On June 2, 2018 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that results from the Phase III IMpower131 study showed Tecentriq (atezolizumab) plus chemotherapy (carboplatin and Abraxane [albumin-bound paclitaxel; nab-paclitaxel]) reduced the risk of disease worsening or death (progression-free survival; PFS) by 29 percent compared with chemotherapy (carboplatin and nab-paclitaxel) alone in the initial (first-line) treatment of people with advanced squamous non-small cell lung cancer (NSCLC) (median PFS=6.3 vs. 5.6 months; hazard ratio [HR]=0.71, 95% CI: 0.60, 0.85, p=0.0001) (Press release, Hoffmann-La Roche, JUN 2, 2018, View Source [SID1234527077]).1 The 12-month PFS rate was doubled for people who received the Tecentriq combination (24.7 percent) compared to those who received chemotherapy alone (12.0 percent). A statistically significant overall survival (OS) benefit was not observed at the interim analysis, and the study will continue as planned. The safety profile of the Tecentriq plus chemotherapy combination was consistent with the safety profiles of the individual medicines, and no new safety signals were identified with the combination.

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"The IMpower131 data further inform our understanding of this difficult-to-treat type of lung cancer and will continue to as we evaluate additional outcomes from this study," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "IMpower131 is one of eight Phase III trials from our extensive research programme evaluating Tecentriq alone or in combination with other medicines in different types of lung cancer."

Data will be featured in the official American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting press programme on Saturday, 2 June, 2018, at 08:00 am CDT. The oral data presentation will be on Monday, 4 June, 2018, at 15:00–15:12 pm CDT (Abstract LBA9000).

About the IMpower131 study
IMpower131 is a Phase III, open-label, multicentre, randomised study evaluating the efficacy and safety of Tecentriq in combination with carboplatin and nab-paclitaxel or Tecentriq in combination with carboplatin and paclitaxel versus chemotherapy (carboplatin and nab-paclitaxel) alone in people with stage IV squamous-cell NSCLC who have not been previously treated with chemotherapy. The study enrolled 1,021 people who were randomised equally (1:1:1) to receive:

Tecentriq plus carboplatin and paclitaxel (Arm A), or
Tecentriq plus carboplatin and nab-paclitaxel (Arm B), or
Carboplatin and nab-paclitaxel (Arm C, control arm)
During the treatment-induction phase, people in Arm A received four or six cycles of Tecentriq plus carboplatin and paclitaxel, given on day one of each 21-day cycle. This was followed by maintenance therapy with Tecentriq every three weeks until progression of the cancer, or for as long as clinical benefit was observed.

During the treatment-induction phase, people in Arm B received four or six cycles of Tecentriq, carboplatin and nab-paclitaxel. Tecentriq and carboplatin were administered on day one of each 21-day cycle. Nab-paclitaxel was administered on days one, eight and 15 of each 21-day cycle. This was followed by maintenance therapy with Tecentriq every three weeks until progression of the cancer, or for as long as clinical benefit was observed.

During the treatment-induction phase, people in Arm C received four or six cycles of carboplatin and nab-paclitaxel. Carboplatin was administered on day one of each 21-day cycle, and nab-paclitaxel was administered on days one, eight and 15 of each 21-day cycle. In the maintenance phase, participants received best supportive care.

The co-primary endpoints were:

PFS as determined by the investigator using RECIST v1.1 in the intention-to-treat (ITT) population (Arm B vs. Arm C)
OS in the ITT population (Arm B vs. Arm C)
Key secondary endpoints were:

PFS as determined by the investigator using RECIST v1.1 in the Tumour Cell (TC) 2/3 or Tumour-Infiltrating Immune Cell (IC) 2/3 population
PFS as determined by the investigator using RECIST v1.1 in the TC1/2/3 or IC1/2/3 population
OS in the TC2/3 or IC2/3 population
OS in the TC1/2/3 or IC1/2/3 population
Percentage of participants with objective response (OR) as determined by the investigator using RECIST v1.1 in the ITT population
Duration of response (DoR) as determined by the investigator using RECIST v1.1 in the ITT population
IMpower131 met its PFS co-primary endpoint per study protocol. This analysis of IMpower131 evaluated Arm B vs. Arm C. Due to pre-specified statistical testing hierarchy, Arm A vs Arm C has not been formally tested yet. As per the statistical analysis plan, Arm B (Tecentriq plus carboplatin and nab-paclitaxel) must demonstrate a statistically significant OS result vs. Arm C (carboplatin and nab-paclitaxel), before an analysis between Arm A (Tecentriq plus carboplatin and paclitaxel) and Arm C can be made for PFS and OS.

