On April 19, 2024 GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, reported US Food and Drug Administration (FDA) has granted the clinical trial approval for GFH925 (KRAS G12C inhibitor) in a multi-center, open-label, randomized and controlled phase III study treating refractory metastatic colorectal cancer (CRC) patients (Press release, GenFleet Therapeutics, APR 19, 2024, View Source [SID1234642176]).

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It is the first phase III trial of KRAS G12C inhibitor monotherapy targeting CRC patients worldwide, with GFH925 being the first G12C inhibitor that received Breakthrough Therapy Designation (BTD) from China’s National Medical Products Administration (NMPA) for previously treated advanced CRC. GFH925 was also granted BTD and New Drug Application acceptance with Priority Review Designation by NMPA for previously treated advanced non-small cell lung cancer（NSCLC）patients with G12C mutation.

The trial (GFH925X0301) will enroll refractory metastatic CRC patients harboring KRAS G12C mutation who have progressed or experienced disease recurrence on or after at least two prior lines of therapies, or intolerant to the last treatment. The primary objective is to compare the efficacy of GFH925 versus the current standard of care.

A pooled analysis from the two phase I studies was published at ESMO (Free ESMO Whitepaper) Asia 2023: GFH925 monotherapy for CRC demonstrated efficacy (including objective response rate and median progression-free survival) superior to other single-agent KRAS G12C inhibitors and comparable to the combination regimens of other G12C inhibitors with anti-EGFR antibodies.

"We appreciate the FDA’s recognition of GFH925′ efficacy and safety profile, as this is our first global phase III monotherapy study in treating advanced stage CRC. We believe the approval of our proposed trial design highlights the potential of GFH925 monotherapy in this indication, thus bringing more therapeutic options and clinical benefits to the patients. This is a significant step forward in the development of GFH925, paving the way for its potential future use as a front-line treatment for CRC. "stated Yu Wang, Ph.D/M.D., Chief Medical Official of GenFleet. "Additionally, the study of GFH925 in combination with cetuximab is ongoing in Europe treating advanced NSCLC in the first-line setting and the phase II trial has completed the enrollment; the preliminary data analysis of this combination study, accepted as a late breaking abstract, has been selected for oral presentation during the 2024 ASCO (Free ASCO Whitepaper) annual meeting. GFH925’s global development reflects GenFleet’s forward-thinking strategy, the expertise of our clinical team and the deep understanding of biology for our RAS-targeted pipeline."

According to GLOBOCAN 2022 report, there were over 1.9 million new CRC cases and over 900,000 deaths worldwide, both accounting for over 9% in all cancer types. Approximately 40% of CRC patients carry KRAS mutations, with the prevalence of mutated G12C allele in CRC being only next to NSCLC. Standard first- and second-line treatments are based on combination of fluoropirimidines plus oxaliplatin or irinotecan, associated to an anti-EGFR (RAS wild type) or anti-VEGF antibody.

Among the patients that eventually develop metastases to liver, lung and/or peritoneum, KRAS mutation in CRC is a prognostic factor associated with advanced disease status, poor tumor differentiation, distant metastasis, and inferior survival. On the other hand, a limited number of CRC patients receive checkpoint inhibiting therapies, especially when compared with patients of other hot tumors such as lung cancer; more targeted agents with a safety profile are called for those patients. Moreover, prior-line EGFR inhibitors may lead to secondary KRAS mutations. There is consequently a substantial unmet clinical need, coupled with vast market potential, for developing innovative KRAS inhibitors.

References:
1. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA: A Cancer Journal for Clinicians, Apr. 2024
2. Targeting KRAS G12C Mutation in Colorectal Cancer, A Review: New Arrows in the Quiver, International Journal of Molecular Science, Mar. 2024
3. Disease Burden of Total and Early-Onset Colorectal Cancer in China from 1990 to 2019 and Predictions of Cancer Incidence and Mortality, Clinical Epidemiology, Feb. 2023
4. Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors, Precision Oncology, Dec. 2022

About GFH925 and RAS
The clinical data of two phase I studies of GFH925 monotherapy for CRC treatment were posted at 2023 ESMO (Free ESMO Whitepaper) Asia. For 600mg BID patients (n=48), confirmed ORR and DCR were of 45.8% and 89.6% respectively; median PFS was 7.6 months. GFH925 the first China-developed KRAS G12C inhibitor that has its NDA submission accepted and granted with Priority Review Designation by NMPA. GFH925 also received Breakthrough Therapy Designations this year for treating advanced KRAS G12C-mutant NSCLC patients that have received at least one systemic therapy and CRC patients who have received at least two systemic therapies.

RAS protein family can be divided into KRAS, HRAS and NRAS categories. KRAS mutations are detected in nearly 90% of pancreatic cancer, 30-40% of colon cancer, and 15-20% lung cancer patients. The occurrence of KRAS G12C mutation subset is more frequently observed than those with ALK, ROS1, RET and TRK 1/2/3 mutations combined. GFH925 is a novel, orally active, potent KRAS G12C inhibitor designed to effectively target the GTP/GDP exchange, an essential step in pathway activation, by modifying the cysteine residue of KRAS G12C protein covalently and irreversibly. Preclinical cysteine selectivity studies demonstrated high selectivity of GFH925 towards G12C. Subsequently, GFH925 effectively inhibits the downstream signal pathway to induce tumor cells’ apoptosis and cell cycle arrest.

On April 19, 2024 Nykode Therapeutics ASA (OSE: NYKD), a clinical-stage biopharmaceutical company dedicated to the discovery and development of novel immunotherapies, reported the initiation of the Phase 2 clinical trial VB-C-04 (Press release, Nykode Therapeutics, APR 19, 2024, View Source [SID1234642175]). The trial evaluates VB10.16, the company’s off-the-shelf therapeutic cancer vaccine candidate for HPV16-positive cancers, alone or in combination with Roche’s checkpoint inhibitor atezolizumab (Tecentriq1) in patients with HPV16-positive, PD-L1-positive, recurrent, or metastatic cervical cancer.

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Step 1 of VB-C-04 is a two-arm Phase 2 trial evaluating the efficacy and safety of VB10.16 alone or in combination with atezolizumab in patients with recurrent or metastatic cervical cancer refractory to firstline treatment with pembrolizumab plus chemotherapy +/-bevacizumab.

The Phase 2 trial (GOG-3091) will be conducted in the United States (U.S.) in collaboration with The GOG Foundation, Inc. (GOG Foundation)), a U.S. based not-for-profit organization with the purpose of promoting excellence in the quality and integrity in clinical trials in gynecologic malignancies. The GOG Foundation is the only clinical trialist group in the United States that focuses its research on patients with pelvic malignancies, such as cancer of the ovary (including surface peritoneal malignancies), uterus (including endometrium, soft tissue sarcoma, and gestational trophoblastic neoplasia), cervix, and vulva.

Dr. Bradley Monk, Director of GOG, said "Today marks an important step forward in our efforts to advance cancer treatment with the initiation of the Phase 2 trial of VB10.16 in second line HPV16-positive cervical cancer. This is a collaborative effort between GOG and Nykode, introducing a novel and promising approach to address a significant unmet medical need. As we embark on this Phase 2 trial, we are optimistic about the potential impact on reshaping the landscape of cancer care and look forward to contributing to advancements that can make a meaningful difference in patients’ lives."

"Initiating the VB10.16 trial for HPV16-positive cervical cancer addressing a high unmet medical need, is a significant step in our clinical development strategy," said Klaus Edvardsen, Chief Development Officer of Nykode Therapeutics. "The encouraging clinical profile and favorable tolerability exhibited by VB10.16 in combination with atezolizumab among patients with advanced HPV16 positive cervical cancer observed in VB-C-02 supports our dedication to advancing VB10.16 as an innovative immunotherapy for HPV16 positive cancers."

Atezolizumab is supplied by Roche. Nykode retains all commercial rights to VB10.16 worldwide.

