Aslan Pharmaceuticals announced positive data from an ongoing multicentre phase 1b/2 clinical trial of varlitinib plus gemcitabine and cisplatin, or gem/cis, in first-line biliary tract cancer, or BTC. Varlitinib in combination with gem/cis has been well tolerated in BTC patients and the data also demonstrate increased activity of varlitinib in combination with gem/cis compared to gem/cis alone. The data will be presented during a poster presentation at the upcoming American Society of Clinical Oncology Gastrointestinal Cancers Symposium in San Francisco on January 18.
Monday, January 14, 2019
Exelixis: FDA OKs CABOMETYX for Hepatocellular Carcinoma
Exelixis, Inc. (NASDAQ:EXEL) today announced that the U.S. Food and Drug Administration (FDA) approved CABOMETYX® (cabozantinib) tablets for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. HCC is the most common form of liver cancer and the fastest-rising cause of cancer-related death in the U.S.1
“This new indication for CABOMETYX is an important treatment advance for patients with this aggressive form of liver cancer, a community in need of new therapeutic options,” said Michael M. Morrissey, Ph.D., President and Chief Executive Officer of Exelixis. “This approval is an important milestone as we continue to explore how CABOMETYX may benefit people with difficult-to-treat-cancers beyond renal cell carcinoma. We would like to thank the patients and clinicians who participated in CELESTIAL and to acknowledge the team at the FDA for their continued collaboration during the review of our application.”
The FDA’s approval of CABOMETYX was based on results from the CELESTIAL phase 3 pivotal trial of CABOMETYX for patients with advanced HCC who received prior sorafenib. CABOMETYX demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) versus placebo. On November 15, 2018, Exelixis’ partner Ipsen received approval from the European Commission for CABOMETYX tablets as a monotherapy for HCC in adults who have previously been treated with sorafenib.
“Patients with this form of advanced liver cancer have few treatment options, particularly once their disease progresses following treatment with sorafenib,” said Ghassan K. Abou-Alfa, M.D., Memorial Sloan Kettering Cancer Center, New York and lead investigator on CELESTIAL. “Physicians are eager for new options for these patients, and the results of the CELESTIAL trial demonstrate that CABOMETYX has the efficacy and safety profile to become an important new therapy in our efforts to slow disease progression and improve treatment outcomes.”
Some Things To Look For In This Market Going Forward
In my recent Forbes article reviewing historical patterns of bear markets, I noted that it was common to see extended bounces even within the context of longer-term declines. Indeed, we could be seeing just such a bounce in recent markets, which have taken stocks, oil, and high yield bonds meaningfully higher following significant declines. Speaking with investors and traders, I observe a high level of uncertainty and many questions. Is the decline over? Are we beginning a new bull market? Will we retest the lows?
Thanks to a savvy trader for pointing out this perspective from The Fat Pitch, who evaluates historical evidence regarding bounces from highly oversold conditions. See also this useful preview of the coming week from Dash of Insight. In my own trading and investment, I have found it useful to track the relative performance of ETFs as a way of detecting market themes and the unfolding of strength and weakness. Here are a few ETFs that I view in this relative manner. Each of the charts is indexed to 100 as of the start of January, 2016 and each looks at the ETF versus SPY:
* EFA – Here we’re looking at stocks outside the U.S., including Europe, the Far East, and Austral-Asia. Note the ongoing weakness of EFA versus SPY. Many of the market vulnerability themes (disarray in the E.U.; concern over Italy and debt; concern over China and trade wars) stem from overseas. Watching the relative performance of EFA helps me walk forward, day by day, to see if those concerns are growing or waning.
* HYG – This tracks high yield bonds, which have been weak for a while, but which rallied strongly on the Fed chair’s recent reassurances regarding the pace of shrinking the balance sheet. When high yield bonds decline in price, their yields rise. That is not necessarily a good thing, as it can mean that the market is pricing in growing odds of default. When we see high quality bonds (AGG, for example) outperform high yield bonds, it’s a sign that smart bond investors perceive risks and seek safety. Watching the relative performance of HYG is one way of tracking their sentiment going forward.
* XLF – This familiar ETF tracks the performance of financial stocks within the SPX universe. In a stable and growing economy, banks should perform well and other financial firms should benefit from loan activity and loan demand. If we encounter threats to the financial system, such as we saw in 2007-2008 with the housing crisis, then banking and financial stocks should show particular vulnerability relative to the overall stock market. Lately we’ve seen relative weakness from the financial sector and a so-so bounce. I remain concerned about the European banks, which have been unusually weak: DB and CS are examples.
