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Novartis investigational checkpoint inhibitor tislelizumab met primary endpoint of overall survival in pivotal Phase III trial of esophageal cancer after systemic therapy

On June 4, 2021 Novartis reported that results from the pivotal Phase III RATIONALE 302 trial showing the investigational anti-PD-1 immune checkpoint inhibitor tislelizumab improved overall survival (OS) versus chemotherapy (median 8.6 months vs. 6.3 months, p=0.0001) (Press release, Novartis, JUN 4, 2021, View Source [SID1234583564]).1 The study evaluated tislelizumab in patients with unresectable recurrent locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) who had received prior systemic therapy. Results were presented at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

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Results from RATIONALE 302 in ESCC showed tislelizumab extended median OS by 2.3 months compared to chemotherapy with a 30% reduction in the risk of death (HR=0.70, 95% CI: 0.57-0.85, p=0.0001).1 In PD-L1 positive patients, tislelizumab extended median OS by 3.5 months with a 46% reduction in the risk of death (HR=0.54, 95% CI: 0.36-0.79, p=0.0006).1

"These data show that tislelizumab has the potential to help patients with esophageal squamous cell carcinoma – one of the deadliest types of cancers – live longer," said Jeff Legos, Ph.D., MBA, Senior Vice President and Head of Oncology Drug Development. "We are excited about these results from the newest asset in our portfolio of transformational medicines and look forward to sharing these data with regulatory authorities, as we continue to explore the full potential of this uniquely designed anti-PD-1 antibody."

Treatment with tislelizumab demonstrated median progression-free survival (PFS) of 1.6 months compared to 2.1 months (HR=0.83, 95% CI: 0.67–1.01). Tislelizumab demonstrated a higher and more durable anti-tumor activity than chemotherapy (objective response rate [ORR], 20.3% vs. 9.8%; median duration of response [DoR], 7.1 months vs. 4.0 months).1

The discontinuation rate due to treatment-related adverse events (TRAEs) was lower in patients who received tislelizumab (6.7%) compared to chemotherapy (13.8%). The most common all-grade TRAEs (≥10%) with tislelizumab were increased aspartate aminotransferase (11.4%), anemia (11%) and hypothyroidism (10.2%). No new safety signals were identified.1

"Most patients with this type of esophageal cancer are diagnosed with advanced disease, resulting in a poor prognosis for this difficult-to-treat cancer," said Jaffer Ajani, M.D., professor of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center. "The impact tislelizumab had on survival compared to chemotherapy in this study is highly meaningful and encouraging news for patients, caregivers and treating oncologists."

Esophageal squamous cell carcinoma is the most common type of esophageal cancer globally and the sixth leading cause of cancer-related death worldwide.3 Each year, esophageal cancer claims nearly as many lives as colon cancer across the globe.3 More than two-thirds of patients with ESCC have advanced or metastatic disease at the time of diagnosis.4 The average five-year survival rate is only five percent.5

RATIONALE 302 is a randomized, global Phase III study assessing tislelizumab versus chemotherapy in patients with advanced unresectable/metastatic ESCC after prior systemic therapy. The primary endpoint is OS in the intent-to-treat (ITT) population. The key secondary endpoint is OS in PD-L1 positive patients (vCPS ≥10%). Additional secondary endpoints included PFS, ORR, DoR and safety endpoints.1

Data on tislelizumab in MSI-H cancers presented
The RATIONALE 209 study reported that tislelizumab showed durable anti-tumor activity in patients with previously treated, locally advanced, unresectable or metastatic microsatellite instability-high (MSI-H) and mismatch repair deficient (dMMR) cancers, which are known to be more responsive to immune checkpoint modulation. Treatment with tislelizumab demonstrated an ORR of 45.9% among all tumor types, including four complete responses (CR) and 30 partial responses (PR). No disease progression was reported in the 34 responders (CR + PR), with a 12-month DoR rate of 100%).2

Five percent of patients treated with tislelizumab discontinued treatment due to TRAEs, and no new safety signals were identified. Grade ≥3 TRAEs occurred in 42.5% of patients.2

MSI-H cancer cells have a defect in the ability to correct mistakes that occur when DNA is copied, leading to mutations that contribute to cancerous growth. Many types of cancer may have a high level of microsatellite instability, but it is seen most often in CRC, gastric cancer and endometrial cancer.6