About VB10.16

VB10.16 is a potentially first-in-class off-the-shelf therapeutic DNA-based cancer vaccine candidate in development for the treatment of human papillomavirus type 16 (HPV16)-positive cancers. The cancer vaccine is designed based on Nykode’s Vaccibody technology platform of targeting antigens to antigen presenting cells. VB10.16 has reported promising data from a Phase 2 trial in advanced PD-L1 positive cervical cancer patients (NCT04405349) in combination with atezolizumab with mOS not reached, but at least 24 months at the time of analysis. The vaccine-induced significant HPV16-specific T cell responses that were correlated with clinical responses. The candidate has also demonstrated favorable clinical data in a Phase 1/2a study in pre-cancerous HPV16-induced high grade cervical intraepithelial neoplasia (HSIL; CIN 2/3) demonstrating a statistically significant correlation of immune responses and clinical responses. Nykode is currently investigating VB10.16 in VB-C-03, an open-label, dose-finding Phase 1/2a trial evaluating VB10.16 in combination with MSD’s PD-1 inhibitor KEYTRUDA (pembrolizumab) in patients with HPV16-positive, PD-L1-positive, recurrent, or metastatic head and neck squamous cell carcinoma (HNSCC) in addition to the VB-C-04 trial initiated today.

About the Phase 2 Trial

The Phase 2 VB-C-04 trial (NCT06099418) is designed to evaluate the efficacy and safety of VB10.16. Step 1 is randomized and will evaluate VB10.16 as a monotherapy, and in combination with Roche’s checkpoint inhibitor atezolizumab as a second line treatment in patients with recurrent or metastatic cervical cancer. Step 1 of the trial is expected to enroll 60 patients with disease progression after combination treatment with pembrolizumab, chemotherapy +/-bevacizumab into the trial. Step 2 is intended to enroll additional patients in one cohort after reviewing the data from Step 1.

About Cervical Cancer

Cervical cancer is the fourth leading cause of cancer death in women worldwide and is most frequently diagnosed between the ages of 35 and 44. Each year around 600,000 women are diagnosed with cervical cancer worldwide. Almost all cases are caused by human papillomavirus (HPV) infection and HPV16 accounts for more than half of all cervical cancer cases. Approximately 80% of patients with cervical cancer have squamous cell carcinoma and most other patients have adenocarcinomas. Cervical cancer is often curable when detected early and effectively managed, but treatment options are more limited in advanced disease stages or when the cancer has spread.

On April 19, 2024 Iovance Biotherapeutics, Inc. (NASDAQ: IOVA) ("Iovance" or the "Company"), a biotechnology company focused on innovating, developing, and delivering novel polyclonal tumor infiltrating lymphocyte (TIL) therapies for patients with cancer, reported that on April 18, 2024 (the "Date of Grant"), the Company approved the grant of inducement stock options covering an aggregate of 79,310 shares of Iovance’s common stock to thirty-seven new, non-executive employees (Press release, Iovance Biotherapeutics, APR 19, 2024, View Source [SID1234642173]).

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The awards were granted under Iovance’s 2021 Inducement Plan, which was adopted on September 22, 2021 and amended on January 12, 2022, March 13, 2023, and February 26, 2024 and provides for the granting of equity awards to new employees of Iovance by the Company’s compensation committee in accordance with Nasdaq Listing Rule 5635(c)(4). Each of the stock options granted as referenced in this press release has an exercise price of $11.72, the closing price of Iovance’s common stock on the Date of Grant. Each stock option vests over a three-year period, with one-third of the shares vesting on the first anniversary of the employee’s start date (the "First Vesting Date"), and the remaining shares vesting in eight quarterly installments over the next two years, commencing with the first quarter following the First Vesting Date, subject to continued employment with the Company through the applicable vesting dates.

