TG Therapeutics, Inc. requested approval of ublituximab in combination with umbralisib (TGR-1202) to treat patients with chronic lymphocytic leukemia (CLL).

The company expects to complete the rolling submission of its biologics license application (BLA) in the first half of 2021.

“The initiation of a BLA submission for ublituximab in combination with umbralisib is an important milestone for us, and one that brings us one step closer to our goal of developing combination therapies for patients in need,” Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics, said in a press release, adding that the BLA is supported by the phase 3 UNITY-CLL trial.

The global, randomized, controlled trial, which will be presented at the 2020 American Society of Hematology (ASH) annual meeting, met its primary end point of progression-free survival with the combination regimen, compared with Obinutuzumab (Gazyva) plus chlorambucil, in patients with both treatment-naïve and relapsed or refractory CLL.

The trial randomized patients into 4 treatment arms:

an active control arm of obinutuzumab plus chlorambucil

Of the 420 patients enrolled in the 2 combination arms, approximately 60% of patients were treatment-naïve and 40% were relapsed or refractory.

Progression-free survival in the ublituximab plus umbralisib arm served as the primary end points of the study. The UNITY-CLL Phase 3 trial is being conducted under a Special Protocol Assessment agreement with the FDA.

“I want to thank the patients, caregivers and research teams who participated in our clinical trials and helped to advance (ublituximab in combination with umbralisib) to this stage. We believe, if approved, (the combination) has the potential to become an important treatment option to both front line and relapsed/refractory patients with CLL,” Weiss added.

The FDA previously granted fast track designation and orphan drug designation to the combination of ublituximab and umbralisib for the treatment of adult patients with CLL. TG Therapeutics, Inc.

TG Therapeutics, Inc. TG Therapeutics Initiates Rolling Submission of Biologics License Application to U.S. Food and Drug Administration for Ublituximab in Combination with Umbralisib as a Treatment for Patients with Chronic Lymphocytic Leukemia. Published: December 1, 2020. 

https://ir.tgtherapeutics.com/news-releases/news-release-details/tg-therapeutics-initiates-rolling-submission-biologics-license

Articles

The company expects to complete the rolling submission of its biologics license application for ublituximab in combination with umbralisib in the first half of 2021.

TG Therapeutics Initiates BLA for Ublituximab Combo to Treat CLL

The FDA granted fast track designation to irinotecan liposome injection (Onivyde) for the treatment of patients with small cell lung cancer (SCLC) who progressed following a first-line platinum-based regimen, according to Ipsen, the agent’s manufacturer.

“The fast track designation of Onivyde as a potential treatment for people living with small cell lung cancer is an extension of Ipsen’s focus and contribution to the treatment landscape in oncology,” Howard Mayer, MD, executive vice president and head of research and development at Ipsen, said in a press releasee. “With this aggressive and often late-stage diagnosed form of lung cancer, we are proud to be one step closer to making another treatment option available to patients.”

The agent is being evaluated in the ongoing, randomized phase 3 RESILIENT trial (NCT03088813), designed to evaluate the efficacy and safety of irinotecan liposome injection as a monotherapy for patients with SCLC who have progressed on or after a first-line platinum-based regimen.

Irinotecan is currently FDA approved in combination with fluorouracil (5-FU) and leucovorin for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. In addition, the agent also received fast track designation in June, in combination with 5-FU, leucovorin, and oxaliplatin – also known as NALIRIFOX – for the first-line treatment of patients with previously untreated, unresectable, locally advanced and metastatic pancreatic ductal adenocarcinoma. The ongoing, randomized phase 3 NAPOLI-3 study (NCT04083235) is being conducted to assess the efficacy and safety of NALIRIFOX in patients who are not previously treated for metastatic pancreatic cancer.

Ipsen. Ipsen receives FDA Fast Track designation for investigational irinotecan liposome injection (ONIVYDE®) as a second-line monotherapy treatment for small cell lung cancer (SCLC). Published: December 1, 2020. 

https://www.ipsen.com/press-releases/ipsen-receives-fda-fast-track-designation-for-investigational-irinotecan-liposome-injection-onivyde-as-a-second-line-monotherapy-treatment-for-small-cell-lung-cancer-sclc/

The agency granted fast track designation to irinotecan liposome injection for patients with small cell lung cancer who progressed following a first-line platinum-based regimen.

