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NEWS AND PUBLICATIONS

Efficacy and Safety Study of First-line Treatment With Pembrolizumab (MK-3475) Plus Chemotherapy Versus Placebo Plus Chemotherapy in Women With Persistent, Recurrent, or Metastatic Cervical Cancer 

In a double-blind, phase 3 trial, the study team randomly assigned patients with persistent, recurrent, or metastatic cervical cancer in a 1:1 ratio to receive pembrolizumab (200 mg) or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy and, per investigator discretion, bevacizumab. The dual primary end points were progression-free survival and overall survival, each tested sequentially in patients with a PD-L1 combined positive score of 1 or more, in the intention-to-treat population, and in patients with a PD-L1 combined positive score of 10 or more. The combined positive score is defined as the number of PD-L1–staining cells divided by the total number of viable tumor cells, multiplied by 100. All results are from the protocol-specified first interim analysis. In 548 patients with a PD-L1 combined positive score of 1 or more, median progression-free survival was 10.4 months in the pembrolizumab group and 8.2 months in the placebo group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.50 to 0.77; P<0.001). In 617 patients in the intention-to-treat population, progression-free survival was 10.4 months and 8.2 months, respectively (hazard ratio, 0.65; 95% CI, 0.53 to 0.79; P<0.001). In 317 patients with a PD-L1 combined positive score of 10 or more, progression-free survival was 10.4 months and 8.1 months, respectively (hazard ratio, 0.58; 95% CI, 0.44 to 0.77; P<0.001). Overall survival at 24 months was 53.0% in the pembrolizumab group and 41.7% in the placebo group (hazard ratio for death, 0.64; 95% CI, 0.50 to 0.81; P<0.001), 50.4% and 40.4% (hazard ratio, 0.67; 95% CI, 0.54 to 0.84; P<0.001), and 54.4% and 44.6% (hazard ratio, 0.61; 95% CI, 0.44 to 0.84; P=0.001), respectively. The most common grade 3 to 5 adverse events were anemia (30.3% in the pembrolizumab group and 26.9% in the placebo group) and neutropenia (12.4% and 9.7%, respectively).

educed the risk of death by 33% in the allcomers population with a median OS of 24.4 mos for KEYTRUDA vs. 16.5 mos with chemo (Merck)

Cancer cells have co-evolved with the tumor immune microenvironment and developed different strategies to evade T cell immune destruction. Tumor-infiltrating T cells often manifest impaired effector function and fail to eliminate cancer cells. Immune checkpoint inhibitor (ICI) therapies have yielded significant clinical benefits and durable responses in a subset of cancer patients. Yet, many cancer patients do not respond to ICI treatment, and it remains challenging to reach immunotherapy’s full potential. To understand what may affect patients’ immunotherapy response, the group of Dihua Yu retrospectively analyzed data of patients on the use of common pharmaceutical drugs during ICI treatments. Surprisingly, antihistamines could be associated with significantly improved clinical outcome. Antihistamines may achieve this via reinforcing antitumor immunity, raising an interesting question: how do antihistamines that are commonly used to treat allergy symptoms influence antitumor immunity?

The group shows that:

  • Histamine binding of HRH1 on macrophages induces an immunosuppressive phenotype
    • H1-antihistamine treatment enhances immunotherapy response
    • Allergic reaction promotes immune evasion and resistance to immunotherapy
    • High histamine and HRH1 levels correlate with poor immunotherapy response in patients.

The data shows that HRH1 activation reshapes the transcriptomic landscape of macrophages and that allergies induce immunotherapy resistance, which is mitigated by HRH1 blockade.        

Cancer cell-derived or allergy-released histamine binds to HRH1 on tumor-associated macrophages that suppress CD8+ T cell function, accelerate tumor growth, and confer immunotherapy resistance. H1-antihistamines counteract histamine-mediated immunosuppression, reinforce antitumor immunity, and significantly enhance immunotherapy response.

INDUSTRY

Gilead Exercises Options to Three Arcus Biosciences Clinical-stage Programs and Adds Research Collaboration

Arcus Biosciences is a clinical-stage, global biopharmaceutical company developing differentiated molecules and combination medicines for cancer treatment. Founded in 2015, the company has expedited the development of six investigational medicines into clinical studies, including new combination approaches that target TIGIT, PD-1, the adenosine axis (CD73 and dual A2a/A2b) and most recently, HIF-2alfa.

Gilead has exercised its options to three programs in Arcus’s clinical-stage portfolio, including anti-TIGIT molecules, domvanalimab and AB308, as well as etrumadenant and quemliclustat. The companies added a research collaboration.

Domvanalimab is an Fc-silent anti-TIGIT antibody in Phase 2 and Phase 3 studies in non-small cell lung cancer (NSCLC) and AB308 is an Fc-enabled anti-TIGIT antibody under Phase 1 evaluation. Etrumadenant is a dual adenosine A2a/A2b receptor antagonist in Phase 1 and Phase 2 studies in NSCLC, colon cancer and prostate cancer. Quemliclustat is a small molecule CD73 inhibitor in a Phase 1 study in metastatic pancreatic ductal adenocarcinoma (PDAC). Under the terms of the agreement, for the three options that Gilead has exercised, Arcus will receive option payments totaling $725 million. The parties will co-develop and share the global costs related to these programs.