On April 19, 2024 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported that the U.S. Food and Drug Administration (FDA) has approved anaplastic lymphoma kinase (ALK) inhibitor Alecensa (generic name : alectinib) for adjuvant treatment following tumor resection for patients with-ALK positive non-small cell lung cancer (NSCLC) (tumors ≥ 4 cm or node positive) as detected by an FDA-approved test (Press release, Chugai, APR 19, 2024, View Source [SID1234642172]). Alecensa is now the only ALK inhibitor approved for people with ALK-positive early-stage NSCLC who have undergone surgery to remove their tumor. Outside the U.S., the medicine is currently under review for the indication by health authorities including in Europe, Japan, and Taiwan.

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"We are very pleased that Alecensa, a Chugai originated medicine, is now approved by the FDA as the first adjuvant therapy for ALK-positive early-stage NSCLC. Alecensa has shown in a clinical trial to reduce the risk of death or recurrence by 76%. Bringing patients a new treatment option with the possibility of cure, may become a turning point in the treatment of ALK-positive early-stage NSCLC. We will work closely with Roche to deliver this treatment to patients awaiting all over the world, as soon as possible," said Chugai’s President and CEO, Dr. Osamu Okuda.

The approval is based on positive results from the Phase III ALINA study that demonstrated Alecensa reduced the risk of disease recurrence or death by 76% (hazard ratio [HR]=0.24, 95% CI: 0.13-0.43, p<0.001) compared with platinum-based chemotherapy in people with completely resected IB (tumor ≥ 4 cm) to IIIA (UICC/AJCC 7th edition) ALK-positive NSCLC.1 An exploratory analysis also showed improvement of central nervous system (CNS)-disease-free survival, reducing the risk of disease recurrence or death by 78% (HR=0.22; 95% CI: 0.08-0.58) compared with platinum-based chemotherapy.1 The safety and tolerability of Alecensa in this trial were generally consistent with previous trials in the metastatic setting and no unexpected safety findings were observed.1 These data were presented as a late-breaking oral at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2023 Presidential Symposium in October 2023 and were also recently published in the New England Journal of Medicine in April 2024.

Alecensa is a kinase inhibitor currently approved as first- and second -line treatment for ALK-positive metastatic NSCLC. It has demonstrated efficacy in patients, including those with CNS metastases, and now with this approval, these benefits could extend to people with early-stage NSCLC. Routine testing of resected surgical tissue or biopsy for ALK, EGFR and PD-L1 biomarkers in patients with stage IB to IIIA and select IIIB (UICC/AJCC 8th edition) NSCLC, in addition to in the advanced setting, is recommended by international guidelines, including the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines), to support clinicians’ decision-making. Approximately5% of people with NSCLC are ALK-positive, equating to approximately 90,000 people worldwide diagnosed each year.2,3,4

About the ALINA study
The ALINA study [NCT03456076] is a Phase III, randomized, active-controlled, multicenter, open-label study evaluating the efficacy and safety of adjuvant Alecensa (alectinib) compared with platinum-based chemotherapy in people with completely resected stage IB (tumor ≥4cm) to IIIA (UICC/AJCC 7th edition) anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). The study includes 257 patients who were randomly assigned to either the investigational or control treatment arm. The primary endpoint is disease-free survival (DFS). Secondary outcome measures include overall survival, central nervous system-DFS and percentage of patients with adverse events.

About Alecensa
Alecensa is a highly selective, central nervous system-active, oral medicine created at Chugai, a member of the Roche Group, Kamakura Research Laboratories for people with non-small cell lung cancer (NSCLC) whose tumors are identified as anaplastic lymphoma kinase (ALK) positive. Alecensa is already approved in over 100 countries as an initial (first-line) and second-line treatment for ALK-positive, metastatic NSCLC, including in the United States, Europe, Japan and China. In Japan, Alecensa has also been approved for the treatment of recurrent or refractory ALK fusion gene-positive anaplastic large cell lymphoma.

