What to look out for at ASCO

This week, cancer patients, oncologists and investors alike look ahead to the annual meeting of the American Society of Clinical Oncology (ASCO), which kicks off in Chicago on Friday.

In the run-up to what is usually thought of as the world’s foremost cancer meeting, with speculation increasing over what new insights might be revealed by the global pharma and biotech industries, we read the runes to provide our take on what to look out for.

After a quieter-than-usual event in 2017, early signs indicate that this year’s ASCO – the American counterpart to the meeting of the European Society of Medical Oncology (ESMO) – will provide pointers towards a number of key, potentially game-changing clinical trends.

Plenary session

Perhaps the first place to look for headline-grabbing news is the plenary session. This year’s session highlights the following four programs.

“Early signs indicate that this year’s ASCO will provide pointers towards a number of key, potentially game-changing clinical trends.”

TAILORx

A Phase III trial of chemoendocrine therapy versus endocrine therapy alone in certain breast cancer patients.

Report from European Paediatric Soft Tissue Sarcoma Study Group (EpSSG)

Looking at maintenance low-dose chemotherapy in patients with high-risk rhabdomyosarcoma, an aggressive and highly malignant form of cancer.

CARMENA

Results from a Phase III noninferiority study looking at cytoreductive nephrectomy followed by Sutent (sunitinib), versus Sutent alone in metastatic kidney cancer.

KEYNOTE-042

Keytruda (pembrolizumab) versus platinum-based chemotherapy as a first-line non-small cell lung cancer therapy.

Antibody-drug conjugates (ADC)

There is plenty of action on the ADC front this year.

There are currently two marketed ADCs, Adcetris (brentuximab vedotin), approved by the US Food and Drug Administration in 2011 and again in 2015, and Kadcyla (ado-trastuzumab emtansine), which has been marketed in the USA since 2013.

Adcetris developers Takeda Pharmaceutical (TYO: 4502) and Seattle Genetics (Nasdaq: SGEN) are still presenting positive Phase III data to build a case for the drug in Hodgkin’s lymphoma, although investors have been underwhelmed by its potential in this indication.

Roche’s (ROG: SIX) Kadcyla meanwhile has been successful in breast cancer, but has also struggled to gain the levels of reimbursement it requested in certain territories.

Immunomedics

Despite what might appear a thin record of success for this class of therapy, drugmakers are still plugging away, and there may be light at the end of the tunnel.

This year, many will be watching out for Phase I/II data from Immunomedics (Nasdaq: IMMU), related to its ADC candidate sacituzumab govitecan.

Activist shareholders scotched a deal, agreed around this time last year, for Seattle Genetics to gain rights to the therapy, which could be a challenger in  HR-positive/HER2-negative breast cancer.

Now going it alone, Immunomedics has taken longer to develop the candidate, only last week filing for regulatory approval in the USA. Nonetheless, markets have rewarded the firm with a near 200% increase in stock price for its efforts.

Other ADCs

Other firms to present data on ADCs this year include Astrazeneca (LSE: AZN), Immunogen (Nasdaq: IMGN), Menarini and Oxford Biotherapeutics.

Following on from the success of Kadcyla in breast cancer, Japanese pharma major Daiichi Sankyo (TYO: 4568), and fellow Tokyo-based firm Takeda (TYO: 4502) have results from their respective ADC candidates in this indication.

Daiichi is developing trastuzumab deruxtecan against HER2-positive breast cancer, and also U3-1402, another topoisomerase I inhibitor, against HER3-positive patients. Meanwhile Takeda and co-developer Mersana Therapeutics will offer data on XMT-1522.

Pfizer and AbbVie

AbbVie (NYSE: ABBV) and co-developer Pfizer (NYSE: PFE) will show overall response rate (ORR) and progression-free survival (PFS) data on cofetuzumab pelidotin, a PTK7-targeting ADC the firms believe has promise in various cancers.

For AbbVie, it could be the last chance to salvage some value from its $5.8 billion acquisitionof Stemcentryx, which the firm bought in 2016, largely to get its hands on leading ADC candidate Rova-T.

Extremely high hopes for Rova-T in lung cancer were dashed in dramatic fashion earlier this year, sending the Chicago native’s shares crashing.

While it’s probably too much to say the road to ADC success is littered with failures, there have been other high profile misses, including ADCT-502, which Switzerland’s ADC Therapeutics dropped in late April due to safety and tolerability issues.

It’s been a rough year for ADCs so far. For many of the firms mentioned here, ASCO 2018 could provide a platform to reinstil some hope for this approach.

I-O plus chemo combos

In recent months and years, there have been a slew of immuno-oncology trials, following on from the success of landmark checkpoint inhibitors and other immunomodulating therapies from Bristol-Myers Squibb (NYSE: BMY), Merck & Co (NYSE: MRK) and others.

Much of the recent activity has focused on combining established I-O therapies with chemotherapeutics, and data from ASCO 2018 look likely to enhance the potential for this therapeutic approach.

Merck has led the field here, with the first ever combo approval, and the firm has bet heavily on Keytruda (pembrolizumab), with billions invested in hundreds of trials.

Observers eagerly await results from the KEYNOTE-042 trial in lung cancer, to be presented at the plenary session, and will have to be patient until the curtain lifts to find out what the New Jersey-based firm has in store this year.

Merck is not the only one competing, however, with data from the CheckMate-227 trial to go on show, detailing that Bristol-Myers’ Opdivo (nivolumab) plus chemo reduced by 26% the relative risk of PFS, while results from a Roche (ROG: SIX) study will show impressive overall survival benefit.

Also look out for

Cemiplimab

Data from Regeneron Pharmaceuticals (Nasdaq: REGN) and Sanofi’s me-too checkpoint inhibitor cemiplimab. The firms are looking to offer the sixth therapy in this class, and have data showing a 47.5% response rate among certain patients.

The firms are hoping to show that blocking the PD-1 receptor is a better approach than stopping the PD-L1 ligand, as three of the current products on the market do.

Nerlynx (neratinib)

While Puma Biotechnology (Nasdaq: PBYI) has hit a rough patch in its regulatory efforts, the firm has data showing adjuvant use can improve invasive disease-free survival for some breast cancer patients. An exploratory analyses from the Phase III ExteNET trial provides useful learnings that may help to guide treatment practices to promote uptake.

https://bit.ly/2xDPPeP

ASCO’18: Blacks with Advanced Prostate Cancer With Chemo Have Equal Survival

An analysis of pooled data from nine randomized phase III trials of more than 8,000 men with advanced prostate cancer who received chemotherapy shows chances of survival are as good for black men as white men. The median survival was the same in black men and white men overall (21 months), but black men had a 19% lower risk for death than white men when researchers adjusted for various important risk factors that affect survival.

This is the largest analysis to date comparing black men and white men with advanced prostate cancer treated with chemotherapy, according to lead study author Susan Halabi, Ph.D., professor of biostatistics and bioinformatics at Duke University in Durham, NC. The findings will be featured in a press briefing today and presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting.

“By pooling data across clinical trials, this study provided a unique opportunity to evaluate how race might affect prostate cancer response to treatment,” said Dr. Halabi. “This study underscores the importance of increasing the participation of racial minorities in clinical trials. Every patient who participates in a clinical trial contributes to improving care, and all patients should have the opportunity to receive needed therapies.”

In the United States, prostate cancer incidence rates are 60% higher among black men. In addition, black men are more likely to be diagnosed at a younger age, and with advanced-stage and higher-grade cancer. Despite an overall decline in prostate cancer deaths over the years, black men are twice as likely to die of the disease than white men.^1,2

Each of the nine clinical trials included too few black men to be able to determine if black men benefit from docetaxel/prednisone as much as white men. Prior studies have suggested that black men with advanced prostate cancer who received treatment had shorter overall survival than white men, but evidence has been inconsistent.

About the Study: Researchers analyzed data from 8,820 men with metastatic castration-resistant prostate cancer (mCRPC) who participated in nine different randomized, phase III clinical trials. In all trials, patients received chemotherapy docetaxel with prednisone or a regimen containing docetaxel (Taxotere®) and prednisone combined with other treatments. Of the 8,820 participants, 7,528 (85%) were white, 500 (6%) were black, and the rest were Asian or an unspecified race. Only black men and white men were included in this analysis (a total of 8,028 men) in order to test a prior hypothesis that black men had a worse survival than white men.

Because black men in the study had poor-prognostic factors, such as higher prostate-specific antigen (PSA) levels and worse performance status (a measure of a patient’s general well-being and ability to perform activities of daily living), the researchers conducted a multivariable analysis that compared outcomes in black men to white men with the same prognostic factors.

Key Findings: Despite differences in prognostic factors, the median overall survival was 21 months in black men and white men. Adjusting for prognostic factors, such as patient age, performance status, site of metastasis, PSA level, alkaline phosphatase and hemoglobin levels, researchers found that black men were 19% less likely than white men to die from any cause.

Next Steps: As all patients included in this study were eligible to be enrolled in clinical trials and had access to clinical trials, the lower risk of death in black men may reflect differences in the biology of the disease, or it may be that black men have better tolerability to docetaxel-prednisone combination, noted Dr. Halabi. The researchers are planning genomic analyses to evaluate if there are biologic variations that might explain differences in outcomes by race. Meanwhile, this research highlights the importance of enrolling underrepresented populations with advanced prostate cancer in future phase III clinical trials. This study received funding from Congressionally Directed Medical Research Programs.

Study at a Glance
Disease: Advanced prostate cancer
Trial Type: Pooled analysis of data from 9 phase III clinical trials of chemotherapy plus prednisone
Patients on Trials: 8,820
Primary Finding: No difference in overall survival between black men and white men
Secondary Finding(s): Adjusting for prognostic factors, black men were 19% less likely than white men to die

References:
1. Prostate Cancer. (2017, June 19). Retrieved from https://www.cdc.gov/cancer/prostate/statistics/race.htm
2. Cancer Stat Facts: Prostate Cancer. (n.d.). Retrieved from https://seer.cancer.gov/statfacts/html/prost.html

https://bit.ly/2LPoo4J

Stem cell-based phase I trial to repair spinal cord injuries called encouraging

Writing in the June 1 issue of Cell Stem Cell, researchers at University of California San Diego School of Medicine report that a first-in-human phase I clinical trial in which neural stem cells were transplanted into participants with chronic spinal cord injuries produced measurable improvement in three of four subjects, with no serious adverse effects.

“The primary purpose of this first trial was to assess safety. And no procedure-related complications were observed in any of the patients,” said Joseph Ciacci, MD, principal investigator and a neurosurgeon at UC San Diego Health. “Our results suggest the approach can be performed safely and early signs of efficacy warrant further exploration and dose escalation studies.”

The trial used a human spinal cord-derived neural stem cell line developed by Neuralstem, Inc, a biopharmaceutical company based in Maryland. Four trial participants with one- to two-year-old permanent injuries to T2-T12 thoracic vertebrae (located in the middle of the spine) received six injections, each containing 1.2 million neural stem cells.

In previous research, published in 2013 by Ciacci and co-author Martin Marsala, MD, professor in the Department of Anesthesiology at UC San Diego School of Medicine, stem cells were transplanted into rats with spinal cord injuries, resulting in neuronal regeneration and improvement in the animals’ functioning and mobility.

In the latest human clinical trial, the results (measured 18 to 27 months after transplantation) were not dramatic, but encouraging. Analysis of motor and sensory function and electrophysiology results showed improvement in three of the four participants.

“This is a small sample size, but the real strengths of this study are the extensive follow-up period, electrophysiological assessments and the timeline of treatment. Everyone was treated after a year of injury, meaning there was essentially no chance of spontaneous recovery,” said Ciacci. “Our primary objective was to provide proof of safety and tolerability of treatment. We’ve done that. These early signs of potential efficacy, combined with the promising results of earlier animal studies, argue for pressing ahead with new trials and greater doses to see if we can further accelerate repair and recovery.”

A second clinical trial is in development. Its focus will be subjects with cervical injuries.

More information: Erik Curtis et al, A First-in-Human, Phase I Study of Neural Stem Cell Transplantation for Chronic Spinal Cord Injury, Cell Stem Cell (2018). DOI: 10.1016/j.stem.2018.05.014

https://bit.ly/2sqd2fm

Mobile app for autism screening ‘yields useful data’

An iPhone app that helps screen young children for signs of autism creates landmarks on the child’s face for software analysis of her facial expressions. Credit: Duke University

A Duke study of an iPhone app to screen young children for signs of autism has found that the app is easy to use, welcomed by caregivers and good at producing reliable scientific data.

The study, described June 1 in an open access journal npj Digital Medicine, points the way to broader, easier access to screening for autism and other neurodevelopmental disorders.

The app first administers caregiver consent forms and survey questions and then uses the phone’s ‘selfie’ camera to collect videos of young children’s reactions while they watch movies designed to elicit autism risk behaviors, such as patterns of emotion and attention, on the device’s screen.

The videos of the child’s reactions are sent to the study’s servers, where automatic behavioral coding software tracks the movement of video landmarks on the child’s face and quantifies the child’s emotions and attention. For example, in response to a short movie of bubbles floating across the screen, the video coding algorithm looks for movements of the face that would indicate joy.

In this study, children whose parents rated their child as having a high number of autism symptoms showed less frequent expressions of joy in response to the bubbles.

Autism screening in young children is presently done in clinical settings, rather than the child’s natural environment, and highly trained people are needed to both administer the test and analyze the results. “That’s not scalable,” said New York University’s Helen Egger, M.D., one of the co-leaders of the study.

This study, from informed consent to data collection and preliminary analysis, was conducted with an app available for free from Apple Store and based on Apple’s ResearchKit open source development platform.

In one year, there were more than 10,000 downloads of the app, and 1,756 families with children aged one to six years participated in the study. Parents completed 5,618 surveys and uploaded 4,441 videos. Usable data were collected on 88 percent of the uploaded videos, demonstrating for the first time the feasibility of this type of tool for observing and coding behavior in natural environments.

“This demonstrates the feasibility of this approach,” said Geraldine Dawson, Ph.D., Director of the Duke Center for Autism and Brain Development and co-leader of the study. “Many caregivers were willing to participate, the data were high quality and the video analysis algorithms produced results consistent with the scoring we produce in our autism program here at Duke.”

An app-based approach can reach into underserved areas better and make it much easier to track an individual child’s changes over time, said Guillermo Sapiro, Edmund T. Pratt, Jr. School Professor of Electrical and Computer Engineering at Duke and a co-leader of the study.

“This technology has the potential to transform how we screen and monitor children’s development,” Sapiro said.

The reported project was a 12-month study. The entire test took about 20 minutes to complete, with only a few minutes involving the child.

The app also included a widely used questionnaire that screens for autism. Based on the questionnaire, participating families received some feedback from the app about what the child’s apparent risk for autism might be. If parents reported a high level of autism symptoms on the questionnaire, they were encouraged to seek further consultation with their health care providers.

More information: Helen L. Egger et al, Automatic emotion and attention analysis of young children at home: a ResearchKit autism feasibility study, npj Digital Medicine (2018). DOI: 10.1038/s41746-018-0024-6

https://bit.ly/2xzgEAx

AbbVie: Phase 3 lymphoma data suggest improved treatment outcomes

AbbVie announced findings from an interim analysis of the Phase 3 iNNOVATE study evaluating IMBRUVICA plus RITUXAN in previously untreated and relapsed/refractory patients with Waldenstrom’s macroglobulinemia, a rare type of non-Hodgkin’s lymphoma. At a median follow up of 26.5 months, the study successfully met its primary endpoint, demonstrating a significant improvement in progression-free survival with ibrutinib plus rituximab compared to rituximab alone. Patients taking ibrutinib plus rituximab also experienced an 80 percent reduction in relative risk of disease progression or death than those only treated with rituximab. Additionally, the data found that the combination with ibrutinib provided reductions in infusion reactions associated with rituximab and immunoglobin M flare. “The iNNOVATE study provides further evidence of the potential clinical benefit of IMBRUVICA-based combination therapy in patients with Waldenstrom’s macroglobulinemia,” said Thorsten Graef, M.D., Ph.D., Head of Clinical Development at Pharmacyclics LLC, an AbbVie company. “The data from this chemotherapy-free combination regimen suggests that patients with Waldenstrom’s macroglobulinemia, including those who are newly diagnosed, could have another beneficial therapeutic option in the future.”

https://bit.ly/2syrOjo

Mylan, Biocon have results from breast cancer biosimilar study at ASCO

Mylan and Biocon announced that 48-week results from the HERITAGE study will be presented at the 2018 American Society of Clinical Oncology, or ASCO, annual meeting. The HERITAGE study compared Ogivri, the first biosimilar for Herceptin approved in the U.S., to the reference product in patients with metastatic breast cancer in combination with taxanes for the first 24 weeks and then as a monotherapy until progression. Data obtained after 48 weeks of treatment will be included as part of the Clinical Science Symposium titled, “The Arrival of Biosimilars”.

https://bit.ly/2sFrjUT

Newly US-Approved Nonopioid Med Blunts Drug Withdrawal Symptoms

Lofexidine (Lucemyra, US Worldmeds), which has been in use in the United Kingdom for more than 20 years, is now available in the United States. The drug is used in the management of symptoms of severe opioid withdrawal.

Dr Danesh Alam

In a double-blind, placebo-controlled, multicenter trial in opioid-dependent patients, lofexidine significantly improved opioid withdrawal symptoms and significantly increased completion of a 7-day opioid discontinuation treatment program compared with placebo.

“We desperately need something to address the opioid crisis, where we are losing about 100 Americans every day, with some 16 million on opioids,” Danesh Alam, MD, Northwestern Medicine Central Dupage Hospital, