publication date: Apr. 19, 2019

Drugs & Targets

FDA approves Balversa for urothelial carcinoma with FGFR genetic alterations

Janssen Pharmaceuticals said Balversa (erdafitinib) received accelerated approval from FDA for the treatment of adults with locally advanced or metastatic urothelial carcinoma which has susceptible fibroblast growth factor receptor 3 or FGFR2 genetic alterations and who have progressed during or following at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.

Balversa is the first FGFR kinase inhibitor approved by FDA. The accelerated approval follows FDA Breakthrough Therapy Designation in March 2018 and Priority Review Designation of the New Drug Application submitted in September 2018.

Balversa, a once-daily oral FGFR kinase inhibitor, received accelerated approval based on results from a phase II clinical trial (BLC2001, NCT02365597), a multicenter, open-label, single-arm study, of 87 patients with disease that had progressed on or after at least one prior chemotherapy and that had at least one of the following genetic alterations: FGFR3 gene mutations (R248C, S249C, G370C, Y373C) or FGFR gene fusions (FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7), as determined by a clinical trial assay performed at a central laboratory.

The results demonstrated a 32.2% objective response rate as assessed by Blinded Independent Review Committee [95% CI (22.4, 42.0)]. Responders included patients who had previously not responded to anti PD-L1/PD-1 therapy.

In the trial, ORR was defined as the percentage of patients with measurable lesions achieving a complete response [2.3%] or partial response [29.9%] to treatment using the Response Evaluation Criteria in Solid Tumors Version 1.1 criteria, a standard way to measure how well a patient responds to treatment based on whether tumors shrink, stay the same, or get bigger as assessed per investigator.

Results also showed a median duration of response of 5.4 months [95% CI (4.2, 6.9)] in patients treated with Balversa. There were no confirmed responses to Balversa in the FGFR2 fusion patient population (n=6). Data from the BLC2001 study were presented at the ASCO 2018 Annual Meeting (Abstract #4503) and were recognized as a “Best of ASCO” selection.

FDA simultaneously approved a companion diagnostic for use with Balversa, the QIAGEN therascreen FGFR RGQ Reverse-transcription-polymerase chain reaction Kit, which is the first PCR-based companion diagnostic approved to detect FGFR alterations.

The therascreen FGFR test detects the presence of FGFR alterations in the tumor tissue of patients with mUC. If one or more of the genetic alterations or fusions are detected, the patient may be a candidate for treatment with Balversa.

Balversa (erdafitinib) is a once-daily, oral fibroblast growth factor receptor kinase inhibitor indicated for the treatment of adults with locally advanced or metastatic urothelial carcinoma which has susceptible FGFR3 or FGFR2 genetic alterations and who have progressed during or following at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.

In 2008, Janssen entered into an exclusive worldwide license and collaboration agreement with Astex Pharmaceuticals to develop and commercialize Balversa. Balversa will be commercially available through the single-source specialty pharmacy provider US Bioservices.


FDA expands pembrolizumab indication for first-line treatment of NSCLC

FDA has approved pembrolizumab (Keytruda) for the first-line treatment of patients with stage III non-small cell lung cancer who are not candidates for surgical resection or definitive chemoradiation or metastatic NSCLC. Patients’ tumors must have no EGFR or ALK genomic aberrations and express PD-L1 (Tumor Proportion Score ≥1%) determined by an FDA-approved test.

Keytruda is sponsored by Merck.

Pembrolizumab was previously approved as a single agent for the first-line treatment of patients with metastatic NSCLC whose tumors express PD-L1 TPS ≥50%.

Approval was based on KEYNOTE‑042 (NCT02220894), a randomized, multicenter, open-label, active-controlled trial conducted in 1274 patients with stage III or IV NSCLC who had not received prior systemic treatment for metastatic NSCLC and whose tumors expressed PD-L1 (TPS ≥1%). PD-L1 expression was determined by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx Kit.

Patients were randomized (1:1) to receive pembrolizumab 200 mg intravenously every 3 weeks or investigator’s choice of a carboplatin-containing regimen with either pemetrexed or paclitaxel. Randomization was stratified by ECOG performance status, histology, geographic region, and PD-L1 expression (TPS ≥50% vs. TPS 1 to 49%).