About lung cancer
Lung cancer is one of the leading causes of cancer death globally.5 Each year 1.8 million people die as a result of the disease; this translates into more than 4,900 deaths worldwide every day.5 In Japan, 127 thousand people are affected by this disease (2019).6 Lung cancer can be broadly divided into two major types: non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). NSCLC is the most prevalent type, accounting for around 85% of all cases.7 Today, about half of all people with early lung cancer (45-76%, depending on disease stage) still experience a cancer recurrence following surgery, despite adjuvant chemotherapy.8 Treating lung cancer early, before it has spread, may help prevent the disease from returning and provide people with the best opportunity for a cure.9

Trademarks used or mentioned in this release are protected by law.

Source:

Wu Y-L et al. Alectinib in Resected ALK-Positive Non–Small-Cell Lung Cancer. N Engl J Med 2024;390:1265-1276
Barlesi, et al. Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT). Lancet 2016. 387(10026):1415-1426.
Tian, et al. Clinical characteristics and sequence complexity of anaplastic lymphoma kinase gene fusions in Chinese lung cancer patients. Lung Cancer 2017. 114:90-95.
Cancer.Net. Lung Cancer – Non-Small Cell: Statistics. [Internet; cited April 2024]. Available from: View Source
Thandra KC, et al. Epidemiology of lung cancer. Contemp Oncol. 2021;21(1):45-52.
Cancer Statistics, Cancer Information Service, National Cancer Center, Japan (National Cancer Registry) [Internet; cited 2024 April] Available from: View Source (Japanese Only)
American Cancer Society: What Is Lung Cancer? [Internet; cited 2024 April] Available from: View Source
Pignon JP et al. Lung Adjuvant Cisplatin Evaluation: A Pooled Analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26:3552-3559.
Hendricks LE et al. Oncogene-addicted metastatic non-small-cell lung cancer: ESMO (Free ESMO Whitepaper) Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(4): 339-357.

On April 18, 2024 Pacylex Pharmaceuticals Inc. (Pacylex) is a clinical-stage pharmaceutical company focused on the development of a new class of targeted therapies, N-myristoyltransferase inhibitors (NMTi) for the treatment of hematologic and solid tumor cancers, reported that the first patient has been dosed in a Phase 2a expansion study in patients with refractory metastatic colorectal cancer (Press release, Pacylex Pharmaceuticals, APR 18, 2024, View Source [SID1234645052]).

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The Phase 1 dose escalation safety and tolerability study was conducted in 29 heavily pre-treated solid tumor and lymphoma patients who averaged 4 lines of prior drug therapy on which they relapsed or were refractory. Eight colorectal cancer patients were among those included in the study. The most common treatment related adverse events identified in the trial were mild to moderate gastrointestinal side effects which were self-limiting and occurred in a minority of patients. A recommended Phase 2 dose (RP2D) for expansion studies was established. Zelenirstat prolonged progression free and overall survival in Phase 1 solid tumor patients receiving the RP2D, compared to those receiving lower doses. Prolonged Stable Disease of 6 months or longer was observed in 57% (4/7) of the patients receiving RP2D, including a patient with metastatic colorectal cancer continuing on treatment for more than 1 year with reductions of approximately 50% in CEA (carcinoembryonic antigen) and tumor volumes.

"Given the patient benefits and excellent tolerability seen in our Phase 1 study, and particularly in our sentinel colorectal cancer patient, we are eager to see if other colorectal cancer patients receiving our Phase 2 dose will also benefit," said Dr. John Mackey, CMO of Pacylex. "People with refractory colorectal cancer desperately need new treatment options, and we are investigating whether zelenirstat can provide that."

"Adding colorectal cancer as our first solid tumor indication explores the broad potential for zelenirstat, a first-in-class oral cancer therapy, in both hematologic cancers and solid tumors," said Pacylex CEO Dr. Michael Weickert. "The importance of myristoylation to many cancer processes is underappreciated, and Pacylex is way ahead in developing this novel therapeutic class, NMT inhibitors, to treat cancer refractory to available treatments."

The Company has an ongoing Phase 2a study of patients with B-cell non-Hodgkin lymphoma. This colorectal cancer Phase 2a expansion study will enroll up to 20 subjects to assess the preliminary clinical activity and confirm the safety of zelenirstat in refractory colorectal cancer.