A summary of the IMpower131 results are included below:

The safety profile of the Tecentriq plus chemotherapy combination was consistent with the safety profiles of the individual medicines, and no new safety signals were identified with the combination. Serious adverse events related to treatment were observed in 20 percent of people who received Tecentriq plus chemotherapy compared to 10 percent of those who received chemotherapy alone.

About NSCLC
Lung cancer is the leading cause of cancer death globally.2 Each year 1.59 million people die as a result of the disease; this translates into more than 4,350 deaths worldwide every day.3 Lung cancer can be broadly divided into two major types: NSCLC and small cell lung cancer. NSCLC is the most prevalent type, accounting for around 85% of all cases.3 NSCLC comprises non-squamous and squamous-cell lung cancer, the squamous form of which is characterised by flat cells covering the airway surface when viewed under a microscope. The squamous form tends to grow near the centre of the lung, and accounts for approximately 25-30% of all NSCLC cases.4

About Tecentriq (atezolizumab)
Tecentriq is a monoclonal antibody designed to bind with a protein called PD-L1 expressed on tumour cells and tumour-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, Tecentriq may enable the activation of T cells. Tecentriq Q has the potential to be used as a foundational combination partner with cancer immunotherapies, targeted medicines and various chemotherapies across a broad range of cancers.

Currently, Roche has eight Phase III lung cancer studies underway, evaluating Tecentriq alone or in combination with other medicines.

Tecentriq is already approved in the European Union, United States and more than 70 countries for people with previously treated metastatic NSCLC and for people with locally advanced or metastatic urothelial cancer (mUC) who are not eligible for cisplatin chemotherapy, or who have had disease progression during or following platinum-containing therapy.

Abraxane is a registered trademark of Abraxis Bioscience, LLC, a wholly owned subsidiary of Celgene Corporation.

On June 2 Nektar Therapeutics (Nasdaq: NKTR) and Bristol-Myers Squibb (NYSE: BMY) reported presentation of preliminary data from the ongoing PIVOT Phase 1/2 Study, which is evaluating the combination of Bristol-Myers Squibb’s Opdivo (nivolumab) with Nektar’s investigational medicine, NKTR-214 (Press release, Bristol-Myers Squibb, JUN 2, 2018, View Source [SID1234527062]). The preliminary results presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) reported safety, efficacy and biomarker data for patients enrolled in the Phase 1 dose-escalation stage of the study and for the first patients consecutively enrolled in select dose expansion cohorts in Phase 2. Data were presented today in an oral presentation (Oral Abstract Session: Developmental Therapeutics—Immunotherapy, Abstract #3006, 5:00 p.m. – 5:15 p.m. CT, Hall B1).

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Enrollment is ongoing in the Phase 2 stage of the PIVOT study in over 400 patients with melanoma, renal cell, urothelial, non-small cell lung and triple negative breast cancers.

Preliminary results from the ongoing PIVOT study presented today showed that pre-specified efficacy criteria were achieved in three tumor types: first-line melanoma, first-line renal cell carcinoma and first-line urothelial cancer. As a result, Nektar and Bristol-Myers Squibb will initiate a Phase 3 registrational trial in first-line advanced melanoma patients in Q3 2018, and pivotal studies are also being designed in renal cell carcinoma and urothelial cancer.

"In the Phase 1 dose-escalation and Phase 2 expansion stages of the PIVOT trial to-date, we’ve observed important responses, including activity in PD-L1 negative patients," said Mary Tagliaferri, M.D., Senior Vice President of Clinical Development and Chief Medical Officer at Nektar Therapeutics. "We look forward to advancing this combination into Phase 3."

The PIVOT study incorporates a Fleming 2-Stage Design, with efficacy targets separately pre-defined for each tumor type using a historical objective response rate (for single-agent checkpoint inhibitor).1 If the efficacy criteria at the recommended Phase 2 dose (RP2D) is met in the first stage (N1) of patients consecutively enrolled or in the second stage (N1 + N2) of patients consecutively enrolled, the combination regimen would be advanced to registrational trials in that tumor type.