EMA

In November the CHMP made the following recommendations on new medicines:

  • Granting of a conditional marketing authorisation for the medicinal product Lumykras (sotorasib, Amgen Europe B.V.) intended for the treatment of patients with KRAS G12C mutation non-small cell lung cancer (NSCLC). The active substance is sotorasib, a KRAS G12C (Kirsten rat sarcoma viral oncogene homolog) inhibitor (ATC code: L01XX73) which covalently and irreversibly binds to the unique cysteine of KRAS G12C. Inactivation of KRAS G12C by sotorasib blocks tumor cell signaling and survival, inhibits cell growth and promotes apoptosis selectively in tumors harboring KRAS G12C, an oncogenic driver of tumor igenesis.

FDA

In November, the FDA granted approval for:

  • Pembrolizumab (Keytruda, Merck) for the adjuvant treatment of patients with renal cell carcinoma (RCC) at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. Efficacy was evaluated in KEYNOTE-564 (NCT03142334), a multicenter, randomized (1:1), double-blind, placebo-controlled trial in 994 patients with intermediate-high or high risk of recurrence of RCC, or M1 no evidence of disease. Patients were randomized to pembrolizumab 200 mg intravenously every 3 weeks or placebo for up to 1 year until disease recurrence or unacceptable toxicity. The major efficacy outcome measure was investigator-assessed disease-free survival (DFS), defined as time to recurrence, metastasis, or death. An additional outcome measure was overall survival (OS). A statistically significant improvement in DFS was demonstrated at a prespecified interim analysis, with 109 (22%) events in the pembrolizumab arm and 151 (30%) events in those receiving placebo (HR 0.68; 95% CI: 0.53, 0.87; p=0.0010). Median DFS was not reached in either arm. At the time of the DFS analysis, OS data were not mature, with 5% deaths in the overall population. The recommended pembrolizumab dose is 200 mg every 3 weeks or 400 mg every 6 weeks until disease recurrence, unacceptable toxicity, or up to 12 months.
  • Sirolimus protein-bound particles for injectable suspension (albumin-bound) (Fyarro, Aadi Bioscience, Inc.) for adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa). Efficacy was evaluated in AMPECT (NCT02494570), a multicenter, single-arm clinical trial in 31 patients with locally advanced unresectable or metastatic malignant PEComa. Patients received sirolimus protein-bound particles at 100 mg/m2 on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity. The main efficacy outcome measures were overall response rate (ORR) and duration of response (DOR), as assessed by blinded independent central review, using RECIST v.1.1. ORR was 39% (95% CI: 22%, 58%), including 2 patients with complete responses. Median DOR was not reached (95% CI: 6.5 months, not estimable). Among responders, 67% had a response lasting greater than 12 months and 58% had a response lasting greater than 24 months. The recommended dosage is 100 mg/m2 administered as an IV infusion over 30 minutes on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity.
  • Pafolacianine (Cytalux, On Target Laboratories, LLC), an optical imaging agent, for adult patients with ovarian cancer as an adjunct for interoperative identification of malignant lesions. Pafolacianine is a fluorescent drug that targets folate receptor which may be overexpressed in ovarian cancer. It is used with a Near-Infrared (NIR) fluorescence imaging system cleared by the FDA for specific use with pafolacianine. Efficacy was evaluated in a single arm, multicenter, open-label study (NCT03180307) of 178 women diagnosed with ovarian cancer or with high clinical suspicion of ovarian cancer scheduled to undergo primary surgical cytoreduction, interval debulking, or recurrent ovarian cancer surgery. All patients received pafolacianine. One hundred and thirty-four patients received fluorescence imaging evaluation in addition to standard of care evaluation which includes pre-surgical imaging, intraoperative palpation and normal light evaluation of lesions. Among these patients, 36 (26.9%) had at least one evaluable ovarian cancer lesion detected with pafolacianine that was not observed by standard visual or tactile inspection. The patient-level false positive rate of pafolacianine with NIR fluorescent light with respect to the detection of ovarian cancer lesions confirmed by central pathology was 20.2% (95% CI 13.7%, 28.0%). The recommended pafolacianine dose is 0.025 mg/kg administered intravenously over 60 minutes, 1 to 9 hours before surgery.

FDA draft guidance documents of interest:

Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products Guidance for Industry

The 21st Century Cures Act (Cures Act) was intended to accelerate medical product development and bring innovations and advances faster and more efficiently to the patients who need them. Among other provisions, the Cures Act added section 505F to the Federal Food, Drug, and Cosmetic Act (FD&C Act). In response to the requirements in section 505F, the Food and Drug Administration (FDA) created a framework for a Real-World Evidence (RWE) Program to evaluate the potential use of real-world evidence to help support the approval of a new indication for a drug already approved under section 505(c) of the FD&C Act or to help support or satisfy post approval study requirements.

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