The FDA approved niraparib (Zejula) for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy.1
Efficacy for the agent was investigated in the double-blind placebo-controlled phase III PRIMA trial, designed to evaluate niraparib, versus placebo, in 733 patients who were in a complete or partial response to first-line platinum-based chemotherapy.
Patients were randomized in a 2:1 fashion within 12 weeks of finishing their last cycle of chemotherapy.2 Overall, 487 participants were randomized to niraparib and 246 were randomized to placebo.
The main efficacy outcome measure was progression-free survival (PFS), and this was first tested by researchers in the homologous recombination deficient population, then in the overall population. Tumor samples were tested for homologous recombination deficiency status, defined by either presence of tumor breast cancer susceptibility gene (tBRCA) mutation or genomic instability score (GIS) ≥42. Notably, an FDA-approved companion diagnostic is not required to initiate treatment with niraparib for this indication.
The trial showed a statistically significant improvement in PFS for patients who were randomized to niraparib compared with placebo in the homologous recombination deficient and overall population. Median PFS in the homologous recombination deficient population was 21.9 months (range, 19.3 to NE) for patients receiving niraparib, while PFS was 10.4 months (range, 8.1-12.1) for those receiving placebo (HR, 0.43; 95% CI, 0.31-0.59; P < 0.0001). Additionally, median PFS in the overall population was 13.8 months (range, 11.5-14.9) for patients receiving niraparib compared with 8.2 months (range, 7.3-8.5) for individuals receiving placebo (HR, 0.62; 95% CI, 0.50-0.76; P < 0.0001).
The most common adverse events observed in ≥10% of all patients administered niraparib in the PRIMA trial were thrombocytopenia, anemia, nausea, fatigue, neutropenia, constipation, musculoskeletal pain, leukopenia, headache, insomnia, vomiting, dyspnea, decreased appetite, dizziness, cough, hypertension, AST/ALT elevation, and acute kidney injury.
According to the FDA, the recommended dose of niraparib for the first-line maintenance treatment of advanced ovarian cancer is based on body weight or platelet count. For patients weighing less than 170 lbs or who have a platelet count of less than 150,000/μL, the FDA recommends a dose of 200 mg taken orally once daily. For patients weighing greater than or equal to 170 lbs and who have a platelet count greater than or equal to 150,000/μL, the FDA recommends a dose of 300 mg taken orally once daily.
The application for this indication was approved 2 months prior to the FDA goal date. Further, this application was previously granted priority review.
Reference:
1. FDA. FDA approves niraparib for first-line maintenance of advanced ovarian cancer. FDA website. Published April 29, 2020. fda.gov/drugs/drug-approvals-and-databases/fda-approves-niraparib-first-line-maintenance-advanced-ovarian-cancer. Accessed April 29, 2020.
2. Han SN, Monk BJ, Gonzalez-Martin A. Time to first subsequent therapy (TFST) and progression-free survival 2 (PFS2) from the phase 3 randomized, double-blind PRIMA/ENGOT-OV26/GOG-3012 study in patients with newly diagnosed ovarian cancer. Data made available as part of the virtual platform for the SGO 2020 Annual Meeting. Abstract 32.
For the first time, a blood test has been shown to help detect many types of cancer in a study of thousands of people with no history or symptoms of the disease.
The test is still experimental. Even its fans say it needs to be improved and that Tuesday’s results are not ideal. Yet they show what benefits and drawbacks might come from using these gene-based tests, called liquid biopsies, in routine care — in this case, with PET scans to confirm or rule out suspected tumors.
“We think that it’s feasible,” said Nickolas Papadopoulos, a Johns Hopkins University scientist who helped develop the test. Using it along with standard screening methods “doubled the cancers that were detected” in the study, he said.
But the test also missed many more cancers than it found and raised some false alarms that led to unnecessary followup procedures. It was only studied in women 65 to 75 years old and needs to be tried in men, other ages and more diverse groups.
“This is not at the place where it could be used today,” said Dr. Len Lichtenfeld, deputy chief medical officer for the American Cancer Society. “It will need many more studies to demonstrate value,” including whether it improves survival, he said.
Results were published in the journal Science and discussed at an American Association for Cancer Research conference that was held online because of the coronavirus pandemic.
Many companies are working on liquid biopsies, which look for DNA and other things that tumors shed into blood, to try to find cancer at an early stage. This test was invented by Hopkins doctors who formed a company, Thrive Earlier Detection Corp., to develop it with Third Rock Ventures, a biotech finance firm.
Until now, these multi-cancer detection tools have been tested on blood samples from people with and without cancer to estimate their accuracy. The new study was the first “real world” test in routine medical care, following patients through surgery or other treatment to see how they fared.
Nearly 10,000 women 65 to 75 years old with no history of cancer were recruited through the Geisinger Health System in Pennsylvania and New Jersey. That’s because some deadly cancers such as ovarian have no screening test now, and women in this age group have a higher risk for cancer yet are young enough to benefit from finding it early, Papadopoulos said.
They were encouraged to continue regular screenings such as mammograms and colonoscopies and were given the blood test, which was repeated if findings suggested cancer. If the second test also was suspicious, they were given a whole-body PET-CT scan, an imaging test that costs around $1,000 and can reveal the location of any tumors.
After one year, 96 cancers had been diagnosed. Usual screenings found 24 and the blood test helped find 26 others. The remaining 46 were found because symptoms appeared or the cancer was discovered in other ways, such as an imaging test for a different reason.
Blood testing “made a genuine difference in discovering cancers in a small number of patients,” took seven months on average, and led 1% of women to get a PET scan they turned out not to need, Lichtenfeld said.
The blood test helped reveal six ovarian cancers, including one in Rosemary Jemo, 71, a hairdresser and exercise instructor who lives near Hazleton in eastern Pennsylvania.
“I would have never known … I didn’t feel anything” before the football-sized tumor was found, she said. Surgeons were able to remove it and she is being monitored now.