* DBC – This ETF tracks commodities and is sensitive to oil prices, which were quite weak and which have rallied nicely in recent sessions. In a growing global economy, rising production and consumption and increased building lead to an increased appetite for many commodities. Conversely, economies in recession will tend to consume less and that can lead to declining commodity prices. Oil and industrial metals are especially valuable to follow in this regard.
Note that overseas equities, high yield bonds, financial stocks, and commodities are all below their 2017 levels in relative terms. Should we see economic weakness not only overseas but in the U.S. as well, these measures could weaken further. Conversely, if we retest lows and these measures hold up well in relative terms, I will be open to a more benign thesis. The key is staying open-minded and letting the evidence speak for itself. We can’t be open to possibilities–and profit from them–if we can’t tolerate degrees of market uncertainty.
Merck says keytruda met primary endpoint in KEYNOTE-181 trial
Merck announced the first presentation of results from KEYNOTE-181, a Phase 3 trial investigating KEYTRUDA, Merck’s anti-PD-1 therapy, as monotherapy for the second-line treatment of advanced or metastatic esophageal or esophagogastric junction carcinoma. In this pivotal study, KEYTRUDA met a primary endpoint by significantly improving overall survival in patients with squamous cell carcinoma or adenocarcinoma who progressed after standard therapy and whose tumors expressed PD-L1. This represents the first time an anti-PD-1 therapy has demonstrated a survival benefit for this patient population. The primary endpoint of OS was also evaluated in patients with squamous cell histology and in the entire intention-to-treat study population. While directionally favorable, statistical significance for OS was not met in these two patient groups. These results, as well as other study findings, are being presented at the 2019 Gastrointestinal Cancers Symposium in San Francisco in an oral presentation on Thursday, Jan. 17. “The prognosis for patients diagnosed with esophageal cancer is poor, and for those who experience disease progression, there is no established standard of care, underscoring the need for improved therapies in the second-line setting,” said Dr. Takashi Kojima, professor at the Department of Gastroenterology and Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan. “The significant improvement in overall survival observed with KEYTRUDA in patients with squamous cell carcinoma or adenocarcinoma whose tumors expressed PD-L1 with a CPS of 10 or greater represents an important scientific advancement and has the potential to benefit patients who currently have limited treatment options.”
Array Updates Colorectal Cancer Safety, Efficacy Data in Phase 3 Trial
Array BioPharma Inc. (Nasdaq: ARRY) today announced updated safety and efficacy results, including mature overall survival (OS), from the safety lead-in of the Phase 3 BEACON CRC trial evaluating the triplet combination of BRAFTOVI® (encorafenib), a BRAF inhibitor, MEKTOVI® (binimetinib), a MEK inhibitor and ERBITUX® (cetuximab), an anti-EGFR antibody, in patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC). The results showed that mature median OS was 15.3 months (95% CI, 9.6–not reached) for patients treated with the triplet. These data will be presented on Saturday, January 19 at the ASCO 2019 Gastrointestinal Cancers Symposium in San Francisco, California.
Updated median progression-free survival (mPFS) and updated confirmed overall response rate (ORR) results for patients treated with the triplet in the safety lead-in remain the same, as previously reported, with 8 months mPFS (95% CI, 5.6-9.3) and a 48% ORR (95% CI, 29.4–67.5). Among the 17 patients who received only one prior line of therapy, the ORR was 62%.
A BRAF mutation is present in up to 15% of all patients with mCRC and V600 is the most common BRAF mutation. [1-5] BRAFV600E-mutant mCRC patients have a mortality risk more than double that of mCRC patients without the mutation, and currently there are no U.S. Food and Drug Administration (FDA)-approved therapies specifically indicated for this high unmet need population. [3-10]
“The mature median overall survival of 15.3 months demonstrated in the safety lead-in of the BEACON CRC trial is unprecedented in this patient population and, for context, represents a substantial improvement compared to the observed historical published benchmarks of approximately 4 to 6 months for median overall survival with current standards of care in patients with BRAF-mutant mCRC,” said Axel Grothey, M.D., BEACON CRC trial lead investigator and Co-Chair of the National Cancer Institute’s Gastrointestinal Cancer Steering Committee, West Cancer Center, Memphis, TN. “These updated data further underscore the potential of this triplet for patients with BRAF-mutant mCRC who are in desperate need of effective new treatment options.”
