade 4 treatment-related adverse events were observed;

Across both studies, there were only three treatment-related serious adverse events: Grade 3 cognitive impairment and Grade 3 myocarditis, both of which occurred above the RP2D, and Grade 2 fatigue. All events were reversible and resolved upon dose modification;

The fixed daily dose RP2D was determined to be 600 mg, taken orally once per day (QD);
18 patients across both clinical trials met the company’s expected Phase 2 eligibility criteria, which include:
Presence of NTRK1/2/3, ROS1 or ALK gene rearrangements, as opposed to other types of molecular alterations (e.g., SNPs, amplifications, deletions);

ALK-inhibitor and/or ROS1-inhibitor naïve; and

Treatment at or above the RP2D;

The response rate in the 18 patients who met these criteria across both studies was 72% (13 responses out of 18 treated patients, as assessed by the clinical sites). Nine of these responders remain on study treatment with durable responses of up to 21 treatment cycles. An additional 3 patients remain on study with stable disease. The responses included:

3 responses out of 4 patients with NTRK1/2/3 gene rearrangements, including patients with non-small cell lung cancer (NSCLC), colorectal cancer and salivary gland cancer, with one of the responding patients remaining on treatment at 6 months; a fourth patient with an astrocytoma remains on treatment after two months with stable disease;

6 responses, including one complete response, out of 8 patients with ROS1 gene rearrangements, all of which were in NSCLC. All of the patients who responded remain on treatment, the longest at 21 months; and

4 responses out of 6 patients with ALK gene rearrangements, including two NSCLC patients and two patients with other solid tumors; two of the 4 responders subsequently progressed.

Entrectinib has demonstrated objective tumor response in the central nervous system (CNS), a frequent site of metastases and progression of advanced solid tumors.

On Wednesday, September 30, 2015, Ignyta will file a Form-8-K with the U.S. Securities and Exchange Commission (SEC) containing the materials presented at the ECC 2015. The company’s SEC filings can be found on the company’s website at www.ignyta.com and on the SEC’s website at www.sec.gov.

On September 28, 2015 Boehringer Ingelheim reported at the European Cancer Congress (ECC) in Vienna, Austria, new data from the Phase III LUX-Lung 8 trial which further highlights the benefits of afatinib* compared to erlotinib for the treatment of patients with previously treated advanced SCC of the lung (Press release, Boehringer Ingelheim, SEP 26, 2015, View Source [SID:1234507556]).2 Data from the trial showed that treatment with afatinib resulted in superior progression-free survival (PFS) and superior overall survival (OS) compared to erlotinib in this patient population.2 These improved survival outcomes observed with afatinib were not driven by the presence of EGFR mutations, according to a new analysis presented at ECC.2 Furthermore, a higher number patients treated with afatinib in the LUX-Lung 8 trial reported improvements in overall health and quality of life, as well as improvements in some lung cancer-related symptoms, compared to those treated with erlotinib.3

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LUX-Lung 8 clinical trial investigator Glen D. Goss, M.D., Director of Clinical and Translational Research, The Ottawa Hospital Cancer Center, University of Ottawa, Canada, commented: "These latest data not only demonstrate benefits of afatinib compared to erlotinib for patients with SCC of the lung, but also suggest that afatinib is an effective treatment option for a broad group of patients and not just those whose tumours harbour EGFR mutations. We know that dysregulation of ErbB receptors plays a role in the underlying mechanisms of SCC of the lung and the fact that afatinib targets this family of receptors rather than only EGFR, may explain why it offered additional benefits for this patient population."

Afatinib is an oral, once daily targeted treatment which works by irreversibly blocking the ErbB family of receptors. Unlike other targeted treatments such as erlotinib which are reversible and specifically target EGFR (ErbB1), afatinib aims to provide a sustained, selective and complete ErbB Family Blockade. The Phase III LUX-Lung 8 trial compared afatinib to erlotinib in patients with advanced SCC of the lung progressing after treatment with first-line platinum-based chemotherapy. Data from the trial showed that treatment with afatinib resulted in superior PFS, reducing the risk of cancer progression by 19%, and superior OS, reducing the risk of death by 19% compared to erlotinib in this patient population.1,2 The PFS and OS advantages observed with afatinib compared to erlotinib were independent of the EGFR mutation status of the tumours analysed from this trial.2

Further data presented at ECC confirm the efficacy of afatinib observed in the LUX-Lung 8 trial was associated with improvements in patient reported outcomes.3 More patients had improved overall health-related quality-of-life (36% vs 28%, p=0•041), cough (43% vs 35%, p=0•029) and dyspnoea (51% vs 44%, p=0•061) with afatinib than with erlotinib.3 The rate of severe adverse events in the LUX-Lung 8 trial was similar between the two treatment arms with differences observed in the incidence of certain side effects.1 A higher incidence of severe diarrhoea and stomatitis (mouth sores) was observed with afatinib compared to erlotinib (grade 3 diarrhoea: 10% vs 2%; grade 3 stomatitis: 4% vs 0%), while a higher incidence of severe rash/acne was reported with erlotinib compared to afatinib (grade 3 rash/acne: 10% vs 6%).1 Diarrhoea occurring in patients treated with afatinib was manageable.3

Dr. Mehdi Shahidi, Medical Head, Solid Tumour Oncology, Boehringer Ingelheim commented: "We are pleased to present these data at ECC 2015 which confirm that the advantages of afatinib, compared to erlotinib, are not limited to patients with squamous cell lung cancer whose tumours expressed EGFR mutations, which are rare in this disease. The LUX-Lung 8 trial shows that treatment with afatinib versus erlotinib not only leads to improved survival outcomes but also offered patients an improved quality of life. Afatinib is under review by both the FDA and EMA for the treatment of SCC of the lung and we look forward to working with regulatory authorities in the hope of making this much needed new treatment option available to patients."