Opdivo is a PD-1 immune checkpoint inhibitor designed to overcome immune suppression. NKTR-214 is an investigational immuno-stimulatory therapy designed to expand and activate specific cancer-fighting T cells and natural killer (NK) cells directly in the tumor micro-environment and increase expression of cell-surface PD-1 on these immune cells.

"Researching IL-2 pathway agonism and anti-PD-1 in combination may be a key strategy to more effectively activate an anti-tumor immune response," said Fouad Namouni, M.D., Head of Oncology Development, Bristol-Myers Squibb. "These preliminary results from PIVOT are encouraging, particularly in the PD-L1 negative population, and support our belief that that NKTR-214, a CD122 biased IL2 agonist, in combination with Opdivo can potentially expand the treatment benefits we can bring to patients with cancer."

Highlights from the oral presentation include:

Clinical Efficacy (Response measured per RECIST 1.1 for efficacy-evaluable patients (treated at the recommended Phase 2 dose and with >1 on treatment scan. Response and median time on study calculated from data cut as of May 29, 2018):

Stage IV Metastatic Treatment-Naïve 1L Melanoma Patients (Enrolled Per Fleming 2-Stage Design at RP2D):
Pre-specified efficacy criteria were met for Objective Response Rate (ORR) in Stage 1 (N1=13) with 11/13 (85%) of patients achieving either a partial response (PR) or complete response (CR). Median time on study for 28 patients in Stage 2 (N1+N2) is 4.6 months. Responses were observed in 14/28 (50%) patients (3 CR, 10 PR, 1 uPR). Amongst the 25 patients with known PD-L1 status, ORR in PD-L1 negative patients was 5/12 (42%) and in PD-L1 positive patients was 8/13 (62%). One patient with unknown PD-L1 baseline status experienced a CR.
Stage IV Metastatic Treatment-Naïve 1L Renal Cell Carcinoma Patients (Enrolled Per Fleming 2-Stage Design at RP2D):
Pre-specified efficacy criteria were met for ORR in Stage 1 (N1=11) with 7/11 (64%) of patients achieving a partial response (PR). Median time on study for 26 patients in Stage 2 (N1 + N2) is 5.6 months. Responses were observed in 12/26 (46%) patients (11 PR, 1 uPR). Amongst the 24 patients with known PD-L1 status, The ORR in PD-L1 negative patients was 9/17 (53%) and in PD-L1 positive patients was 2/7 (29%). One of two patients (50%) with unknown PD-L1 baseline status experienced a PR.
Stage IV Metastatic Treatment-Naïve 1L Urothelial Carcinoma (Enrolled Per Fleming 2-Stage Design at RP2D):
Pre-specified efficacy criteria were met for ORR in Stage 1 (N1=10) with 6/10 (60%) of patients achieving either a partial or complete response (2 uCR, 3 PR, 1 uPR). Median time on study for 10 patients in Stage 1 is 3.9 months. The ORR in PD-L1 negative patients was 3/5 (60%) and in PD-L1 positive patients was 3/5 (60%).
Biomarkers and Mechanism of Action:

Data presented show conversion of PD-L1 negative status at baseline to PD-L1 positive status at week 3 in 9/17 patients (53%). Of these previously PD-L1 negative patients, 78% achieved clinical benefit as defined by stable disease, partial response or complete response.
Clinical Safety (Safety database as of May 7, 2018):

A total of 283 patients have been treated at the RP2D. The most common treatment-related adverse events (TRAEs) were grade 1-2 flu-like symptoms (58.7%), rash (44.5%), fatigue (42.0%), and pruritus (31.4%). A total of 40/283 (14.1%) of patients experienced a Grade 3 (G3) or higher TRAE with 6/283 (2.1%) patients discontinuing treatment due to a TRAE. 10/283 (3.5%) of patients experienced a G3 or higher immune-mediated AE. There was one nivolumab-related G5 pneumonitis reported.
A copy of the full data presentation made by Dr. Diab is available on Nektar’s corporate website at View Source

Nektar and Bristol-Myers Squibb entered into a global strategic development and commercialization collaboration for NKTR-214 in February 2018. Under the collaboration, the companies will jointly develop and commercialize NKTR-214 in combination with Bristol-Myers Squibb’s nivolumab and Opdivo plus Yervoy (ipilimumab) in more than 20 indications across 9 tumor types, as well as potential combinations with other anti-cancer agents from either of the respective companies and/or third parties.