FDA Grants Fast Track Designation to Irinotecan Liposome Injection for Second-Line Treatment of SCLC

The FDA granted accelerated approval to pralsetinib (Gavreto) to treat adult and pediatric patients aged 12 years and older with advanced or metastatic 

-mutant medullary thyroid cancer (MTC) who require systemic therapy or 

 fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory.

The review of this application was conducted under the FDA’s Real-Time Oncology Review (RTOR) pilot program and Assessment Aid to assist the agency in approving the application 3 months ahead of the FDA goal date.

The agency based its decision on efficacy data from the multicenter, open label, multi-cohort ARROW clinical trial (NCT03037385), designed to evaluate pralsetinib in patients whose tumors had 

Overall response rate (ORR) and duration of response (DOR) determined by a blinded independent review committee using RECIST 1.1 served as the main efficacy outcomes for the study.

Efficacy was evaluated in 55 patients with advanced or metastatic 

-mutant MTC who received prior cabozantinib (Cabometyx) or vandetanib (Caprelsa). Patients in this cohort who were treated with pralsetinib demonstrated an ORR of 60% (95% CI, 46%-73%), with 79% of those patients experiencing a response that lasted 6 months or longer.

Efficacy was also evaluated in 29 patients with 

-mutant MTC who did not receive prior cabozantinib or vandetanib. Patients in this cohort who were treated with pralsetinib demonstrated an ORR of 66% (95% CI, 46%-82%), with 84% of those patients experiencing a response that lasted 6 months or longer.

 fusion-positive thyroid cancer was evaluated in 9 patients who were radioactive iodine-refractory. The ORR was 89% (95% CI, 52%-100%), with all patients experiencing responses lasting 6 months or longer.

The most common adverse events (AEs) included constipation, hypertension, fatigue, musculoskeletal pain, and diarrhea. The most common grade 3-4 laboratory abnormalities were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased calcium, decreased sodium, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased platelets, and increased alkaline phosphatase.

The FDA noted the recommended pralsetinib dose in adults and pediatric patients 12 years and older is 400 mg orally once daily on an empty stomach with no food intake for at least 2 hours before and at least 1 hour after taking pralsetinib.

Of note, under accelerated approval, the application was based on overall response rate and duration of response. Therefore, continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

FDA. FDA approves pralsetinib for RET-altered thyroid cancers Published: December 1, 2020. 

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pralsetinib-ret-altered-thyroid-cancers?utm_medium=email&utm_source=govdelivery

The FDA granted accelerated approval to pralsetinib to treat with advanced or metastatic RET-mutant medullary thyroid cancer or RET fusion-positive thyroid cancer.

FDA Approves Pralsetinib to Treat RET-Altered Thyroid Cancers

The FDA approved the first drug for PET imaging of prostate-specific membrane antigen (PSMA) positive lesions in men with prostate cancer, Gallium 68 PSMA-11 (Ga 68 PSMA-11).

“Ga 68 PSMA-11 is an important tool that can aid health care providers in assessing prostate cancer,” Alex Gorovets, MD, acting deputy director of the Office of Specialty Medicine in FDA’s Center for Drug Evaluation and Research, said in press releasee. “With this first approval of a PSMA-targeted PET imaging drug for men with prostate cancer, providers now have a new imaging approach to detect whether or not the cancer has spread to other parts of the body.”

The FDA based its decision on the safety and efficacy of Ga 68 PSMA-11 proven in 2 prospective clinical trials with a total of 960 men with prostate cancer who each received 1 injection of the drug.

In the first trial, 325 patients who were candidates for surgical removal of the prostate gland and pelvic lymph nodes and were considered at higher risk for metastasis underwent PET/CT or PET/MRI scans performed with Ga 68 PSMA-11. Of the patients who went on to undergo surgery, Ga 68 PSMA-11 PET demonstrated a clinically important rate of metastatic cancer confirmed by surgical pathology in patients with positive readings in the pelvic lymph nodes.

“The availability of this information prior to treatment is expected to have important implications for patient care. For example, it may spare certain patients from undergoing unnecessary surgery,” the FDA states in its release.

In the second trial, 635 patients who had rising serum PSA levels after initial prostate surgery or radiotherapy, 74% had at least 1 positive lesion detected by Ga 68 PSMA-11 PET in at least 1 body region. In total, 91% of atients with positive Ga 68 PSMA-11 PET readings who had correlative tissue pathology from biopsies, who also had results from baseline or follow-up imaging by conventional methods, and serial PSA levels available for comparison, also had local recurrence or metastasis of prostate cancer confirmed.

