On June 2, 2018 X4 Pharmaceuticals, a clinical stage biotechnology company developing novel CXCR4 antagonists to improve immune cell trafficking to treat cancer and rare diseases, reported positive clinical results from the Phase 2 expansion of an ongoing Phase 1/2 study of X4P-001-IO in combination with Inlyta (axitinib) in patients with clear cell renal cell carcinoma (ccRCC).

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The results were the first from the Phase 2 portion of the study and demonstrated that the combination was well tolerated with a manageable safety profile and had encouraging response in heavily pretreated patients. In patients with ccRCC, the combination treatment of X4P-001-IO, a CXCR4 antagonist, and Inlyta, Pfizer’s VEGFR kinase inhibitor, showed an objective response rate (ORR) of 23%, including 1 patient with a confirmed complete response (CR). Nearly 75% of patients received at least two prior lines of therapy prior to entering the study. The data were presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on June 2nd in Chicago, IL.

"X4P represents a novel targeted mechanism of action with demonstrated tolerability and promising efficacy in combination with axitinib in patients with pretreated renal cancer. The results from this study demonstrate that X4P-001-IO has the potential to enhance clinical responses to axitinib and other tyrosine kinase inhibitors that target tumor angiogenesis," said Ulka Vaishampayan, MD, Chair, Karmanos Cancer Center, Professor of Oncology at Wayne State University, and lead investigator of the study.

Results from the 65 patients with advanced ccRCC enrolled in the ongoing study (as of the data cutoff date of March 23, 2018) were presented at ASCO (Free ASCO Whitepaper) and highlights of the poster presentation include:

The combination of 400 mg X4P-001-IO administered once daily and 5 mg axitinib twice daily was well tolerated with a manageable safety profile. The most frequent treatment-related adverse events (AEs) were diarrhea, decreased appetite, fatigue, hypertension, nausea, headache and cough. No grade 4 or 5 AEs were observed.
In the 47 evaluable patients, the overall response rate (ORR) was 23% with one patient achieving a confirmed complete response (CR). Response data from the remaining 18 patients is pending.
Thirteen patients remain on study for 24 weeks or more; the median duration on treatment was 16 weeks (range 2 – 96 weeks).
"These interim results represent an important step in the continued development of X4P-001-IO. In this larger patient population, where many patients are still very early in treatment with the combination, we find promising signs of clinical efficacy. The tumor microenvironment modulating effect of X4P-001-IO is expected to increase and deepen responses over time, and we look forward to the maturation of the data in the coming months," said Sudha Parasuraman, MD, Chief Medical Officer of X4. "Our combined clinical experience continues to demonstrate the important role that CXCR4 antagonism may play in improving outcomes in combination with important cancer therapeutic modalities."

The Phase 2 portion of the study continues to follow patients on study to evaluate the clinical efficacy of X4P-001-IO as measured by objective response rate (ORR), duration of response (DOR), and progression free survival (PFS). (View Source)

About X4P-001-IO in Cancer

X4P-001-IO is an investigational selective, oral, small molecule antagonist of C-X-C receptor type 4 (CXCR4). CXCR4 is a chemokine receptor present in abundance on certain immune cells and cancer cells and it plays a critical role in immune cell trafficking, infiltration and activation in the tumor microenvironment. CXCR4 signaling is disrupted in a broad range of cancers, facilitating tumor growth by allowing cancer cells to evade immune detection and creating a pro-tumor microenvironment. X4P-001-IO has the ability to help restore immunity within the tumor microenvironment and has the potential to enhance the anti-tumor activity of approved and emerging oncology agents, such as checkpoint inhibitors and targeted therapies. X4P-001-IO is being investigated in several clinical studies in solid tumors.

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.