About NKTR-214

NKTR-214 preferentially binds to the CD122 receptor on the surface of cancer-fighting immune cells in order to stimulate their proliferation. In clinical and preclinical studies, treatment with NKTR-214 resulted in expansion of these cells and mobilization into the tumor micro-environment.2,3,4 NKTR-214 has an antibody-like dosing regimen similar to the existing checkpoint inhibitor class of approved medicines.

Nektar will webcast an analyst and investor event to review data presented in the oral session and new additional data from the PIVOT study on Saturday, June 2, 2018 at 6:45 p.m. CDT in Chicago, IL. PIVOT clinical investigators attending include Dr. Adi Diab, Assistant Professor, Melanoma Medical Oncology at the University of Texas MD Anderson Cancer Center, Dr. Scott N. Gettinger, Associate Professor, Medical Oncology at the Yale Cancer Center and Dr. Nizar M. Tannir, Professor, Genitourinary Medical Oncology at the University of Texas MD Anderson Cancer Center. Investors and analysts are invited to listen to a live audio webcast of the event, which will be accessible from the home page of the company’s website www.nektar.com. The webcast will also be available for replay for two weeks following the event.

On June 2, 2018 NantWorks, LLC reported that its affiliate companies, NantHealth, Inc., (NASDAQ: NH), a leading next-generation, evidence-based, personalized healthcare company and NantOmics, LLC, the leader in molecular analysis and a member of the NantWorks ecosystem of companies, will present findings on how 17 percent of next generation sequencing (NGS) 50 gene panel variants are not expressed in RNA sequencing during the tumor biology session at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2018 Annual Meeting, an event bringing together 30,000 oncology professionals from June 1-5, 2018 at McCormick Place in Chicago, Illinois (Press release, NantHealth, JUN 2, 2018, View Source;p=RssLanding&cat=news&id=2352873 [SID1234527096]). NantWorks will be exhibiting at booth #7147 during the event.

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"By determining the frequency of non-expressed variants that would be tested by a standard NGS panel, our data shows that the identification of these genes can yield improved testing algorithms and treatment strategies," said Patrick Soon-Shiong, MD, founder of NantWorks. "We’re excited to share this data and look forward to further exploring how NGS can be used for target therapy in oncology."

Presentation Details

Seventeen percent of NGS 50 gene panel variants are not expressed in RNAseq, Abstract #12118
WHO: NantHealth, LLC and NantOmics, LLC
WHAT: Tumor Biology Session
WHEN: June 4, 1:15-4:45 PM CST
WHERE: Hall A, McCormick Place

Presentation Summary

This study analyzed the frequency of non-expressed variants that would be tested by a standard NGS panel through retrospective analysis of a database from a commercial DNA tumor: normal and RNAseq platform. In the 992 samples that were identified with paired DNA (WGS or WES) / RNAseq NGS, a total of 225,727 SNVs were detected. Across 37 tumor types the range of expression was 57% (melanoma) – 100% (uterine). In this analysis, 17 percent of detected variants were not expressed in the RNA sequence. As a result, the lack of RNA expression may contribute to less than expected clinical benefit with molecularly targeted therapies. Since the distribution is non-uniform, identification of these genes can yield improved testing algorithms and treatment strategies.

On June 2, 2018 NantWorks, LLC reported that its affiliate companies, NantHealth, Inc., (NASDAQ: NH), a leading next-generation, evidence-based, personalized healthcare company and NantOmics, LLC, the leader in molecular analysis and a member of the NantWorks ecosystem of companies, will present findings on how targeting immune checkpoints and employing combinations has led to clinical benefit across a variety of tumor types during the tumor biology session at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2018 Annual Meeting, an event bringing together 30,000 oncology professionals from June 1-5, 2018 at McCormick Place in Chicago, Illinois (Press release, NantHealth, JUN 2, 2018, View Source;p=RssLanding&cat=news&id=2352872 [SID1234527097]). NantWorks will be exhibiting at booth #7147 during the event.