The triplet combination was generally well-tolerated with no unexpected toxicities. The most common grade 3 or 4 adverse events seen in at least 10% of patients were fatigue (13%), anemia (10%), increased creatine phosphokinase (10%), increased aspartate aminotransferase (10%) and urinary tract infections (10%). The rate of grade 3 or 4 skin toxicities continued to be lower than generally observed with ERBITUX in mCRC.
“We are delighted with the updated results from the BEACON CRC safety lead-in. Following consultations with the FDA and European Medicines Agency, we initiated an amendment to the BEACON CRC protocol to allow for an interim analysis based primarily on confirmed ORR and durability of response endpoints, which we believe could support an accelerated approval with positive results,” said Victor Sandor, M.D., Chief Medical Officer, Array BioPharma. “We anticipate topline results from this interim analysis in the first half of this year. This timing allows for the subset of patients required for the interim analysis of ORR to achieve a response and for the durability of responses to be appropriately evaluated.”
On August 7, 2018, Array announced that the FDA granted Breakthrough Therapy Designation to BRAFTOVI, in combination with MEKTOVI and ERBITUX for the treatment of patients with BRAFV600E-mutant mCRC as detected by an FDA-approved test, after failure of one to two prior lines of therapy for metastatic disease.
The triplet combination of BRAFTOVI, MEKTOVI and ERBITUX for the treatment of patients with BRAFV600E-mutant mCRC is investigational and not approved by the FDA.
Asthma Drug Explored for Lupus
Target Audience and Goal Statement: Rheumatologists, primary care physicians, allergy specialists, nurses
The goal was to assess the safety, tolerability, and clinical efficacy of omalizumab in treating mild to moderate systemic lupus erythematosus (SLE).
Questions Addressed:
- What was the safety and tolerability of omalizumab in SLE?
- What were the effects of immunoglobulin E (IgE) blockade on the type I interferon (IFN) gene signature?
Study Synopsis and Perspective:
Omalizumab (Xolair) was well tolerated and associated with improvement in disease activity, according to a study by Sarfaraz Hasni, MD, of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and colleagues.
While rates of all-cause mortality for SLE have declined in recent years due to improved management, there is still room for improvement, the team noted. “Treatment strategies include a variety of immunosuppressive medications used alone or in combination that are limited both in their efficacy and by significant potential toxicities. Clearly there is an unmet need for improved treatment of inflammation in this patient population.”
Molecular mechanisms underlying SLE — a debilitating, multi-organ disease — are known to involve an IgG subclass that contributes to interferon (IFN)-α responses and the eventual proliferation of autoantibodies, the researchers explained. IgE is known for its role in Th2 responses and in the pathogenesis of allergy.
Growing evidence suggests a role for IgE beyond allergy, the investigators noted — for example:
- Autoreactive IgE antibodies were recently implicated in a murine model of lupus
- Autoreactive IgE is believed to increase SLE disease activity through elevated basophil activation
- IFN-α production and DNA-containing immune complexes in phagosomes may be enhanced due to the presence of these autoantibodies in SLE
Overall, IgE might be involved in the maintenance and amplification of autoimmunity in SLE by inducing heightened activation of autoreactive immune responses. Omalizumab, a humanized IgG1 monoclonal antibody against human IgE, is FDA approved for treatment in select patients with moderate to severe persistent asthma and hives (chronic idiopathic urticaria). The drug helps to lower antibodies in the blood that may also be present in some people with SLE.
Hasni and co-authors hypothesized that depleting IgE autoantibodies with omalizumab in SLE patients with elevated autoreactive IgEs might interfere with type 1 IFN production, reduce autoantibodies, and ultimately reduce disease activity. To investigate this, the team randomly assigned 15 SLE patients with elevated levels of autoreactive IgE antibodies (>2 standard deviations above the mean of healthy controls) to receive 16 weeks of treatment with subcutaneous omalizumab at a loading dose of 600 mg followed by 300 mg every 4 weeks or placebo.
A 2:1 ratio was used for randomization. All the patients received open-label omalizumab for 16 weeks and were then observed for 4 weeks following discontinuation of the study medication. Participants were allowed to receive glucocorticoids and immunosuppressive therapy throughout the trial.
Exclusion criteria included the following:
- Having been on biologics prior to study enrollment
- Having a history of asthma, anaphylaxis, or known or suspected helminthic infection/infestation
- Weight >105 kg
- Having a total serum IgE level > 700 IU/mL or serum creatinine > 2.0 mg/dL
Disease activity assessments were made at each visit using the Physician Global Assessment, Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K), and the British Isles Lupus Assessment Group index 2004. Type 1 IFN-induced gene signature (IFI27, IFI44, IFI44L, and RSAD2) was determined using quantitative polymerase chain reaction.