Alberto Bardelli, a cancer specialist at the University of Turin in Italy who discussed the study at the conference, called it “extraordinary” and said it shows a way to move liquid biopsies into routine care.
The test still needs to be improved, but “it can become very valuable,” he said.
The research was funded by foundations and government grants. Many study leaders have financial ties to Thrive or other companies related to the work and Johns Hopkins holds some patent rights.
Some companies may seek to market liquid biopsies under rules that allow certain tests to be sold without federal Food and Drug Administration approval.
Thrive’s CEO Dave Daly said the company plans a larger, definitive study and is committed to working with the FDA, but that “all options are on the table” for developing the test.
Cost hasn’t been decided, he said, but will be “in the hundreds of dollars, not the thousands.”
The Circulating Cell-free Genome Atlas Study is a large multicenter, case-controlled, observational study of 15,254 participants, 56% with cancer and 44% without cancer, with longitudinal follow-up to support the development of a cell-free DNA (cfDNA) multicancer early detection test. In this phase III clinical study investigating the ability to predict the presence or absence of cancer and tissue of origin using cell-free DNA from plasma in individuals with a clinical suspicion of cancer—but without a pathologic diagnosis or treatment—has found that the early detection test was accurate and could accelerate the diagnostic resolution. The study by Thiel et al was presented during the American Association for Cancer Research (AACR) Virtual Annual Meeting (Abstract CT021).
Study Methodology
The researchers collected plasma cfDNA from blood samples taken prior to study participants’ clinical diagnosis and subjected them to targeted methylation sequencing. The samples were divided into a training set and an independent validation set to train and validate a machine-learning classifier to assess and predict tissue of origin in individuals with clinical suspicion of cancer, but without a pathologic diagnosis or treatment at the time of enrollment into the trial.
Performance was assessed in a subset of participants with a suspicion of cancer. Subsequently, cancer was confirmed by evaluating a pathologic specimen.
Study Results
The study participants being evaluated for suspicion of cancer were classified as confirmed cancer (> 20 cancer types; n = 164 in training, n = 75 in validation) or confirmed noncancer (n = 49 in training, n = 15 in validation). In the confirmed noncancer group, all training and validation samples were correctly predicted as noncancer (100% specificity). In the confirmed cancer group, cancer detection across all stages was 40.2% (66 of 164, 95% confidence interval [CI] = 32.7%–48.2%) in training and 46.7% (35 of 75, 95% CI = 35.1%–58.6%) in validation.
Excluding stage I renal cancers, in which detection/tumor fraction is low in plasma and which comprised 20% of participants in this subset, detection across stages was 50.4% (66 of 131, 95% CI = 41.5%–59.2%) and 59.3% (35 of 59, 95% CI = 45.7%–71.9%), respectively. In stages II and above, detection was 70.7% (58 of 82, 95% CI = 59.6%–80.3%) and 78.9% (30 of 38, 95% CI = 62.7%–90.4%), respectively.
For detected cancers, tissue of origin was predicted in 93.9% (62 of 66) samples in training and 100% (35 of 35) in validation. Of those with a tissue of origin call, accuracy was 85.5% (53 of 62, 95% CI = 74.2%–93.1%) and 97.1% (34 of 35, 95% CI = 85.1%–99.9%), respectively.
The study authors concluded, “A cfDNA multicancer detection test has shown the potential to predict cancer and tissue of origin in individuals with [a] suspicion of cancer ahead of histologic diagnosis with performance comparable to those with confirmed cancer at the time of blood collection. This was achieved with high specificity and tissue of origin accuracy. The high specificity suggests that the false positive rate could be comparable in populations with average vs higher risk (suspicion) of cancer. These findings suggest that a cfDNA multicancer detection test could accelerate the diagnostic resolution of suspicion of cancer.”
Disclosure: For full disclosures of the study authors, visit abstractsonline.com.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
BOSTON–(BUSINESS WIRE)– Verastem, Inc. (Nasdaq:VSTM) (also known as Verastem Oncology), a biopharmaceutical company committed to developing and commercializing new medicines for patients battling cancer, today announced results from the ongoing investigator-initiated Phase 1 clinical study investigating VS-6766, its RAF/MEK inhibitor, in combination with defactinib, its FAK inhibitor, in patients with KRAS mutant advanced solid tumors. The data will be presented as a virtual poster today at the American Association for Cancer Research (AACR)2020 Virtual Annual Meeting I.
This ongoing study is an open label, dose escalation and expansion study. The expansion cohorts are currently ongoing in patients with advanced solid tumors, including low-grade serous ovarian cancer (LGSOC), KRAS mutant non-small cell lung cancer (NSCLC) and KRAS mutant colorectal cancer (CRC). In the LGSOC cohort, among the patients with KRAS mutant tumors (n=6), 4 patients responded, for an overall response rate (ORR) of 67%. Median time on treatment was 20.5 months. In the KRAS mutant NSCLC cohort (n=10), 1 patient achieved a partial response and 8 patients achieved disease control. In this cohort, 70% of patients continued on treatment at least 12 weeks and 30% of patients continued on treatment at least 24 weeks.
Based on an observation of higher response rates seen in patients with KRASG12V mutations in the investigator-initiated Phase 1 combination study, we conducted a combined analysis with data from the combination study and the prior single-agent study that utilized a twice-weekly dosing schedule of VS-67661 to get a more complete picture of activity in KRASG12V mutations. The subsequent, combined analysis (VS-6766 monotherapy and defactinib combination) showed a 57% ORR (4/7 patients); as a single agent (2/5 patients) and in combination with defactinib (2/2 patients) in KRASG12V mutant NSCLC. Similarly, the combined analysis showed a 60% ORR (3/5 patients); as a single agent (1/2 patients) and in combination with defactinib (2/3 patients) in KRASG12V mutant gynecologic cancers. These additional analyses were conducted by Verastem Oncology to understand the impact that various KRAS variants may have had on response to identify potential signals to pursue in future prospective studies. This additional analysis was not part of the AACR 2020 poster presentation.
“Earlier research has demonstrated MEK inhibitors can cause upregulation of FAK in KRAS mutant tumors, which are notoriously difficult to treat and quite common across solid tumors. The combination of a RAF/MEK and FAK inhibitor can potentially overcome this challenge and opens up an exciting new pathway for treatment,” stated Professor Udai Banerji, Professor of Molecular Cancer Pharmacology at The Institute of Cancer Research, London, and Honorary Consultant in Medical Oncology, MBBS, MD, DNB, PhD, FRCP at The Royal Marsden NHS Foundation Trust, London, and lead investigator of the clinical study. “We found that the combination of VS-6766 and defactinib in low-grade serous ovarian cancer (LGSOC) was well tolerated by the patients in the trial and shows promising clinical activity, including durable response that is associated with clinically meaningful benefit. The study continues to enroll additional patients into the ovarian, lung and colorectal expansion cohorts with additional responses seen in all cohorts.”
“We are encouraged by these early response rates in KRAS mutant LGSOC and in KRASG12V mutant tumors as they underscore the significant potential of this novel approach in areas of high unmet medical need,” said Brian Stuglik, Chief Executive Officer of Verastem Oncology. “The potential of the combination of VS-6766 and defactinib is rapidly evolving as we continue to gain more insights and analyze the data. We plan to initiate discussions with regulatory authorities as soon as possible to define a path forward, with the goal of commencing a registration-directed clinical trial during 2020.”
Initial Results from the Phase 1 Study Investigating the Combination of VS-6766 and Defactinib in Patients with KRAS Mutant Cancers and Subsequent Analyses
The poster presentation describes safety and dose response data from the dose-escalation portion and expansion cohorts from an open-label, investigator-initiated Phase 1 study conducted in the United Kingdom assessing the combination of RAF/MEK and FAK inhibitor therapy in patients with LGSOC and KRAS mutant NSCLC. The study evaluated the combination of VS-6766 and defactinib. VS-6766 was administered using a twice-weekly dose escalation schedule and was administered 3 out of every 4 weeks. Defactinib was administered using a twice-daily dose escalation schedule, also 3 out of every 4 weeks. Dose levels were assessed in 3 cohorts: cohort 1 (VS-6766 3.2mg, defactinib 200mg); cohort 2a (VS-6766 4mg, defactinib 200mg); and cohort 2b (VS-6766 3.2mg, defactinib 400mg).
In the patients with LGSOC (n=8), the ORR was 50% (n=4). Among the patients with KRAS mutant LGSOC (n=6), the ORR was 67% (n=4). Of the 4 patients who have responded, 3 had a prior MEK inhibitor and as of November 2019 had been on study for a median of 20.5 months (range 7-23 months). In the patients with NSCLC (n=10), all of which had KRAS mutations, 1 patient achieved a partial response and 1 patient with a 22% tumor reduction still on treatment as of November 2019. Median time on treatment for this cohort was approximately 18 weeks.
Based on an observation of higher response rates seen in patients with KRASG12Vmutations in the investigator-initiated Phase 1 combination study, we conducted a combined analysis with data from the combination study and the prior single-agent study that utilized a twice-weekly dosing schedule of VS-67661 to get a more complete picture of activity in KRASG12V mutations. The subsequent, combined analysis (VS-6766 monotherapy and defactinib combination) showed a 57% ORR (4/7 patients); as a single agent (2/5 patients) and in combination with defactinib (2/2 patients) in KRASG12V mutant NSCLC. Similarly, the combined analysis showed a 60% ORR (3/5 patients); as a single agent (1/2 patients) and in combination with defactinib (2/3 patients) in KRASG12V mutant gynecologic cancers. These additional analyses were conducted by Verastem Oncology to understand the impact that various KRAS variants may have had on response to identify potential signals to pursue in future prospective studies. This additional analysis was not part of the AACR 2020 poster presentation.
The most common side effects seen in the Phase 1 study were rash, creatine kinase elevation, nausea, hyperbilirubinemia and diarrhea, most being NCI CTC Grade 1/2 and all were reversible. The recommended Phase 2 dose was determined to be cohort 1 (VS-6766 3.2mg, defactinib 200mg).
The preliminary data reported in the study suggest that a novel intermittent dosing schedule of RAF/MEK and FAK inhibitor combination therapy has promising clinical activity in patients with KRAS mutant LGSOC and KRASG12V mutant NSCLC, including patients previously treated with a MEK inhibitor. Expansion cohorts remain ongoing.
Details for the AACR 2020 Virtual Meeting I presentation are as follows:
Title: Phase 1 study of the combination of a RAF-MEK inhibitor CH5126766 (VS-6766) and FAK inhibitor defactinib in an intermittent dosing schedule with expansions in KRAS mutant cancers Lead author: Udai Banerji, The Institute of Cancer Research and The Royal Marsden Poster #: CT143 Session: VPO.CT01 – Phase I Clinical Trials Date and Time: Monday, April 27, 2020; 9:00 a.m. to 6:00 p.m. ET URL: https://www.abstractsonline.com/pp8/#!/9045/presentation/10642
Conference Call and Webcast Information
The Verastem Oncology management team will host a conference call and webcast on Monday, April 27, 2020, at 8:00 AM ET to discuss the Phase 1 RAF/MEK/FAK combination data. The call can be accessed by dialing (877) 341-5660 (U.S. and Canada) or (315) 625-3226 (international), five minutes prior to the start of the call and providing the passcode 8390795.
The live, listen-only webcast of the conference call can be accessed by visiting the investors section of the Company’s website at www.verastem.com. A replay of the webcast will be archived on the Company’s website for 90 days following the call.