Afatinib is currently approved in more than 60 countries for the first-line treatment of specific types of EGFR mutation-positive non-small cell lung cancer (NSCLC) (under brand names: GIOTRIF / GILOTRIF). Both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have recently accepted filing applications for afatinib for the treatment of patients with advanced SCC of the lung progressing after treatment with first-line chemotherapy, based on the positive PFS and OS data from the LUX-Lung 8 trial. Afatinib has also been granted orphan drug designation by the FDA – a status given to a product intended for the treatment of a rare disease or condition.

On September 28, 2015 Boehringer Ingelheim reported at the European Cancer Congress (ECC) in Vienna, Austria, further data to support the efficacy of VARGATEF (nintedanib*) in combination with docetaxel for the treatment of advanced non-small cell lung cancer (NSCLC) with adenocarcinoma histology (Press release, Boehringer Ingelheim, SEP 26, 2015, View Source [SID:1234507557]). Further analysis of the data from the pivotal LUME-Lung 1 trial showed that after first-line chemotherapy adenocarcinoma patients receiving VARGATEF plus docetaxel had a significantly reduced rate of tumour growth over time, compared to patients receiving docetaxel alone.1 At the time of treatment initiation, the average tumour size of the 658 adenocarcinoma patients who took part in the trial was 82.5mm (diameter). After six months of treatment, the adenocarcinoma patients receiving VARGATEF plus docetaxel experienced about 10% less tumour growth over time (9.7mm), compared to those receiving placebo plus docetaxel (tumour size at 6 months: 98.4mm placebo plus docetaxel vs 88.7mm nintedanib plus docetaxel).1

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Advanced adenocarcinoma patients with the poorest prognosis received an even more pronounced benefit from VARGATEF plus docetaxel, compared to docetaxel alone, after first-line chemotherapy:

Adenocarcinoma patients whose disease progressed within nine months of starting first-line chemotherapy (T<9) received a 16.8mm reduction in tumour size over time after six months (tumour size at baseline 88.3mm; tumour size at 6 months: 114.6mm placebo plus docetaxel vs 97.8mm nintedanib plus docetaxel; difference in growth over time of 13%)
Adenocarcinoma patients who had continuously progressed during first-line therapy (PD-FLT) experienced a 19.7mm reduction in tumour size over time after six months (tumour size at baseline 98.1mm; tumour size at 6 months: 124.7mm placebo plus docetaxel vs 105mm nintedanib plus docetaxel; a difference in growth over time of 15%)

Professor Martin Reck, lead investigator of the LUME-Lung 1 trial said, "The reduction in tumour burden seen in adenocarcinoma patients receiving nintedanib plus docetaxel is very encouraging and it is particularly positive to see the additional benefit for those patients who progress quickly when receiving first-line therapy as they often have the poorest prognosis. Tumour burden is commonly associated with clinical outcomes and as such is a relevant and valuable measurement. These latest data add to our wealth of knowledge and reiterate the efficacy of nintedanib which has previously been shown to extend overall survival to over one year for this difficult to treat cancer."

The Phase III LUME-Lung 1 trial randomised 1,314 patients with stage IIIB/IV recurrent NSCLC to receive either VARGATEF plus docetaxel or placebo plus docetaxel (1:1).2 Tumour growth was evaluated in a planned post-hoc analysis using all available tumour measurements. Mixed-effects models were employed to measure the relationship between time from treatment initiation and tumour size (measured as the sum of longest diameter of target lesions [SLD]).1

Dr Mehdi Shahidi, Medical Head, Solid Tumour Oncology, Boehringer Ingelheim commented, "The announcement of the latest data from the LUME-Lung 1 trial further illustrates how VARGATEF in combination with docetaxel can potentially improve the lives of lung cancer sufferers following its EU approval in 2014. We have a long-term commitment to discovering novel and innovative treatments to better the lives of patients with different types of cancer and look forward to bringing further advances in the future."

VARGATEF in combination with docetaxel was approved in the EU in 2014 for use by adult patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy. The LUME-Lung 1 study demonstrated the efficacy and safety of the treatment:2

VARGATEF plus docetaxel significantly prolonged progression-free survival compared to docetaxel alone for patients with adenocarcinoma (PFS: primary endpoint; 4.0 vs 2.8 months)
VARGATEF plus docetaxel significantly extended overall survival to beyond one year for patients with adenocarcinoma, compared to docetaxel alone (OS: key secondary endpoint; 12.6 vs 10.3 months)
VARGATEF plus docetaxel enabled one in four patients with adenocarcinoma to live for at least two years after first-line chemotherapy

VARGATEF in combination with docetaxel demonstrated a familiar and generally manageable side-effect profile without further compromising patients’ overall, health-related, quality of life compared to docetaxel alone. The most common adverse events for patients taking docetaxel vs VARGATEF plus docetaxel included: nausea 18% vs 24%; vomiting 9% vs 17%; diarrhoea 22% vs 42% and elevated liver enzymes 8% vs 29%.

Adenocarcinoma is the most common type of lung cancer and the majority of patients are diagnosed in an advanced stage.3 Most patients will experience disease progression during or after first-line chemotherapy and there is a significant need for new, effective second-line treatments.2,3