RATIONALE 209 is a single-arm, open-label Phase II study evaluating the efficacy and safety of tislelizumab monotherapy in adult patients with previously treated, locally advanced, unresectable or metastatic histologically confirmed MSI-H/dMMR solid tumors. Radiological imaging was performed at nine weeks, then every six weeks for the first year of therapy and every 12 weeks thereafter. The primary endpoint was IRC-assessed ORR. Secondary endpoints included time to response, DoR, disease control rate, PFS, OS and safety.2

Visit View Source for the latest information from Novartis, including our commitment to the Oncology community, and access to our ASCO (Free ASCO Whitepaper)21 Virtual Scientific Program data presentations (for registered participants).

About tislelizumab
Tislelizumab was specifically engineered to minimize binding to macrophage Fcγ receptors, a potential mechanism of anti–PD-1 resistance.7 Tislelizumab is an important component of Novartis’s immuno-oncology strategy – one of four bold approaches to reimagining cancer and transforming patients’ lives.

In an agreement finalized earlier this year, BeiGene granted Novartis rights to develop, manufacture, and commercialize tislelizumab in North America, Europe, and Japan through a collaboration and license agreement.

MEI Pharma to Host Investor and Analyst Video Webcast Event Following 2021 ASCO Annual Meeting

On June 4, 2021 MEI Pharma, Inc. (NASDAQ: MEIP), a late-stage pharmaceutical company focused on advancing new therapies for cancer, reported it will host an investor and analyst video webcast event on Thursday, June 10, 2021 at 12:00 PM ET following the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, MEI Pharma, JUN 4, 2021, View Source [SID1234583563]). The event will include a review of the zandelisib program, including recent data presented at ASCO (Free ASCO Whitepaper), and commentary from key opinion leader Deepa Jagadeesh, M.D., MPH, a board-certified medical oncologist/hematologist and assistant professor, Cleveland Clinic Lerner College of Medicine, Lymphoma and Bone Marrow Transplant Program, and Taussig Cancer Institute. The event will include additional zandelisib data as well as an overview and update of MEI’s business.

Video Webcast Information
You can access the live video webcast under the investor relations section of MEI’s website on the "Events and Presentation" page at: www.meipharma.com. A replay of the video webcast will be archived for at least 30 days after the conclusion of the live event.

Vincerx Pharma Presents Clinical Data on VIP512, its PTEFb/CDK9 Inhibitor, in Patients with Double-Hit Lymphoma at ASCO 2021

On June 4, 2021 Vincerx Pharma, Inc. (Nasdaq: VINC) a biopharmaceutical company aspiring to address the unmet medical needs of patients with cancer through paradigm-shifting therapeutics, reported the presentation of safety and efficacy data from the Phase 1 study of VIP152, the Company’s PTEFb/CDK9 inhibitor, in patients with double-hit lymphoma at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held virtually from June 4-8, 2021 (Press release, Vincerx Pharma, JUN 4, 2021, View Source [SID1234583562]).

"The data generated in double-hit lymphoma are compelling, providing early evidence that on-target activity of VIP152 has the potential to provide durable responses in patients who have no standard of care therapy and poor prognoses," said Ahmed Hamdy M.D., Chief Executive Officer of Vincerx. "The achievement of durable metabolic complete responses with once weekly monotherapy lasting beyond two and three years is remarkable. These efficacy signals were also obtained with a favorable safety profile, with no patients stopping treatment due to adverse events, and the patients with metabolic complete responses stopping treatment only due to the COVID-19 pandemic. Our Phase 1 results, which also include durable disease control in solid tumors, provide a strong foundation of data, which support targeting MYC and MCL1-driven malignancies with our potent and selective PTEFb/CDK9 inhibitor. We look forward to further investigating the potential of VIP152 in challenging patient populations with our ongoing Phase 1b expansion study, which is currently enrolling patients with relapsed/refractory aggressive lymphoma and advanced solid tumors, and our soon to be launched Phase 1b dose-escalation in CLL relapsed/refractory to venetoclax and BTK inhibitors."