Overall survival in the TPS ≥50% NSCLC subgroup, the TPS ≥20% NSCLC subgroup, and the overall population (TPS ≥1%) were the major efficacy measures. The trial demonstrated statistically significant OS improvements for those randomized to pembrolizumab compared with chemotherapy in all three populations.

In the TPS ≥1% population (overall population), the median OS was 16.7 and 12.1 months for the pembrolizumab and chemotherapy arms, respectively (HR 0.81; 95% CI: 0.71, 0.93; p=0.0036).

For the TPS ≥ 20% subgroup, the median OS was 17.7 months for the pembrolizumab arm and 13.0 months for the chemotherapy arm (HR 0.77; 95% CI: 0.64, 0.92; p=0.004). For the TPS ≥50% subgroup, the estimated median OS was 20 months and 12.2 months for those receiving pembrolizumab and chemotherapy, respectively (HR 0.69; 95% CI: 0.56, 0.85; p=0.0006).

There were no significant differences in progression-free survival or overall response rate between arms in any population.


Aprea Therapeutics receives FDA Fast Track and Orphan Drug designations for APR-246 for MDS

Aprea Therapeutics said FDA has granted Fast Track designation to APR-246 for the treatment of patients with MDS having a TP53 mutation. In addition, FDA has also granted Orphan Drug Designation to APR-246 for treatment of MDS.

The FDA’s Fast Track program facilitates the development of drugs intended to treat serious conditions and that have the potential to address unmet medical needs. A drug program with Fast Track status is afforded greater access to the FDA for the purpose of expediting the drug’s development, review and potential approval.

In addition, the Fast Track program allows for eligibility for accelerated approval and priority review, if relevant criteria are met, as well as for Rolling Review, which means that a drug company can submit completed sections of its New Drug Application for review by FDA, rather than waiting until every section of the NDA is completed before the entire application can be submitted for review.

The p53 tumor suppressor gene is the most frequently mutated gene in human cancer, occurring in approximately 50% of all human tumors. These mutations are often associated with resistance to anti-cancer drugs and poor overall survival, representing a major unmet medical need in the treatment of cancer.

APR-246 has been shown to reactivate mutant and inactivated p53 protein—by restoring wild-type p53 conformation and function—and thereby induce programmed cell death in human cancer cells. APR-246 has demonstrated pre-clinical anti-tumor activity in a wide variety of solid and hematological tumors, including MDS, AML, and ovarian cancer, among others.

Additionally, strong synergy has been seen with both traditional anti-cancer agents, such as chemotherapy, as well as newer mechanism-based anti-cancer drugs and immuno-oncology checkpoint inhibitors. In addition to pre-clinical testing, a Phase I/II clinical program with APR-246 has been completed, demonstrating a favorable safety profile, biological activity and clinical responses in hematological malignancies and solid tumors with mutations in the TP53 gene.


Intensity Therapeutics receives Fast Track designation for development of INT230-6 in breast cancer

Intensity Therapeutics Inc. said FDA has granted Fast Track designation to the company’s development program evaluating INT230-6 for the treatment of patients with relapsed or metastatic triple negative breast cancer who have failed at least two prior lines of therapy.

Approximately 15-20% of breast cancers test negative for estrogen receptors, progesterone receptors, and excess HER2 protein, qualifying them as triple negative.According to a study published in the Journal of Clinical Oncology, patients who fail two lines of therapy for TNBC typically progress within nine weeks. Those who have failed three lines progress within four weeks.

INT230-6, Intensity’s lead product candidate designed for direct intratumoral injection, is comprised of two proven, potent anti-cancer agents and a penetration enhancer molecule that helps disperse the drugs throughout tumors and diffuse into cancer cells.

INT230-6 is being evaluated in a phase I/II clinical study (NCT03058289) in patients with various advanced solid tumors. In preclinical studies, INT230-6 eradicated tumors by a combination of direct tumor kill and recruitment of dendritic cells to the tumor micro-environment that induced anti-cancer T-cell activation.