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"We are excited to share data on how profiling the tumor and associated microenvironment can help tailor rational combinations of immunotherapeutic strategies," said Patrick Soon-Shiong, MD, founder of NantWorks. "This data is an important step in enhancing response rates through individualized immune checkpoints in PD-L1 expression, and we look forward to continued exploration and potential solutions for patients."

Presentation Details

Co-expression patterns of immune checkpoint molecules in relation to PD-L1 expression, Abstract #12113
WHO: NantHealth, LLC and NantOmics, LLC
WHAT: Tumor Biology Session
WHEN: June 4, 1:15-4:45 PM CST
WHERE: Hall A, McCormick Place

Presentation Summary

In order to determine if tailored rational combinations of immunotherapeutic strategies can be achieved by profiling the tumor and associated microenvironment, whole transcriptomic sequencing of 1,880 unselected clinical cases, reflecting 38 distinct histologies, was performed. Cases were categorized as PD-L1-low, PD-L1-normal and PD-L1-high by cutoffs defined in TCGA expression profiles. The results found that high and low PD-L1 expression in the tumor and adjacent microenvironment are associated with variations in key checkpoint molecules. The results also found that low expression of PD-L1 may be an ideal setting for use of IDO- or TIM3-directed therapies.

On June 2, 2018 NantWorks, LLC reported that its affiliate companies, NantHealth, Inc., (NASDAQ: NH), a leading next-generation, evidence-based, personalized healthcare company and NantOmics, LLC, the leader in molecular analysis and a member of the NantWorks ecosystem of companies, the leader in molecular diagnostics and a member of the NantWorks ecosystem of families, reported that it will present data on three-fold overestimation of tumor mutation burden (TMB) using a 248 gene list as a panel to impute TMB during the tumor biology session at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2018 Annual Meeting, an event bringing together 30,000 oncology professionals from June 1-5, 2018 at McCormick Place in Chicago, Illinois. NantWorks will be exhibiting at booth #7147 during the event.

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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

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The data presented here have significant implications on the use of immunotherapies such as Keytruda and Opdivo given previous data touting the effectiveness of these drugs in patients whose tumors bear high TMB. The NantWorks companies’ data presented here caution against overestimation of TMB and thus immunotherapy overuse when extrapolating TMB from smaller panel tests (<500 genes) versus simply identifying all actual mutations by surveying the entire genome. Further, whether performing analysis on the entire genome or in a panel test, clinical validity for the use of immunotherapies is made appreciably more precise by confirming the expression of identified mutations. The patient’s immune system recognizes and targets non-self proteins, not DNA, thus underscoring the need to append the mutated genomic data with expression data. Maximal accuracy as established in this presentation by the use of tumor-normal DNA interpretation of TMB from surveying all genes and further amplified by derivation of expressed TMB is what is required for future immunotherapies such as neoepitope vaccines.

"We’re excited to share our data from our retrospective analysis, which may impact ICT prescription and expectation of clinical benefit," said Patrick Soon-Shiong, MD, founder of NantWorks. "Our analysis builds on our breadth of actionable insight and molecularly driven support for cancer patients and their providers, and we look forward to continuing to build upon our diagnostic capabilities."

Presentation Details

Three-fold overestimation of tumor mutation burden using 248 gene panel versus whole exome, Abstract, #12117
WHO: NantHealth, LLC and NantOmics, LLC
WHAT: Tumor Biology Session
WHEN: June 4, 1:15-4:45 PM CST
WHERE: Hall A, McCormick Place

Presentation Summary

This study analyzed if actual TMB (aTMB), consisting of mutations across the exome, and expressed TMB (eTMB), consisting of expressed genes, would differ substantially from iTMB. Retrospective analysis of a database from a commercial DNA tumor:normal and RNAseq platform was carried out. 890 clinical samples were analyzed, composing of both primary and metastatic disease by whole genome sequencing (WGS) or WES and RNA sequencing (RNA-Seq), and compared true tumor mutational burden to a predicted tumor mutational burden from a list of 248 genes thought to drive cancer. The study showed an estimated tumor mutational burden based only on the list of 248 genes had an average of 15.79 mutations per megabase whereas WGS/WES derived TMB had an average of 5.09 mutations per megabase of coding DNA. As a result, the study indicates that a roughly 3-fold over-estimate of TMB was observed, which may impact ICT prescription and expectation of clinical benefit.