Key Presentation Highlights:

Poster presentation, titled, "Safety and efficacy of VIP152, a PTEFb / CDK9 inhibitor, in patients with double-hit lymphoma", include:

CDK9 mediates the transcription of oncogenes such as MYC and MCL-1, which play a critical role in a variety of cancers.
VIP152, a potent and selective inhibitor of CDK9, has completed dose escalation in patients with advanced malignancies (NCT02635672). Significant monotherapy clinical activity was observed with a favorable safety profile:
Seven patients with solid tumors had disease control during the dose escalation portion of the study, including a patient with pancreatic cancer (~14 cycles; dose 30 mg once weekly) and a patient with salivary gland cancer (~24 cycles; dose 22.5 mg once weekly).
One patient with double-hit DLBCL (DHL), who was treated with VIP152 30 mg once weekly, achieved metabolic complete remission. DHL is defined as a dual arrangement or overexpression of the MYC gene and either the B-cell lymphoma 2 (BCL2) or BCL6 genes.
No patients discontinued due to adverse events.
An expansion cohort of 6 additional patients with DHL were dosed with VIP152 30 mg once weekly:
All patients with DHL (median [range] age 70 [58-84] years) had received front-line R-CHOP or R-EPOCH, with two patients having had prior stem cell transplant, and additional therapies include R-DHAP, R-GemOx, R-ICE and durvalumab. Four patients had 2 prior lines of therapy and 3 patients had ≥3 prior lines of therapy. Three patients had been refractory to their last treatment. Six patients had advanced disease (Ann Arbor Stage III or IV) at study entry.
VIP152 had a favorable safety profile, with most common adverse events (AEs) being Grade 1 and Grade 2 severity. Two patients had a serious AE (Grade 3 syncope and Grade 3 tumor pain). No patients withdrew from treatment due to any AEs.
Pharmacodynamic biomarker analysis showed significant reduction, lasting at least 4 hours, of MYC, PCNA and MCL-1 mRNA in all patients.
Anti-tumor activity consisted of 2 metabolic complete responses (CRs) in 7 patients (29%), based on investigator-assessed FDG-PET scans.
Both metabolic CRs were durable, with patients remaining on treatment for 3.7 and 2.3 years until study withdrawal due to the COVID pandemic. Both patients had metabolic CRs at the time of study exit.
The results from this expansion cohort of 7 patients with DHL, a cancer known to have MYC translocations, suggests that reduction of MYC expression for at least 4 hours can provide durable complete remissions lasting several years. The favorable safety profile of VIP152 allowed for long-term dosing in elderly patients with advanced disease.
A Phase 1b expansion study in MYC-driven advanced cancers is ongoing, evaluating up to 30 patients with relapsed/refractory aggressive lymphoma, and up to 40 patients with advanced solid tumors.
The poster can be accessed on the presentations section of the Vincerx website.

Phio Pharmaceuticals Presents New In Vivo Data at the 2021 ASCO Annual Meeting Showing Dual-Targeting INTASYL Offers Increased Efficacy and Safety Potential Over Other Therapeutic Approaches

On June 4, 2021 Phio Pharmaceuticals Corp. (Nasdaq: PHIO), a biotechnology company developing the next generation of immuno-oncology therapeutics based on its proprietary self-delivering RNAi (INTASYL) therapeutic platform, reported positive in vivo data that provide further evidence on the utility of its INTASYL self-delivering RNAi therapy platform in the field of immuno-oncology (Press release, Phio Pharmaceuticals, JUN 4, 2021, View Source [SID1234583561]). The new study data show how INTASYL can be easily deployed to target multiple proteins and provide evidence of the synergy of the Company’s pipeline products. In the study, INTASYL specifically dual-targeting BRD4 and PD-1 elicited complete tumor responses in an in vivo hepatoma model, and significantly outperformed the efficacy of small molecule and antibody treatments towards the same targets.

In this study, the Company assessed the efficacy of mouse/human BRD4-targeting INTASYL PH-894 as monotherapy or co-formulated with mouse PD-1 targeting INTASYL mPH-762, in treating a subcutaneous Hepa1-6 model of murine hepatoma in C57BL/6N mice. Positive controls included JQ-1, a small molecule inhibitor of BRD4 and anti-mouse PD-1 monoclonal antibody (mAb) or both treatments.

