Immunotherapy appears better than chemo for aggressive type of skin cancer

The first study of the immunotherapy drug pembrolizumab as the initial treatment for patients with a rare but aggressive form of skin cancer known as Merkel cell carcinoma reports better responses and longer survival than expected with conventional chemotherapy.

The study, co-led by Suzanne Topalian, M.D., associate director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy at the Johns Hopkins Kimmel Cancer Center, is the longest observation to date of Merkel cell carcinoma patients treated with any anti-PD-1 immunotherapy drug used in the first line. The findings, published in the Journal of Clinical Oncology, supported the recent (Dec. 19, 2018) U.S. Food and Drug Administration accelerated approval of pembrolizumab, marketed as Keytruda, as a first-line treatment for adult and pediatric patients with advanced Merkel cell carcinoma.

For this study, investigators from the Bloomberg~Kimmel Institute collaborated with researchers from the Fred Hutchinson Cancer Research Center in Seattle, along with 11 other U.S. medical centers. The Bloomberg~Kimmel Institute team includes Topalian, William Sharfman, M.D., Evan Lipson, M.D., Abha Soni, D.O., M.P.H., and Janis Taube, M.D., M.Sc.

In the 50-patient study of pembrolizumab as the initial treatment for patients with recurrent, locally advanced or metastatic Merkel cell carcinoma, more than half of the patients (28 patients, 56 percent) had long-lasting responses to the treatment, 12 of whom (24 percent) experienced a complete disappearance of their tumors. Nearly 70 percent of patients in this study were alive two years after starting treatment.

“This is the earliest trial of immunotherapy as a front-line therapy for Merkel cell carcinoma, and it was shown to be more effective than what would be expected from traditional therapies, like chemotherapy,” says Topalian, who is a Bloomberg~Kimmel professor of cancer immunotherapy at the Kimmel Cancer Center. “Immunotherapy provides an effective treatment for patients with Merkel cell carcinoma who before had few options. Immunotherapy is unique in cancer treatment, because it does not directly target cancer cells but rather removes constraints on the immune system’s natural ability to find and destroy cancer cells.”

The 50 patients in this study were treated at 13 centers across the United States in a clinical trial conducted by the Cancer Immunotherapy Trials Network, which is sponsored by the National Cancer Institute (NCI). The Kimmel Cancer Center, where much of the medical science contributing to the development of pembrolizumab unfolded, was a lead institution. Preliminary findings regarding the first 26 patients enrolled in the study were published in the New England Journal of Medicine in 2016. The study was subsequently amended to add 24 more patients.

The National Institutes of Health (NIH) classifies Merkel cell carcinoma as an “orphan disease,” as it is diagnosed in fewer than 2,000 people annually in the United States. It typically occurs in older people and those who have suppressed immune systems. About 80 percent of Merkel cell carcinomas are caused by a virus called the Merkel cell polyomavirus. The remaining cases are attributed to ultraviolet light exposure and other, unknown factors.

In the study, treatment with pembrolizumab worked well against both virus-positive and virus-negative Merkel cell carcinomas, resulting in high response rates and durable progression-free survival in both subtypes. The findings also showed that tumors expressing a PD-1-related protein called PD-L1 tended to respond longer to treatment, although patients whose tumors did not express PD-L1 also responded.

“These findings could be a precursor to developing more effective treatments for other virus-related cancers, which account for about 20 percent of cancers worldwide,” says Sharfman, the Mary Jo Rogers Professor of Cancer Immunology and Melanoma Research.

The non-virus-related subtype is characterized by high numbers of genetic mutations in cancer cells, which has also been shown by the Bloomberg~Kimmel Institute group to be a biomarker of response in various cancers to checkpoint inhibitors such as pembrolizumab.

Pembrolizumab works against Merkel cell carcinoma by blocking PD-1, a molecule on the surface of immune cells that regulates immune responses, turning them on and off. Cancer cells often manipulate PD-1 to send a “stop” signal to the immune system. Blocking that signal with a checkpoint inhibitor, such as pembrolizumab, initiates a “go” signal, sending immune cells to attack cancer cells. A protein on the surface of cancer cells, called PD-L1, is one mechanism cancer cells use to manipulate PD-1 and disrupt the immune response.