Treatment with INT230-6 in in vivo models of severe cancer resulted in substantial improvement in overall survival compared to standard therapies. Further, INT230-6 provided complete responder animals with long-term, durable protection from multiple re-inoculations of the initial cancer and resistance to other cancers. In mouse models, INT230-6 has shown strong synergy with checkpoint blockage, including anti-PD-1 and anti-CTLA4 antibodies. INT230-6 was discovered from Intensity’s DfuseRxSM platform.


Kitov announces milestone in FameWave acquisition

Kitov Pharma Ltd. announced a milestone in the acquisition of FameWave Ltd., following signature of a clinical collaboration agreement between FameWave and Bristol Myers Squibb for their planned phase I/II clinical trials to evaluate the combination of CM-24, a monoclonal antibody targeting the novel immune checkpoint carcinoembryonic antigen-related cell adhesion molecule 1 with nivolumab in patients with non-small cell lung cancer.

Preclinical studies have shown a strong synergetic anti-cancer effect using CM-24 in combination with a PD-1 antibody. Based on Kitov’s review of the initial phase I dose ranging study of CM24 as a single agent, performed by Merck Sharpe & Dohme, Kitov plans to explore higher doses in order to reach receptor saturation,.

Kitov is acquiring FameWave, pending completion of certain additional closing conditions, including approval by the shareholders of Kitov of the acquisition.

CM-24 is a humanized monoclonal antibody directed against carcinoembryonic antigen-related cell adhesion molecule 1, an immune checkpoint protein belonging to the Human CEA protein family. Evidence has shown that CEACAM1 is expressed on tumor lymphocytes and is up-regulated in several cancer types.

Preclinical studies have shown evidence that CM-24 enhances the cytotoxic activity of tumor-infiltrating lymphocytes against various CEACAM1-positive tumor cell lines. CM-24 is being developed for multiple oncological indications according to the expression pattern of its target protein.

As part of the recently announced agreement for the acquisition of FameWave by Kitov, cCAM BioTherapeutics Ltd., a wholly owned subsidiary of Merck Sharp and Dohme Corp., known as “MSD” in Israel, has returned the rights to CM-24 to former cCAM shareholders and founders of FameWave, following an initial phase I dose ranging study of CM-24 as single agent.


Stanford partners with  Notable and Tempus to make rapid personalized treatment in blood cancer patients

Notable and Stanford Medical Center announced the results of a new study on the feasibility of personalized medicine. The study’s objective was to rapidly sequence MDS blood cancer samples; analyze each sample against hundreds of drugs and drug combinations; and make personalized treatment recommendations for each sample—all within a maximum of 30 days.

Twenty patients were represented in the study, and Stanford/Notable were able to complete their personalized recommendations within Stanford’s target of 30 days for all 20 patients. With respect to accuracy, interim clinical data demonstrated both positive and negative predictive value average of 84%.

Effective treatment and time-to-treatment are both essential elements of fighting cancer. Advances in personalized medicine now make it possible to analyze samples for individual patients and point physicians and patients towards the drugs and drug combinations that are likely to be most effective for their unique cancer. This technique has the potential to drastically improve the way physicians treat cancers, and save more lives.

Steps involved in the study:

  1. Stanford Medical Center sent the blood samples to Notable and Tempus;

  2. Notable analyzed hundreds of requested drugs and drug combos against each sample; Tempus did the DNA sequencing;

  3. The Stanford MDS tumor board combined data for each patient into a report; and

  4. The report and personalized treatment recommendation was then shared with physician for each patient.

“Ex vivo drug sensitivity technology must have a rapid turnaround time, accuracy and efficacy in order to be useful in the clinic,” said Peter Greenberg, professor of medicine (hematology) and director of Stanford MDS Center at Stanford University Cancer Center, said in a statement.

“Notable Lab’s ex vivo drug sensitivity assay screened marrow samples we sent them from patients in our recent biologically focused feasibility trial against a collection of investigational and FDA-approved compounds,” Greenberg said. “These patients had higher risk myelodysplastic syndromes and were refractory to standard therapy. Potentially actionable therapeutic results were returned to us for the patients enrolled in our trial within a clinically actionable time frame. These data suggest the potential utility of this methodology to aid in decision-making for novel therapeutic drug selection in MDS patients with HMA-refractory disease.”

Further data regarding the trial and methodology used will be presented at the upcoming European Hematology Association annual meeting hosted in Amsterdam in June.

Founder Matt De Silva started the company when his own father was suffering from a deadly brain cancer—his goal was to find a way to help physicians quickly match patients with the most effective treatments. “This partnership represents the future of precision medicine because it combines the strength of molecular sequencing with next-generation functional drug sensitivity tests,” said De Silva. “It’s the type of trial I wish had existed for my dad because these approaches produce immediately actionable treatment options for physicians and their patients.”

Stanford Medical Center, Notable and Tempus are working to prepare a detailed paper on the study’s approach and results, for publication later this year.


OncoSec anounces collaboration with Duke to study TAVO + plasmid DNA vaccines in breast cancer

OncoSec Medical Inc. and Duke University School of Medicine said they have entered into a collaborative research agreement to evaluate the use of OncoSec’s proprietary TAVOPLUS (enhanced IL-12 DNA-plasmid) in combination or sequence with a HER2-plasmid vaccine administered with OncoSec’s novel intratumoral delivery system.

The research will be led by Herbert Kim Lyerly, George Barth Geller Professor, Professor of Immunology, Surgery and Pathology at Duke University School of Medicine.

“We are eager to expand our immunotherapy research in breast cancer through this collaboration with OncoSec. We have previously demonstrated, in a variety of breast cancer models, that local delivery of IL-12 stimulates an anti-breast cancer immune response with applicability beyond end-stage cancer,” Lyerly said in a statement.

“This delivery system has the potential to be a foundational therapeutic in the treatment of early-stage disease. The translational work with TAVOPLUS has been very encouraging and we are excited to explore the potential of OncoSec’s IL-12 plasmid delivery technology to enhance immune responses targeting HER2+ tumors and to elicit superior T-cell and B-cell responses to HER2 in a variety of preclinical breast cancer models.”

Under the agreement, OncoSec will provide its proprietary TAVO (IL-12 plasmids) and its new electroporation generator, APOLLO, using lower voltage and a longer pulse width which greatly increased DNA-plasmid cellular transfection rates, to Duke University’s Center for Applied Therapeutics.

Duke investigators will conduct preclinical studies using plasmid vaccines targeting HER2 in combination with plasmid vaccines and TAVO in a newly developed endogenous mouse model of HER2+ breast cancer. Additionally, Duke investigators will use TAVO with their high-intensity ultrasound tumor ablation models to explore the impact of IL-12 delivery on the development of systemic immunity.


Roswell Park selects Circuit Clinical as collaborator for CIMAvax clinical trial

Circuit Clinical announced a collaboration with Roswell Park Comprehensive Cancer Center to support the expansion of clinical trial opportunities to its outpatient oncology practices. This collaboration marks Circuit Clinical’s entry into oncology clinical research, with both digital and clinical services.

Circuit Clinical will be delivering both research operational support and TrialScout– its patient experience platform– in support of Roswell Park’s groundbreaking CIMAvax-EGF Clinical Trial.

Circuit Clinical will be providing patient identification, engagement, enrollment and ongoing patient experience support services under the direction of the Roswell Park Comprehensive Cancer Center clinical research leadership team.

In addition to its main campus on Carlton Street in the City of Buffalo, Roswell Park offers care at satellite offices in Amherst and Niagara Falls and at five affiliated community practices.

Through this collaboration, eligible patients with certain forms of lung and head/neck cancer will have the opportunity to participate in the CIMAvax Clinical Trial onsite at one or more of the following practices:

  • Roswell Park Jamestown Medical Oncology & Hematology,

  • Roswell Park Hematology Oncology of Niagara,

  • Roswell Park Hematology Oncology Southtowns,

  • Roswell Park Hematology Oncology Northtowns.

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