"We are excited by these new in vivo study results presented at ASCO (Free ASCO Whitepaper) today, which highlight the potential of INTASYL as a mono- or dual-targeting therapy platform. By using doses that were well below the optimal single agent therapeutic dose identified in previous animal studies, we can obtain very high efficacy by dual-targeting BRD4 and PD-1. Even at these suboptimal concentrations, the dual-targeting INTASYL compound elicited complete responses in 83% of mice, and outperforming JQ-1 and anti-PD-1 mAb treatments, either used individually or in combination. Data from the study also suggests that the dual targeting INTASYL treatment resulted in a superior safety profile, as compared to the JQ-1 and anti-PD-1 mAb treatments," stated Dr. Simon Fricker, Phio’s VP of Research. He added, "These data further support our message that INTASYL can outperform other therapeutic approaches, and that synergistic drug combination approaches can be easily executed with a single INTASYL formulation."

A poster further detailing the data presented at the 2021 ASCO (Free ASCO Whitepaper) Annual Meeting titled "INTASYL self-delivering RNAi therapy specifically dual-targeting BRD4 and PD-1 elicits complete tumor responses and evidence of synergy in a subcutaneous Hepa1-6 model of murine hepatoma in C57BL/6N mice" will be made available on the "Investors – Events and Presentations" section of the Company’s website (click here).

SRF388, a First-in-Class IL-27 Antibody, Demonstrates Monotherapy Activity in Data Presented at American Society of Clinical Oncology Annual Meeting

On June 4, 2021 Surface Oncology (Nasdaq: SURF), a clinical-stage immuno-oncology company developing next-generation immunotherapies that target the tumor microenvironment, reported the presentation of new data from the ongoing Phase 1 studies of SRF388 and SRF617 (Press release, Surface Oncology, JUN 4, 2021, View Source [SID1234583560]). Data from the SRF388 study are to be presented in a scientific poster at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2021 Annual Meeting, being held virtually June 4-8, 2021 . In conjunction, Surface will host a webcast on Friday, June 4, 2021, at 8:00 a.m. ET to provide updates on both SRF388 and SRF617.

"Generating evidence of monotherapy activity is a highly sought after, yet elusive, goal in immuno-oncology and we are excited to report that one of our molecules, SRF388, has produced a partial response in a heavily pretreated patient with lung cancer," said Rob Ross, M.D., chief executive officer. "These findings validate our scientific rationale and represent an important step forward in our pursuit of transformative treatments to help patients with cancer. We are also pleased to report that SRF617 continues to demonstrate good tolerability with evidence of biological activity. Moving forward, we are opening monotherapy and combination cohorts for both molecules across a range of tumor types, informed by the data we have generated to date."

"SRF388 is an antibody against IL-27, an immunosuppressive cytokine that plays a key role in controlling immunotolerance to cancer. These data from the ongoing SRF388 Phase 1 clinical study reinforce the potential benefit of IL-27 blockade as a promising anticancer strategy, particularly given the monotherapy partial response in a patient with PD-1-refractory lung cancer," said Amita Patnaik, M.D., co-director of clinical research at the START Center for Cancer Care in San Antonio, Texas, and lead author of the SRF388 results summary presented at ASCO (Free ASCO Whitepaper).

SRF388 Highlights:

Preliminary SRF388 results indicate promising single-agent activity in a heavily pretreated population, including a confirmed partial response demonstrating 66% tumor shrinkage and symptomatic improvement in a patient with squamous cell non-small-cell lung carcinoma (NSCLC), whose disease was resistant to three prior regimens including chemotherapy and PD-1 blockade.

In addition, there was evidence of disease stabilization, with 6 of 18 (33%) of evaluable patients experiencing disease stabilization at eight weeks and five (28%) persisting beyond 16 weeks.
SRF388 was well tolerated at all doses tested, with no dose-limiting toxicity observed to date, and with only low-grade treatment-related adverse events.
The recommended Phase 2 dose of 10 mg/kg was confirmed based on observed efficacy, tolerability, optimal pSTAT1 inhibition and pharmacokinetics.
SRF617 Highlights:

Early data from combination cohorts point to SRF617’s potential as a combination therapy, including an unconfirmed partial response with an approximately 50% tumor shrinkage in a patient with pancreatic cancer receiving second-line treatment with SRF617 in combination with gemcitabine/albumin-bound paclitaxel (Abraxane).

In addition, with SRF617 monotherapy, 7 of 19 evaluable patients (37%) achieved disease stabilization at eight weeks, with 4 (21%) persisting beyond 16 weeks.
SRF617 was well tolerated at all tested doses as a monotherapy and has a tolerability profile that is conducive to combination strategies.
"Results from both ongoing clinical trials support further evaluation of SRF388 and SRF617 as monotherapies and in combination with standard and investigational regimens in both immune checkpoint naïve and experienced patients," said Alison O’Neill, M.D., chief medical officer. "We’re pleased to see a profile allowing patients in both studies to escalate to higher doses with good tolerability."