“Thus, the second trial demonstrated that Ga 68 PSMA-11 PET can detect sites of disease in patients with biochemical evidence of recurrent prostate cancer, thereby providing important information that may impact the approach to therapy,” the agency added.

No serious adverse events (AEs) were attributed to Ga 68 PSMA-11. The most common AEs included nausea, diarrhea, and dizziness.

The FDA warned there may be a risk for misdiagnosis, “because Ga 68 PSMA-11 binding may occur in other types of cancer as well as certain non-malignant processes which may lead to image interpretation errors. There are radiation risks because Ga 68 PSMA-11 contributes to a patient’s overall long-term cumulative radiation exposure, which is associated with an increased risk for cancer.”

The drug, which is a radioactive diagnostic agent that is administered in the form of an intravenous injection, is indicated for patients with suspected prostate cancer metastasis who are potentially curable by surgery or radiation therapy and for those with suspected prostate cancer recurrence based on elevated serum prostate-specific antigen (PSA) levels. Ga 68 PSMA-11 binds to PSMA once administered and can be imaged by PET to indicate the presence of PSMA-positive prostate cancer lesions in the tissues of the body.

F 18 fluciclovine and C 11 choline are 2 additional PET drugs that are approved for prostate cancer imaging, the FDA noted; however, they are only approved for use in patients with suspected cancer recurrence.

FDA News Release. FDA Approves First PSMA-Targeted PET Imaging Drug for Men with Prostate Cancer. Published December 1, 2020. 

https://www.fda.gov/news-events/press-announcements/fda-approves-first-psma-targeted-pet-imaging-drug-men-prostate-cancer?utm_medium=email&utm_source=govdelivery

The agency approved the first PSMA-targeted PET imaging drug to treat men with prostate cancer.

FDA Approves Gallium 68 PSMA-11 for Prostate Cancer

The FDA accepted and granted priority review to the new drug application (NDA) for infigratinib to treat patients with cholangiocarcinoma, according to BridgeBio Pharma, Inc., an affiliate QED Therapeutics.

“We want to thank the patients, families, scientists, physicians and all others involved who helped us move this NDA forward. At BridgeBio we believe that every minute counts for patients and their families, and we are eager to help as many people suffering from cholangiocarcinoma as possible – as quickly as possible,” Neil Kumar, PhD, CEO and founder of BridgeBio, said in a press release.

The NDA is being reviewed under the Real-Time Oncology Review (RTOR) pilot program, which is designed by the FDA’s Oncology Center of Excellence to expedite the delivery of safe and effective cancer treatments to patients. Moreover, the company will be submitting the agent for review in Australia and Canada under Project Orbis, another initiative from the FDA’s Oncology Center of Excellence, to allow for concurrent submission and review of oncology drugs among participating international regulatory agencies.

Infigratinib is an oral FGFR1-3 selective inhibitor aimed to treat patients with 

-driven conditions, including cholangiocarcinoma, urothelial carcinoma, and achondroplasia. 

 genetic aberrations are present in approximately 15% to 20% of people who have cholangiocarcinoma – a disease with limited treatment options and a 5-year survival rate of only 9%.

BridgeBio Pharma, Inc. BridgeBio Pharma And Affiliate QED Therapeutics Announce FDA Acceptance Of New Drug Application For Infigratinib For The Treatment Of Cholangiocarcinoma. Published: December 1, 2020. 

https://bridgebio.com/news/bridgebio-pharma-and-affiliate-qed-therapeutics-announce-fda-acceptance-of-new-drug-application-for-infigratinib-for-the-treatment-of-cholangiocarcinoma

The agent’s new drug application will be reviewed under the FDA’s Real Time Oncology Review pilot program and under Project Orbis.

FDA Grants Priority Review to Infigratinib to Treat Cholangiocarcinoma

 suggest that the combination of neoadjuvant paclitaxel (Abraxane), trastuzumab (Herceptin), and pertuzumab (Perjeta) followed by adjuvant trastuzumab for patients with pathologic complete response (pCR) or followed by adjuvant dose-dense anthracycline/cyclophosphamide (DDAC) plus trastuzumab emtansine (T-DM1; Kadycla) for patients with residual disease was associated with the highest health benefits and lowest costs for women with 

-positive breast cancer compared with other treatment strategies.

“Providing patients with neoadjuvant treatment associated with decreased rates of pCR (eg [paclitaxel, trastuzumab, and pertuzumab] vs [docetaxel, carboplatin, trastuzumab, and pertuzumab]) may be associated with decreased neoadjuvant treatment costs. However, it may also be associated with increased adjuvant treatment costs due to patients with residual disease receiving more costly adjuvant treatment when they would have achieved pCR with [docetaxel, carboplatin, trastuzumab, and pertuzumab],” the authors wrote. “Our model estimates total costs associated with each neoadjuvant-adjuvant treatment strategy, accounting for neoadjuvant and adjuvant treatment costs and simulated health states.”

In this economic evaluation, a decision-analytic model was created to assess various neoadjuvant treatment strategies followed by adjuvant treatment strategies for women with 

-positive breast cancer from a health care payer perspective in the US. The model utilized the KATHERINE trial, other clinical trials with different regimens from the KATHERINE trial, the Flatiron Health Database, McKesson Corporation data, and other evidence in the published literature.

Specifically, the model simulated patients receiving 5 different neoadjuvant followed by adjuvant treatment strategies. There were 4 neoadjuvant regimens, including (1) trastuzumab plus pertuzumab; (2) paclitaxel plus trastuzumab plus pertuzumab; (3) DDAC plus paclitaxel, trastuzumab, and pertuzumab; (4) and docetaxel, carboplatin, trastuzumab and pertuzumab. All patients with pCR, regardless of neoadjuvant regimen, received adjuvant trastuzumab.

Patients with residual disease received different adjuvant therapies depending on the neoadjuvant regimen according to the 5 following strategies: (1) neoadjuvant DDAC plus paclitaxel, trastuzumab, and pertuzumab followed by adjuvant trastuzumab, (2) neoadjuvant DDAC plus paclitaxel, trastuzumab, and pertuzumab followed by adjuvant T-DM1, (3) neoadjuvant paclitaxel, trastuzumab, and pertuzumab followed by adjuvant DDAC plus T-DM1, (4) neoadjuvant trastuzumab plus pertuzumab followed by adjuvant DDAC plus paclitaxel, trastuzumab, pertuzumab and T-DM1, or (5) neoadjuvant docetaxel, carboplatin, trastuzumab and pertuzumab followed by adjuvant T-DM1.

In the base-case analysis, costs ranged from $415,833 with neoadjuvant paclitaxel, trastuzumab, and pertuzumab followed by adjuvant DDAC plus T-DM1 to $518,859 neoadjuvant trastuzumab plus pertuzumab followed by adjuvant DDAC plus paclitaxel, trastuzumab, pertuzumab and T-DM1. Moreover, quality of life years (QALYs) ranged from 9.67 with neoadjuvant DDAC plus paclitaxel, trastuzumab, and pertuzumab followed by adjuvant trastuzumab to 10.73 with neoadjuvant paclitaxel, trastuzumab, and pertuzumab followed by adjuvant DDAC plus T-DM1.

Ultimately, treatment with neoadjuvant paclitaxel, trastuzumab, and pertuzumab followed by adjuvant DDAC plus T-DM1 was associated with the highest health benefits and lowest costs, dominating all other strategies. Even further, probabilistic analysis confirmed that this strategy had the highest probability of cost-effectiveness (>70% at willingness-to-pay thresholds of $0-200,000/QALY) and was associated with the highest net benefit.

“This treatment regimen seems to represent the preferred strategy in ER-positive and ER-negative cancers,” the authors wrote.

Moving forward, the investigators indicated that a clinical trial (NCT04457596) with an estimated start date of January 2021 will prospectively test de-escalation strategies using the combination of paclitaxel, trastuzumab, and pertuzumab as neoadjuvant therapy and reserving further treatment for individuals with residual disease.

Kunst N, Wang S, Hood A, et al. Cost-Effectiveness of Neoadjuvant-Adjuvant Treatment Strategies for Women With ERBB2 (HER2)–Positive Breast Cancer. 

. doi: 10.1001/jamanetworkopen.2020.27074

The combination use of neoadjuvant paclitaxel, trastuzumab, and pertuzumab followed by adjuvant trastuzumab for patients with pathologic complete response or followed by adjuvant dose-dense anthracycline/cyclophosphamide plus T-DM1 for patients with residual disease offered the highest health benefits and lowest costs.