About VS-6766
VS-6766 (formerly known as CH5126766, CKI27 and RO5126766) is a unique inhibitor of the RAF/MEK signaling pathway. In contrast to other MEK inhibitors in development, VS-6766 blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK. This unique mechanism allows VS-6766 to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other inhibitors. The combination of VS-6766 and the focal adhesion kinase (FAK) inhibitor defactinib is currently being investigated in an investigator-initiated Phase 1 dose escalation and expansion study. The expansion cohorts are currently ongoing in patients with KRAS mutant advanced solid tumors, including low grade serous ovarian cancer (LGSOC), non-small cell lung cancer (NSCLC) and colorectal cancer (CRC).2 The ongoing clinical study of the VS-6766/defactinib combination is supported by single-agent Phase 2 studies which investigated defactinib in KRAS mutant NSCLC3 and VS-6766 in KRAS mutant NSCLC and LGSOC.1
About Defactinib
Defactinib is an oral small molecule inhibitor of FAK and PYK2 that is currently being evaluated as a potential combination therapy for various solid tumors. The Company has received Orphan Drug designation for defactinib in ovarian cancer and mesothelioma in the US, EU and Australia. Preclinical research by Verastem Oncology scientists and collaborators at world-renowned research institutions has described the effect of FAK inhibition to enhance immune response by decreasing immuno-suppressive cells, increasing cytotoxic T cells, and reducing stromal density, which allows tumor-killing immune cells to enter the tumor.4,5 Additionally, in both preclinical and clinical studies, FAK activation has been shown to occur as a potential resistance mechanism in response to MEK inhibitor treatment, and synergy of a FAK inhibitor with a RAF/MEK inhibitor has been shown in several preclinical models. The combination of defactinib and VS-6766 is currently being investigated in an investigator-initiated Phase 1 dose escalation and expansion study. The expansion cohorts are currently ongoing in patients with KRAS mutant advanced solid tumors, including low grade serous ovarian cancer (LGSOC), non-small cell lung cancer (NSCLC) and colorectal cancer (CRC).2 The ongoing clinical study of the VS-6766/defactinib combination is supported by single-agent Phase 2 studies which investigated defactinib in KRAS mutant NSCLC3 and VS-6766 in KRAS mutant NSCLC and LGSOC.4 Defactinib is also in clinical testing in combination with pembrolizumab for treatment of patients with pancreatic cancer, NSCLC and mesothelioma.6
About Verastem Oncology
Verastem Oncology (Nasdaq: VSTM) is a commercial biopharmaceutical company committed to the development and commercialization of new medicines to improve the lives of patients diagnosed with cancer. Our pipeline is focused on novel small molecule drugs that inhibit critical signaling pathways in cancer that promote cancer cell survival and tumor growth, including phosphoinositide 3-kinase (PI3K), focal adhesion kinase (FAK) and RAF/MEK inhibition.
Our first FDA approved product is available for the treatment of patients with certain types of indolent non-Hodgkin’s lymphoma (iNHL).
This press release includes forward-looking statements about Verastem Oncology’s strategy, future plans and prospects, including statements related to the potential clinical value of the RAF/MEK/FAK combination and the timing of commencing a registration-directed trial for the RAF/MEK/FAK combination. The words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “project,” “target,” “potential,” “will,” “would,” “could,” “should,” “continue,” “can,” “promising” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Each forward-looking statement is subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statement.
Applicable risks and uncertainties include the risks and uncertainties, among other things, regarding: the success in the development and potential commercialization of our product candidates, including defactinib in combination with VS-6766 (; the occurrence of adverse safety events and/or unexpected concerns that may arise from additional data or analysis or result in unmanageable safety profiles as compared to their levels of efficacy; our ability to obtain, maintain and enforce patent and other intellectual property protection for our product candidates; the scope, timing, and outcome of any legal proceedings; decisions by regulatory authorities regarding labeling and other matters that could affect the availability or commercial potential of our product candidates; whether preclinical testing of our product candidates and preliminary or interim data from clinical trials will be predictive of the results or success of ongoing or later clinical trials; that the timing, scope and rate of reimbursement for our product candidates is uncertain; that third-party payors (including government agencies) may not reimburse; that there may be competitive developments affecting our product candidates; that data may not be available when expected; that enrollment of clinical trials may take longer than expected; that our product candidates will experience manufacturing or supply interruptions or failures; that we will be unable to successfully initiate or complete the clinical development and eventual commercialization of our product candidates; that the development and commercialization of our product candidates will take longer or cost more than planned; that we or Chugai Pharmaceutical Co., Ltd. will fail to fully perform under the VS-6766 (CH5126766) license agreement; that we may not have sufficient cash to fund our contemplated operations; that we may be unable to make additional draws under our debt facility or obtain adequate financing in the future through product licensing, co-promotional arrangements, public or private equity, debt financing or otherwise; that we will be unable to execute on our partnering strategies for defactinib in combination with VS-6766; that we will not pursue or submit regulatory filings for our product candidates, and that our product candidates will not receive regulatory approval, become commercially successful products, or result in new treatment options being offered to patients.
Other risks and uncertainties include those identified under the heading “Risk Factors” in the Company’s Annual Report on Form 10-K for the year ended December 31, 2019 as filed with the Securities and Exchange Commission (SEC) on March 11, 2020 and in any subsequent filings with the SEC. The forward-looking statements contained in this press release reflect Verastem Oncology’s views as of the date hereof, and the Company does not assume and specifically disclaims any obligation to update any forward-looking statements whether as a result of new information, future events or otherwise, except as required by law.
References
1 Chénard-Poirier, M. et al. Results from the biomarker-driven basket trial of RO5126766 (CH5127566), a potent RAF/MEK inhibitor, in RAS- or RAF-mutated malignancies including multiple myeloma. Journal of Clinical Oncology 2017: 35. 10.1200/JCO.2017.35.15_suppl.2506.
3 Gerber D. et al. Phase 2 study of the focal adhesion kinase inhibitor defactinib (VS-6063) in previously treated advanced KRAS mutant non-small cell lung cancer. Lung Cancer 2020: 139:60-67.