Presentation at American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper):

Presentation Type: e-poster (Abstract: 2551)
Title: Results of a phase 1 study of SRF388, a first-in-human, first-in-class, high-affinity anti-IL-27 antibody in advanced solid tumors
Session: Developmental Therapeutics – Immunotherapy
Lead Authors: Amita Patnaik, M.D. and Daniel Morgensztern, M.D.

The ASCO (Free ASCO Whitepaper) e-poster website will be launched on Friday, June 4, 2021, and will remain available for viewing through Tuesday, July 6, 2021. The full poster can be found on Surface Oncology’s website following the presentation.

Webcast Information:

The webcast, scheduled for June 4, 2021, at 8:00 a.m. ET, can be accessed online, and by telephone by dialing (866) 394-2883 (US/Canada) or (314) 888-4236 (international) five minutes prior to the start time and referring to conference ID 4567647. A recording of the webcast will be posted on the Surface website and available on-demand for one year.

About the SRF388-101 Clinical Trial:
The trial is a Phase 1, open-label, multicenter, first-in-human dose-escalation trial of SRF388, a monoclonal antibody targeting IL-27, conducted in patients with advanced solid tumors refractory to standard therapy. The first portion of the study will establish the preliminary safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of SRF388 as a monotherapy and identify a dose suitable for expansion studies. In the second portion of the study, indication-specific expansion cohorts will evaluate the safety, preliminary efficacy, tolerability, PK and PD of SRF388 monotherapy and SRF388 in combination with pembrolizumab in patients with advanced or metastatic kidney and liver cancer.

About SRF388:
SRF388 is a fully human anti-IL-27 antibody designed to inhibit the activity of this immunosuppressive cytokine. Surface Oncology has identified particular tumor types, including liver, kidney and lung cancer, where IL-27 appears to play an important role in the immunosuppressive tumor microenvironment and may contribute to resistance to treatment with checkpoint inhibitors. SRF388 targets the rate-limiting p28 subunit of IL-27, and preclinical studies have shown that treatment with SRF388 blocks the immuno-suppressive biologic effects of IL-27, resulting in immune cell activation in combination with other cancer therapies including anti-PD-1 therapy, as well as potent anti-tumor effects as a monotherapy. Furthermore, Surface Oncology has identified a potential biomarker associated with IL-27 that may be useful in helping to identify patients most likely to respond to SRF388. In November 2020, Surface announced that SRF388 was granted Orphan Drug designation and Fast Track designation for the treatment of hepatocellular carcinoma from the FDA.

About the SRF617-101 Clinical Trial:
The trial is a Phase 1, open-label, multicenter, first-in-human dose-escalation trial of SRF617, a monoclonal antibody that binds and inhibits CD39 activity, in patients with advanced solid tumors. The monotherapy dose escalation portion of the study will evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of SRF617 as a monotherapy in patients with advanced solid tumors. The monotherapy tumor biopsy expansion portion of the study will further evaluate the safety and intratumoral PD of SRF617 as a monotherapy. The combination therapy dose escalation portion of the study will evaluate the safety, tolerability, PK and preliminary efficacy of SRF617 in combination with gemcitabine + albumin-bound paclitaxel (Abraxane), or SRF617 in combination with pembrolizumab, in patients with locally advanced or metastatic solid tumors.

About SRF617:
SRF617 is a fully human antibody designed to inhibit the enzymatic activity of CD39 in the tumor microenvironment, allowing for a dual mechanism of action to promote anti-tumor immunity via reduction of immunosuppressive adenosine in addition to increasing levels of immunostimulatory ATP. A substantial body of research supports a role for CD39 in allowing cancer to evade immune responses. For example, pancreatic cancer stromal cells within the tumor micro-environment express high levels of CD39 which may inhibit anti-cancer immune responses. In preclinical studies, SRF617 has exhibited strong affinity for and inhibition of CD39, the ability to reduce adenosine and increase ATP levels and anti-tumor activity both as a single agent and in combination with multiple therapeutic agents. SRF617 has been granted Orphan Drug designation for the treatment of advanced pancreatic cancer by the FDA.