“Under the microscope, PD-L1 looks like an armor around the cancer cell,” says Taube, an associate professor of oncology, dermatology and pathology. “Pembrolizumab interrupts PD-1 signaling by blocking the communication between PD-1 and PD-L1, removing the stop signal and re-engaging the immune system to go after cancer cells.”

Patients in the just-published study received the immune checkpoint blocking drug pembrolizumab intravenously every three weeks for up to two years. During this time, the status of their cancer was monitored periodically with imaging scans. Overall, most patients tolerated the treatment well. However, 28 percent of patients experienced serious side effects, including one treatment-associated death.

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Story Source:

Materials provided by Johns Hopkins Medicine. Note: Content may be edited for style and length.

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Journal Reference:

1. Paul Nghiem, Shailender Bhatia, Evan J. Lipson, William H. Sharfman, Ragini R. Kudchadkar, Andrew S. Brohl, Phillip A. Friedlander, Adil Daud, Harriet M. Kluger, Sunil A. Reddy, Brian C. Boulmay, Adam I. Riker, Melissa A. Burgess, Brent A. Hanks, Thomas Olencki, Kim Margolin, Lisa M. Lundgren, Abha Soni, Nirasha Ramchurren, Candice Church, Song Y. Park, Michi M. Shinohara, Bob Salim, Janis M. Taube, Steven R. Bird, Nageatte Ibrahim, Steven P. Fling, Blanca Homet Moreno, Elad Sharon, Martin A. Cheever, Suzanne L. Topalian. Durable Tumor Regression and Overall Survival in Patients With Advanced Merkel Cell Carcinoma Receiving Pembrolizumab as First-Line Therapy. Journal of Clinical Oncology, 2019; JCO.18.01896 DOI: 10.1200/JCO.18.01896

https://www.sciencedaily.com/releases/2019/02/190207125025.htm

Express Scripts: lowest spend hike by commercial health insurers in 25 years

In an era where drugmakers and prescription drug managers (PBMs) point fingers at each other when it comes to justifying the reasons behind rising drug prices — the largest US PBM, Express Scripts, on Wednesday released a report indicating that in 2018 employer-sponsored plans paid roughly 6 cents more, on average, for a 30-day prescription (0.4% hike) versus the preceding year, marking the smallest increase in commercial plans in a quarter century.

The company analyzed prescription drug use data of roughly 34.2 million members with a pharmacy benefit plan and calculated that it had saved its members $45 billion in prescription drug costs in 2018.
Although spending on traditional, non-specialty medications dipped 5.8%, spending on specialty medications rose 9.4%, Express Scripts said. Drugs for inflammatory conditions such as rheumatoid arthritis and Crohn’s disease accounted for the costliest therapy class for the third consecutive year, costing employers $174.45 per member per year in 2018, up 14% from 2017, it added. Globally, AbbVie’s inflammatory drug Humira — the world’s best-selling medicine — generated nearly $20 billion in 2018 sales.

Diabetes was the second costliest therapy class for employers at $114.85 per member per year, an increase of 4.1% over 2017, the company said, adding that spending on insulin, which accounts for 15.3% of diabetes prescriptions, rose 0.3% in 2018 (a 1.5% decline in unit costs and a 1.8% rise in utilization). Anecdotal reports of diabetics rationing or forgoing life-saving insulin in the United States are on the rise.

For a long time drugmakers justified their policy of sustained drug price hikes on the heavy cost of innovation. However, as PBMs increasingly threaten to exclude treatments from formularies — unless they manage to negotiate a discount satisfactory to their demands — drugmakers in response have boosted rebates, and in turn hiked prices in order to maintain their cut of sales.

Despite list price inflation of 7.3% for the most commonly used traditional brand medications in 2018, costs for such drugs dipped 6.5% for its employer-sponsored plans, Express Scripts said.

The company has driven a 0.4% decline in drug unit costs by steering members to lower cost therapies, and by securing deeper discounts from manufacturers and pharmacies, it said, adding that about half of commercial plans saw a fall in per member drug spending, and a 0.3% decline across Medicare plans.

Twenty five years ago, the era of blockbuster drugs was taking off, characterized by mid-to-high-double-digit annual increases in drug spending, the company said, noting that today we are in the age of breakthrough treatments with “break-the-bank pricing.”

“We expect manufacturers of high-priced specialty drugs, which currently consume half of all drug spending, to continue to raise prices faster than core inflation. And we expect the contentious public policy debate on how to make prescription medicine, and especially insulin and other biologics, more affordable for the uninsured and underinsured to continue,” the company said, forecasting an annual drug trend of 2% for the next three years.

Data increasingly suggest that pricing is contributing to a smaller slice of biopharma growth than ever before. In a note published earlier this week, Leerink’s Geoffrey Porges said “positive list pricing has contributed at least two thirds of industry growth in recent years and this contribution appears to be fading, if not disappearing…in many striking cases we are seeing significant absolute reductions in price, which was previously unthinkable for this industry.” For example, PCSK9 antibodies by Amgen as well as partners Sanofi and Regeneron have recently seen heavy discounts, while CGRP antibodies from Teva, Lilly as well as partners Amgen and Novartis have taken a largely conservative approach to pricing.

Drug pricing has emerged as a bipartisan issue and a host of lawmakers, including those representing the Trump administration, have proposed a number of solutions to lower the burden of drug costs on consumers.

https://endpts.com/as-magnitude-and-frequency-of-drug-price-hikes-thaw-express-scripts-reports-lowest-increase-in-spending-by-commercial-plans-in-25-years/

Medicare Won’t Pay for Prostate Cancer Risk Test

A big issue in prostate cancer is differentiating patients with an aggressive tumor that needs immediate treatment from patients with lower-risk disease that may never spread and can be managed with active surveillance.

One test that addresses this problem is the 4Kscore (Opko Health), a blood test that predicts the likelihood of having a high-grade prostate cancer after an elevated prostate-specific antigen (PSA) test result.

However, this test has received a “noncoverage” determination from a Medicare administrative contractor, according to a report in the South Florida Business Journal.

The Medicare contractor, Novitas Solutions, said they found flaws with clinical studies of the test.

Opko will appeal the decision with the US Centers for Medicare & Medicaid Services, the report added.

More than 12,000 practicing physicians have ordered the 4Kscore test, according to the company.

4Kscore is an assay panel that combines three PSA measures (total, free, and intact) with another prostate-specific measure, human kallikrein 2, in an algorithm that takes into account a patient’s age, digital rectal examination result, and previous biopsy status.

The test reportedly helps distinguish men who are at higher risk for aggressive disease from those at lower risk, possibly aiding in personal decisions to undergo biopsy.

Novitas, which acts as stand-in for Medicare and makes coverage decisions in 10 states and Washington, DC, issued a proposed ruling that Medicare should not reimburse for the 4Kscore in May 2018.

Last week, the test manufacturer said that Novitas set March 20 as the date that the noncoverage determination goes into effect, according to the South Florida Business Journal.

“We remain committed to our goal of widespread and affordable access to 4Kscore,” said Phillip Frost, CEO of Opko.

In an apparently unrelated matter, Frost recently agreed to a settlement with the Securities and Exchange Commission in a civil case related to “lucrative market manipulation schemes” worth $27 million, per CNBC.

Clinician Support for the 4Kscore Test

The new Medicare ruling may come as a surprise to clinicians who have followed the story of the blood test.

In 2014, 4Kscore investigator Daniel Lin, MD, from the University of Washington in Seattle, told Medscape Medical News that “this is a test that can personalize the risk of having a clinically relevant prostate cancer that deserves diagnosis.”

In 2015, Medscape urology expert commentator Gerald Chodak, MD, highlighted the fact that the American Medical Association has issued a CPT (current procedural technology) code rating of level I for the test, “which means that it is likely that insurance companies and Medicare will find the test more acceptable for reimbursement in the future.”

Chodak said the 4Kscore test “clearly is better” than traditional PSA testing in identifying men at risk for high-grade disease before biopsy.

However, he also said that one of the test’s shortcomings is that “it misses in the range of 10% to 18% of potentially high-risk cancers.”

https://www.medscape.com/viewarticle/908785

Noxopharm Combo with Radiotherapy Delivers Clinical Benefits

Interim (12-week) DARRT-1 readout
 Combination Veyonda + low-dose
radiotherapy well tolerated
 PSA, pain and tumour responses at higher doses
 24-week readout to indicate longevity of
response.
Noxopharm (ASX: NOX) announces interim (12-week)
results from the dose-ranging component of the DARRT-1 study.
1. Key findings:
 combining Veyonda with low-dose radiotherapy applied to a single
metastasis (lesion) is able to produce an anti-cancer response in both the
irradiated and non-irradiated lesions as evidenced by PSA response, pain
reduction, and/or tumour measurements
 a dose-response was observed, with the 1200 mg dose confirmed as the
therapeutic dose
 clinical responses were achieved with no serious side-effects related to
Veyonda.
2. Rationale: The DARRT treatment regimen involves using Veyonda to trigger a generalised anticancer response to radiotherapy against cancer cells throughout the body. This is known as an
abscopal response and is thought to involve a generalised immune response. Veyonda has been
shown to activate the body’s innate immune system, an action that the company believes will provide
a transformative approach to the use of radiotherapy in oncology, enabling low dosages of focused
radiation to be used to create a generalised anti-cancer effect.
3. DARRT and prostate cancer: The Company’s ultimate goal in prostate cancer is to evaluate the
DARRT treatment regimen across the full spectrum of prostate cancer from early-stage to late-stage.
The DARRT-1 study is the starting point in this program involving end-stage prostate cancer.
Prostate cancer preferentially spreads to bone and lymph nodes. Late-stage (metastatic castrateresistant) prostate cancer typically involves multiple secondary lesions in the skeleton (vertebrae, ribs,
pelvis, hips, skull, long bones) and pelvic lymph nodes; secondary lesions in soft tissues such as the
lungs, liver and brain are less common. The tumour burden in Stage IV prostate cancer generally is
greatest in the skeleton and is associated with significant pain. Treatment in these men nearing end

of life is palliative, with pain relief a major objective through the use of radiotherapy and pain
medications.
NOX is developing the DARRT regimen in advanced prostate cancer with the dual objectives of
providing better palliation (pain relief) and extending survival and doing so in a well-tolerated way.
4. Interim data: The DARRT-1 study has two stages. Stage 1 involving 12 patients was designed to
provide an indication of the benefit:risk profile of three different doses of Veyonda (400, 800, 1200
mg daily) including four patient per dose. Patients included in this phase were required to have at
least one soft tissue lesion that was amenable to accurate radiographic measurement (according to
RECIST 1.1).
Stage 2 involved expansion into an additional 12 patients at a dose selected by an independent data
safety monitoring board (DSMB). As previously announced, Stage 2 of the trial was initiated at the
1200 mg dose following DSMB review of the 6-week data. Stage 2 includes patients who lack a soft
tissue lesion and whose lesion requiring radiatherapy is located in the bone, which often cannot be
accurately measured (according to RECIST 1.1). Determination of a generalised (abscopal) response in
such patients will be on the basis of PSA and pain responses. The final 4 patients in this stage have
been screened and the study is expected to be fully enrolled within 2 weeks.
Today’s announcement concerns the 12-week data on the 12 patients in Stage 1.

https://www.noxopharm.com/site/PDF/1816_3/VeyondaandRadiotherapyDeliversClinicalBenefits

Skeletal Impact of Cancer Therapies

Abstract

Both cancer and therapies used in the treatment of cancer can have significant deleterious effects on the skeleton, increasing the risks for both bone loss and fracture development. While advancements in cancer therapies have resulted in enhanced cancer survivorship for patients with many types of malignancies, it is increasingly recognized that efforts to reduce bone loss and limit fractures must be considered for nearly all patients undergoing cancer therapy in order to diminish the anticipated future skeletal consequences. To date, most studies examining the impact of cancer therapies on skeletal outcomes have focused on endocrine associated cancers of the breast and prostate, with more recent advances in our understanding of bone loss and fracture risk in other malignancies. Pharmacologic efforts to limit the adverse effects of cancer therapies on bone have nearly universally employed anti‐resorptive approaches, although studies have frequently relied on surrogate outcomes such as changes in bone mineral density or bone turnover markers, rather than on fractures or other skeletal‐related events, as primary study endpoints. Compounding current deficiencies for the provision of optimal care is the recognition that despite clearly written and straightforward society‐based guidelines, vulnerable eligible patients are very often neither identified nor provided with appropriate treatments to limit the skeletal impact of their cancer therapies.

Even before the initiation of cancer treatment therapies, patients with cancer
are at increased risk for accelerated bone loss, as evidenced by lower bone mineral
density in cancer patients relative to subjects without cancer, regardless of cancer
type 1
. Adding to this underlying skeletal insult is the further damage that results
from many cancer therapies. Thus bone loss in patients with cancer reflects both the
effects of the cancer itself, as well as the skeletal response to therapies currently
used to treat cancer including a wide range of chemotherapeutics, as well as agents
such as glucocorticoids, aromatase inhibitors, and androgen deprivation therapies. In
addition, bone is also a very common site of cancer metastasis, with tumor cells
exerting both direct and indirect effects on bone cells to cause systemic as well as
localized bone loss. When viewed through the prism of the increased survivorship
now commonly seen in patients with many types of malignancies, efforts to limit
bone loss and fractures that can significantly diminish quality of life, have become
increasingly important for the care of cancer patients.
This manuscript will focus on currently used cancer therapies, the impact of
these therapies on the skeleton, and available data for limiting bone loss and
fractures in cancer patients treated with these therapies. Given that the majority of
work to date has focused on patients with breast and prostate cancers, this review
will emphasize those cancers, but will also include discussion of more general
treatments such as glucocorticoids, as well as data on cancer therapies for
hematologic malignancies.

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bcp.13866

Galapagos continues fibrosis pipeline build-out with Evotec deal

Galapagos has secured the global rights to a preclinical fibrotic disease program from Evotec. The small molecule will slot into the growing fibrosis pipeline Galapagos is building through internal R&D and deals.

Belgium-based Galapagos indicated its interest in striking deals to bolster its fibrosis pipeline last month when it struck a deal to collaborate on a novel idiopathic pulmonary fibrosis (IPF) target with Fibrocor Therapeutics. Fibrocor worked with CRO Evotec to generate the data package that attracted the interest of Galapagos.

For its latest deal, Galapagos has gone direct to Evotec, which discovers drugs as well as working on assets owned by other companies. Evotec’s in-house activities have yielded a small molecule fibrosis drug that Galapagos sees as a good fit for its pipeline.

Galapagos is paying an upfront fee and committing to milestones and royalties to secure global rights to the drug. The Belgian biotech will assume responsibility for taking the drug forward, with Evotec providing access to specific screening formats to support the final steps in preclinical development.

Neither company has shared details of the financial package or the drug itself, beyond a comment about Evotec and Galapagos sharing a “focus on novel, first-in-class therapeutic candidates.” Details of the drug and its target should emerge as Galapagos wraps up the preclinical program and moves the candidate into human testing.

If the drug makes it that far, it will add another strand to Galapagos’ fibrosis pipeline. Galapagos recently began two phase 3 trials of oral, once daily autotaxin inhibitor GLPG1690 in IPF. And is moving a second IPF prospect, GPR84 inhibitor GLPG1205, through a midphase trial in the disease.

Galapagos owns the full rights to GLPG1690 and GLPG1205, making the drugs important parts of its efforts to develop into a sustainable, independent mid-sized biotech. The company’s efforts to set itself up for long-term independence have taken place against a backdrop of chatter about a possible buyout from one of its bigger partners, most recently Gilead.

https://www.fiercebiotech.com/biotech/galapagos-continues-fibrosis-pipeline-buildout-evotec-deal

LabCorp shares already pricing in bad news, says Piper Jaffray

Piper Jaffray analyst William Quirk says LabCorp’s Q4 results were in-line with the company’s lowered guidance. Expect to see more deal activity as well as share buy backs with capital allocation priorities shifting in 2019, Quirk tells investors in a post-earnings research note. He believes “most of the bad news” is already reflected in LabCorp’s valuation. As such, he maintains an Overweight rating on the shares with a $177 price target.
https://thefly.com/landingPageNews.php?id=2861149