4 Jiang H et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med 2016: Aug 22(8) 851-60.
5 Sulzmaier F.J. et al. FAK in cancer: mechanistic findings and clinical applications. Nature Rev Cancer. 2014 14: 598-610.
Updated interim data from an ongoing Phase I dose-escalation phase clinical study (NCT03748186) evaluating the folate receptor alpha (FRα) antibody-drug conjugate (ADC) STRO-002 (Sutro Biopharma) shows encouraging results.[1]
The trial was designed to study the safety and anti-tumor activity results in heavily pre-treated patients with ovarian cancer.
Folate receptor alpha or FRα is a glycosylphosphatidylinositol (GPI)-anchored membrane protein is overexpressed in solid tumors, including in 80% of ovarian and endometrial carcinoma. However, the show minimal expression in normal, healty tissues. FRα, has been demonstrated to contribute to cancer malignancy by acting as a signaling molecule, has become an attractive therapeutic target for cancer therapy using antibody drug conjugates (ADCs).[2]
Antibody-drug conjugates Antibody-drug conjugates are highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with highly potent anti-cancer agents linked via a chemical linker.
With eight approved and commercially available drugs, ADCs have demonstrated to be a powerful class of therapeutic agents in oncology and hematology. With their clinical success and a growing number of promising ADCs now in clinical trials, these targeted agents may potentially revolutionize current strategies in treating cancers. Among the ADCs in clinical trials os STRO-00. Results of a Phase I trial were presented during the virtual annual meeting (part 1) of the American Association for Cancer Research (AACR) being held on April 27 and 28, 2020.
STRO-002 STRO-002 is an antibody-drug conjugate or ADC composed of SP8166 (H01), an anti-folate receptor alpha human immunoglobulin G1 antibody, conjugated to a proprietary cleavable drug linker, SC239, containing a tubulin-targeting 3-aminophenyl hemiasterlin payload (SC209). The investigational drug was discovered and developed, Sutro’s using proprietary XpressCF+™ cell-free protein synthesis technology. The drug is being developed for the treatment of patients diagnosed with ovarian and/or endometrial cancers. [3]
A wider therapeutic window “We designed STRO-002 to have a wider therapeutic window, with the potential for improved tumor control and better patient tolerability, than other FolRα targeted therapies,” said Bill Newell, CEO of Sutro Biopharma.
“The data we present today from this all-comers trial suggest that our optimally designed ADC can achieve these objectives. In 75% (15 of 20) of ovarian cancer patients at STRO-002 dose levels of 2.9 milligrams per kilogram (mg/kg) or higher (of body weight), we saw in the initial post-baseline scans one partial response and 14 patient with stable disease,” Newell added
Difficult to achieve “This level of tumor control is typically very difficult to achieve in these patients who have been heavily pre-treated, with a median of five prior lines of other therapies, and who have such advanced disease. Equally encouraging are the data showing that 13 patients had a ≥50% reduction or normalization of CA-125, including six confirmed responses, six unconfirmed responses, and one prolonged CA-125 normalization,” Newell explained.
“Of these 13 patients, one patient is not yet evaluable under RECIST criteria. All of the other 12 patients (100%) have also achieved stable disease (confirmed or unconfirmed) or a confirmed partial response. With 89% of adverse events (AEs) reported to be grade 1 or 2, we believe the emerging safety profile reflects our optimized design approach,” he concluded.
Interim clinical data The interim clinical data for STRO-002 in patients treated at dose levels of 2.9 mg/kk or higher included one patient with an ongoing confirmed partial response (36 weeks), five patients with confirmed stable disease (three up to 18 weeks, two up to 27 weeks), and seven ongoing patientswho have an unconfirmed stable disease at the six-week assessment point.
Adverse events In the trial, STRO-002 was generally well-tolerated and was mostly associated with mild adverse events (AEs). Eighty-nine percent (89%) of AEs were grade 1 or grade 2 and prophylactic corticosteroid eye drops have not been necessary. Grade 3 treatment-emergent AEs included fatigue, neutropenia, arthralgia, diarrhea, peripheral neuropathy, and myalgia, with the only grade 4 treatment-emergent AE being neutropenia; all neutropenias were reversible within one week.
“The preliminary evidence of anti-tumor activity we observed is encouraging, particularly in this heavily pre-treated patient population,” said Wendel Naumann, M.D., a gynecologic oncologist at Levine Cancer Institute and a principal investigator on the STRO-002 study.
“With limited therapeutic options for these patients, we are excited to continue to advance this clinical program to further investigate its therapeutic potential,” Nauman added.
“These data support Sutro’s continued development of targeted therapies for cancer patients and joins two other Sutro-developed and manufactured ADCs in clinical trials, including our BCMA-targeted ADC which is in a Phase I trial being conducted by our collaborator Bristol Myers Squibb,” noted Arturo Molina, MD, Sutro’s Chief Medical Officer.
“It is extremely encouraging that we see this preliminary evidence of anti-tumor activity at this stage of development. As we advance STRO-002 in the clinic, we plan to share additional data on the efficacy and safety of STRO-002 by the end of 2020 and we look forward to the potential to bring a new treatment option to ovarian cancer patients,” Molina said.
Trial participation Through April 20, 2020, the Phase I trial of STRO-002 has enrolled 30 patients with recurrent platinum-resistant or refractory ovarian cancer, without regard to FolRα expression levels. A dose-expansion phase of this trial is planned to commence in the second half of 2020. Although the maximum tolerated dose (MTD) has not been reached, Sutro is continuing to actively explore the 5.2 mg/kg o 6.0 mg/kg dose levels as it seeks to determine the recommended Phase II dose.
The ongoing Phase I, open-label, multicenter, dose-escalation trial with dose expansion of STRO-002 was designed to identify the MTD, the recommended Phase II clinical dose and to evaluate the safety, tolerability, and preliminary anti-tumor activity of STRO-002 in adults with advanced epithelial ovarian cancer, including fallopian or primary peritoneal cancer, and endometrial cancer.
Clinical trials Study of STRO-002, an Anti-Folate Receptor Alpha (FolRα) Antibody-drug Conjugate in Ovarian & Endometrial Cancers – NCT03748186
Reference [1] STRO-002-GM1, a First in Human, Phase 1 Study of STRO-002, an anti-Folate Receptor-alpha (FRα) Antibody Drug Conjugate (ADC), in Patients with Advanced Platinum-Resistant/Refractory Epithelial Ovarian Cancer (OC), including Fallopian Tube or Primary Peritoneal Cancers. Presented during the Virtual Annual Meeting of the American Association for Clinical Research (AACR). Poster: CT125 [Download] [2] Li X, Abrahams C, Zhou S, Krimm S, Henningsen R, Stephenson H, Hanson J, Masikat MR, et al. Discovery and activity of STRO-002, a novel ADC targeting folate receptor alpha for ovarian and endometrial cancer. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl): Abstract nr 1782. [Abstract] [3] STRO-002 ADC Review | Journal of Antibody-drug Conjugates [Overview]
In a first-time disclosure of IPN60090, a small-molecule inhibitor of the metabolic enzyme glutaminase (GLS1), researchers from The University of Texas MD Anderson Cancer Center’s Therapeutics Discovery division and Ipsen Biopharmaceuticals reported the preclinical discovery and early-stage clinical development of this novel drug. IPN60090, now under investigation in a Phase I trial, may hold benefit for certain patients with lung and ovarian cancers.
“This effort is a great example of our strategy within Therapeutics Discovery, taking a comprehensive approach to personalized medicine,” said Kovacs. “Our preclinical data suggest that IPN60090 may be effective in underserved groups of patients who need better treatment options, and we look forward to results from our ongoing clinical trials.”
Dysregulation of cellular metabolism is a hallmark of cancer development, and the GLS1 enzyme plays a key role in many metabolic processes. Thus, it makes an attractive target for cancer therapy, explained Kovacs.
IACS drug-discovery scientists identified IPN60090 as a potent and selective inhibitor of GLS1 suitable for clinical trials, and translational researchers in TRACTION demonstrated its activity against subsets of lung and ovarian cancer preclinical models.
Further analysis revealed biomarkers of response, which have been leveraged to identify patients most likely to benefit. In lung cancers, mutations in the KEAP1 and NFE2L2 genes, which regulate response to oxidative stress, sensitize cells to treatment with IPN60090. Similarly, low expression of the metabolic protein asparagine synthetase (ASNS) in ovarian cancers predicts response to IPN60090 in preclinical models.
“Identifying these putative predictive biomarkers of response is critical for our ongoing clinical efforts to ensure that we’re able to offer patients the most relevant therapies,” said Timothy A. Yap, M.B.B.S., Ph.D., F.R.C.P., associate professor of Investigational Cancer Therapeutics and medical director of IACS. “These patient groups in particular, which represent distinct niches within those cancer types, are in need of more effective treatment options.”
For example, patients with lung cancers harboring KEAP1/NRF2 mutations have not benefited from treatment with immune checkpoint inhibitors and have poorer outcomes overall, explained Yap, who leads the IPN60090 clinical trial at MD Anderson.
IPN60090 currently is under investigation in a Phase I dose-escalation and dose-expansion study for patients with advanced solid tumors that harbor KEAP1/NFE2L2 mutations or have low ASNS levels. The team has developed novel CLIA-certified assays to identify patients likely to benefit and monitor how effectively the drug is acting. Initial data from the clinical trial indicate that IPN60090 is effectively inhibiting GLS1 activity in peripheral blood mononuclear cells from patients.
Future trial cohorts plan to investigate IPN60090 in combination with checkpoint inhibitors, chemotherapy and targeted therapies identified by the researchers as having potential synergistic benefits with GLS1 inhibition.
The ongoing research is supported by Ipsen through a global licensing and development agreement. The research is managed according to MD Anderson’s Institutional Conflict of Interest Management and Monitoring Plan. Kovacs is a co-inventor on material and method-of-use patent applications related to IPN60090. The Therapeutics Discovery division is supported in part by MD Anderson’s Moon Shots Program.
In this image of mouse model used to test the efficacy of drugs, including T Cell, zCAR-T, switchable zCAR-T, the mice within red mark are clear of cancer cells.
Antibody-based therapeutics developer Abclon said Tuesday that it has successfully drawn final candidates for the clinical trials of the next-generation chimeric antigen receptor T (CAR-T) cell therapy for ovarian cancer.
Abclon plans to enter clinical trials in the first half of next year as it confirmed that the new drug candidate, AT501, completely removed cancer cells in an ovarian cancer mouse model with a single dose.
Ovarian cancer is called “silent killer” because the symptoms appear after cancer has been progressed for a long time. If the patients find cancer during the early phase, 85 percent of them can completely recover from cancer. If the cancer cells spread to the abdominal cavity, however, the recovery rate drops down to about 25 percent, which is why treatment for late-stage ovarian cancer patients is needed.
CAR-T therapy genetically modifies T cells in patients and induces them to attack and remove specific cancer cells. The existing CAR-T treatment shows excellent efficacy in treating hematologic malignancy, but it also has an issue of toxicity and no precise results in the field of solid cancer.
Pharmaceuticals around the globe are focusing on developing technologies to find breakthroughs. If Abclon’s AT501 begins clinical trials this year as scheduled, the company expects it will be able to be a leader in the field.
Abclon’s switchable CAR-T platform (zCAR-T) uses cotinine switch molecules to regulate the activity of CAR-T and solve the problems of the same existing type of treatments, which are toxicity, resistance, and disease scalability. AT501 derived from the zCAR-T platform is expected to break through the limitations of the existing therapies.
Abclon said that CAR-T treatments from leading global companies are offering new treatment opportunities for patients with blood cancer, but they are having a hard time treating solid cancer.
“The zCAR-T technology is an innovative platform in the field of CAR-T therapy. We will continue to expand the pipeline of CAR-T therapeutics for solid cancers, including pancreatic and colon cancer, starting with treatments for ovarian cancer, as it is expected to improve safety and increase efficacy,” an Abclon official said.
Replacing gemcitabine (Gemzar) with pegylated liposomal doxorubicin in a standard platinum-based regimen improved survival in recurrent ovarian cancer, a phase III trial has shown.
In a cohort of nearly 700 women receiving carboplatin plus bevacizumab (Avastin), median progression-free survival (PFS) was 13.3 months for the group that also received pegylated liposomal doxorubicin, as compared with 11.6 months for those assigned to standard gemcitabine therapy (HR 0.81, 95% CI 0.68-0.96, P=0.012), Jacobus Pfisterer, MD, PhD, of the Gynecologic Oncology Center in Kiel, Germany, and colleagues reported.
Median OS was also improved for the group receiving pegylated liposomal doxorubicin, reaching 31.9 months versus 27.8 months with the standard combination (HR 0.81, 95% CI 0.67-0.98, P=0.032), a 4-month improvement that the authors called “clinically meaningful.”
“These results suggest that carboplatin-pegylated liposomal doxorubicin-bevacizumab is the new standard regimen for patients with recurrent ovarian cancer suitable for platinum-based and antiangiogenic treatment,” Pfisterer’s group wrote in the Lancet Oncology.
Commenting on the findings in an accompanying editorial, Richard Penson, MD, of Massachusetts General Hospital in Boston, took it one step further, suggesting that the “findings merit a more emphatic conclusion: that carboplatin-pegylated liposomal doxorubicin-bevacizumab should be the new standard of care, and clinicians need good reasons not to use it.”
But Penson added that there is currently a “sea change” in thinking about how to manage ovarian cancer, including the use of poly ADP-ribose polymerase (PARP) inhibitors and antiangiogenic agents in combination.
Of note was the absence of PARP inhibitors in the trial, Pfisterer and coauthors said, as these agents are now approved as maintenance therapy in patients with recurrent ovarian cancer after successful retreatment with platinum. They also acknowledged that not having any information on patients’ BRCA mutational status was another weakness of the study.
Penson stressed that patients should have access to the best treatment option available to them, and that a good reason to avoid bevacizumab would be so as to give only four cycles of chemotherapy for a patient anticipating PARP inhibitor maintenance. Bevacizumab might also be avoided if a patient has an unacceptable risk of gastrointestinal perforation or fistula, even though this toxicity is rare, at only 1.2-1.5% of patients with ovarian cancer.
On the other hand, said Penson, “a good reason to add bevacizumab to a platinum-based regimen is that this combination is associated with a higher objective response rate than is chemotherapy.” For example, the response rate was 21% higher when bevacizumab was added to carboplatin and gemcitabine in the OCEANS trial.
“A higher response rate means more patients are eligible for switch maintenance with a PARP inhibitor,” Penson pointed out. On the other hand, women with BRCA-mutated ovarian cancer have a much better prognosis than those whose tumors do not express BRCA and should be preferentially treated with a PARP inhibitor, as BRCA mutations are a target for these agents.
The multicenter phase III trial from Pfisterer and colleagues was conducted at 159 academic centers in Europe from 2013 to 2015, and organized by the European Network for Gynaecological Oncological Trial groups and Gynecologic Cancer Intergroup. In all, 682 women with recurrent epithelial ovarian, primary peritoneal, or fallopian tube carcinoma were randomized 1:1 to either of the two combinations. An eligibility requirement was disease recurrence occurring more than 6 months since first-line platinum-based chemotherapy.
In the standard arm, patients received bevacizumab (5 mg/kg on day 1), gemcitabine (1,000 mg/m2 on days 1 and 8), and carboplatin (area under the concentration curve [AUC] 4 on day 1), with the regimen repeated every 3 weeks for six cycles. This was followed by single-agent maintenance bevacizumab at the same dose every 3 weeks until disease progression or unacceptable toxicity.
In the investigational arm, women received bevacizumab (10 mg/kg on days 1 and 15), carboplatin (AUC 5 on day 1), and pegylated liposomal doxorubicin (30 mg/m2 on day 1), with this regimen repeated every 4 weeks for a maximum of 6 cycles. This was again followed by maintenance bevacizumab (15 mg/kg) given every 3 weeks until disease progression or unacceptable toxicity.
Almost half of the patients in each treatment group had previously received an antiangiogenic drug, usually bevacizumab.
With 12.4 months follow-up in the investigational group and 11.3 months in the standard group, the median biological PFS was 11.5 months versus 10.0 months, respectively (HR 0.76, 95% CI 0.64-0.90).
Adverse events (AEs) of grade 3 or higher were slightly more common in the gemcitabine arm than in the pegylated liposomal doxorubicin arm (81% vs 75%, respectively), while rates of serious AEs were similar (9% vs 10%). Fatal AEs occurred in 2% of the standard group and 1% in the investigational group.
However, AEs leading to treatment discontinuation were slightly lower in the standard group, at 24% compared with 31% in the investigational group. Rates of hematological toxicity were also nearly twice as common in the investigational arm. Quality-of-life scores favored the investigational group at 6 months, after which average scores declined to below baseline levels in both groups.
Disclosures
The study was funded by Hoffmann-La Roche.
Pfisterer disclosed relationships with Hoffmann-La Roche, AstraZeneca, Tesaro, Amgen, Clovis, Merck Sharp and Dohme, and PharmaMar. Coauthors reported various relationships with industry.
Treatment with olaparib demonstrated similar outcomes to standard-of-care chemotherapy treatment in patients with BRCA wild-type, platinum-sensitive, recurrent epithelial ovarian cancer in the phase II CLIO study. As such, olaparib failed to demonstrate a significant improvement in survival over chemotherapy.
Treatment with olaparib (Lynparza) demonstrated similar outcomes to standard-of-care chemotherapy treatment in patients withBRCAwild-type, platinum-sensitive, recurrent epithelial ovarian cancer in the phase II CLIO study (NCT02822157). As such, olaparib failed to demonstrate a significant improvement in survival over chemotherapy.
Data from the CLIO trial were reported by investigators from Leuven, Belgium, as part of the virtual platform for the 2020 Society for Gynecologic Oncology (SGO) Annual Meeting.
The open-label, randomized trial enrolled patients with measurable germlineBRCAwild-type platinum-sensitive ovarian cancer who had received at least 1 prior line of chemotherapy and had relapsed at least 6 months after platinum-based chemotherapy. In addition, patients were required to have World Health Organization (WHO) performance status score of 0 to 2 and normal organ and bone marrow function when measured up to 28 days before randomization.
Patients with platinum-refractory disease or known hypersensitivity to olaparib were excluded from the trial. Additionally, those with a resting ECG with QTc of more than 470 msec, concomitant use of potent CYP3A4 inhibitors, an inability to absorb the medication, or symptomatic uncontrolled brain metastases were also not eligible for participation in the trial. Prior use of bevacizumab (Avastin), however, was allowed.
Sixty patients were randomized 2:1 to receive either 300-mg olaparib tablets twice daily (n = 40) or physician’s choice of chemotherapy (n = 20). In the trial, chemotherapy consisted of carboplatin area under the curve (AUC) 5 with pegylated liposomal doxorubicin 30 mg/m2every 4 weeks, or carboplatin AUC 4 on day 1 with gemcitabine 1000 mg/m2on days 1 and 8 given every 3 weeks.
Baseline characteristics were not significantly different between the 2 treatment arms. In the olaparib arm, the median age at randomization was 70 years (range, 63-76) versus 66 (range, 58-73) in the chemotherapy arm. A majority of patients had a WHO score of 0 (62.5% in the olaparib arm vs 60% in the chemotherapy arm) and high-grade serous histology (95% in each arm). In the olaparib arm, patients had a median of 34.1 months (range, 19.8-52.9) since their initial diagnosis versus 43.3 months (range, 22-60) in the chemotherapy arm.
In both groups, patients had received a median of 2 prior lines of therapy, which included bevacizumab for about half of the patients (n = 31). Nine patients, 5 in the olaparib arm (12.5%) and 4 in the chemotherapy arm (20%), had received at least 4 prior treatments.
The objective response rate with olaparib, as evaluated by RECIST v1.1 criteria, was 40% with responses in 14 patients compared with 60% in the chemotherapy group with responses in 12 patients (P= .12). The disease control rate, which was defined as response or stable disease at 12 weeks, was 80% (32 of 40 patients) with olaparib versus 85% (17 of 20) in the chemotherapy arm.
The median progression-free survival was 6.4 months in patients treated with olaparib compared with 8.5 months in those treated with chemotherapy (HR, 1.11; 95% CI, 0.60-2.04;P= .7). The median overall survival was 23.9 months versus 27.7 months for the olaparib and chemotherapy arms, respectively (HR, 1.01; 95% CI, 0.40-2.51).
Adverse events were as expected in the 2 treatment arms and no surprising toxicities were reported.
The CLIO trial is ongoing with active enrollment. The investigators are also looking toward somaticBRCAtesting of the patients with further results expected.
Further updates from the CLIO trial are expected from Liselore Loverix, MD, of Leuvens Kanker Instituut in Leuven, Belgium, during the SGO Annual Meeting.
Reference:
Loverix L, Vanderstichele A, Olbrecht S, et al. Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-sensitive recurrent ovarian cancer. Data made available as part of the virtual platform for the 2020 Society for Gynecologic Oncology Annual Meeting. Abstract 30. bit.ly/2XN0mj1.
Scientists from Mater Research – The University of Queensland, have discovered they can overcome chemotherapy resistance in an ovarian cancer subtype by using low doses of a drug which slows cell growth.
Professor John Hooper. Credit: Mater Research
Led by Professor John Hooper, the TRI-based Mater Research team collaborated with researchers from the Queensland University of Technology (QUT) and the Mayo Clinic in the United States of America. In a pre-clinical study, they found that the drug, 2-deoxy-D-glucose, could be used at very low levels to significantly improve the effectiveness of chemotherapy in treating clear cell ovarian cancer tumour cells.
Their work, which was published in the prestigious international journal Cancers, provides the rationale for a clinical trial to evaluate the use of low-dose 2-deoxy-D-glucose in treating patients with this type of cancer, according to Professor Hooper.
“Ovarian clear cell carcinoma is a type of ovarian cancer associated with poor prognosis and resistance to chemotherapy,” he said.
“Our pre-clinical work used cells taken from patient tumours, so we were very encouraged that we could use such a low dose of 2-deoxy-D-glucose to overcome the chemotherapy resistance and stop tumour growth.
“This drug has been trialled previously in other cancers, but we were able to use a 10-fold lower dose than previously reported so that it’s safer for patients and is less likely to cause side-effects.”
The team is hoping to begin trialling the treatment combination in patients within the next 12 months, following the announcement they had received an award to progress the ovarian cancer research.
The peak, national gynaecological cancer clinical trials organisation for Australia and New Zealand, ANZGOG, awarded the team its Fund for New Research 2019 – Judith Meschke Memorial Grant to study whether “modulation of metabolism can improve the effectiveness of chemotherapy for clear cell ovarian cancer”.
Professor Hooper gratefully acknowledged the generosity of the ANZGOG funding from a bequest of Judith Meschke.
“The involvement in the project of so many talented people, scientists and clinicians, is in the spirit of the creative process fostered by the diverse and talented Australian arts community exemplified by the achievements of Ms Meschke.”
Reference: Khan, et al. (2020) Disruption of Glycogen Utilization Markedly Improves the Efficacy of Carboplatin against Preclinical Models of Clear Cell Ovarian Carcinoma. Cancers DOI: https://doi.org/10.3390/cancers12040869
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