Omalizumab-treated patients tended to have a lower type 1 IFN-gene signature, especially if they had a high baseline type 1 IFN gene signature. Compared with the placebo group, these patients also showed a significantly greater improvement in median SLEDAI-2K score from baseline to week 16. But Hasni and colleagues noted that the magnitude of the difference was just two and that no other clinical measures differed between the groups.
Omalizumab was well tolerated, and caused no allergic reactions, the researchers reported. A total of 52 adverse events (AEs) occurred in the 15 patients over the course of 36 weeks. Most of the AEs (94.2%) were mild to moderate in severity. During the first 16 weeks of treatment, omalizumab-treated patients (n=10) had nine AEs, compared with 12 for the five on placebo. Mild to moderate AEs were comparable between the two study arms. Moreover, “no trend of involvement of a particular organ system was identified,” the team said.
Three serious AEs occurred during the study: One was in a patient on placebo who had bronchitis and developed chest pain; the second was a West African patient on omalizumab who had no evidence of immunity to chicken pox and developed varicella infection after exposure to the disease; and the third was in a patient who had a pulmonary embolism shortly after switching from placebo to omalizumab.
The researchers said it is worth noting that this exploratory study was not powered for efficacy and a larger sample size will be needed to ascertain if omalizumab has a potential to treat a selected subset of patients with SLE and high levels of anti-IgE antibodies. Additional mechanistic studies controlling for inter-test variability will also need to be done in the future to fully elucidate the mechanism of action of omalizumab in SLE, the team added.
Source Reference: Arthritis and Rheumatology, online Dec. 29, 2018, DOI: 10.1002/art.40828
Study Highlights: Explanation of Findings
In this proof-of-concept study of omalizumab, an anti-IgE antibody, researchers found its safety profile acceptable as an add-on therapy in SLE and there were no immediate or delayed allergic reactions. Improvements in disease activity, as measured only by a change in the SLEDAI 2 score, were noted, but this change of approximately two points was below the threshold typically considered to be a clinically minimally important change. Outcomes did not worsen while patients were on omalizumab during the study period.
However, the development of a pulmonary embolism in one patient following a switch from placebo to omalizumab is cause for concern, Hasni and co-authors said. Was this event related to the study drug? After all, a 5-year observational study of patients with asthma showed a higher incidence rate of cardiovascular/cerebrovascular events in the omalizumab-treated cohort versus the non-omalizumab group. Those authors attributed this result to differences in asthma severity between the cohorts, but said they could not rule out a possible contribution by the study drug to the AEs.
Hasni and colleagues offered an alternative hypothesis for the pulmonary embolism, that it could have been due to an elevated risk of thromboembolic events in SLE. Taken together, this suggests a need for markers of vascular risk and assessments of vascular dysfunction in future studies of omalizumab in SLE, the researchers advised.
They explained that reduced type 1 IFN gene signatures in omalizumab-treated patients suggest that the mechanism of action of the study drug in SLE may involve abrogation of dysregulated IFN pathways, and suggested expanding the list of potential biomarkers that may be involved in this pathway (e.g., CD62L and Th2 cytokines).
“A potential advantage of omalizumab in SLE is a side effect profile different from immunosuppressive drugs and a convenient once-a-month subcutaneous administration schedule,” Hasni and colleagues wrote. “Overall, this is the first trial to test the safety and potential efficacy of blocking IgE autoantibodies as a novel non-immunosuppressive agent in treatment of SLE. Additional larger studies will be needed to more fully evaluate the efficacy and safety of omalizumab in SLE.”
Primary Source
Arthritis & Rheumatology
Secondary Source
MedPage Today
Aimmune says FDA review of BLA delayed by government shutdown
In a regulatory filing, Therapeutics announced that it has been notified by the U.S. Food and Drug Administration that as a result of the U.S. government shutdown and lapse in appropriations, the FDA will not commence review of the company’s Biologics License Application, or “BLA,” for AR101, the company’s investigational biologic oral immunotherapy for the treatment of peanut allergy in children and adolescents ages 4-17. “The FDA indicated that it will initiate review of the BLA when the U.S. government shutdown and lapse in appropriations has ended. As previously announced, the company submitted its BLA for AR101 on December 21, 2018, prior to the U.S. government shutdown,” Aimmune stated.
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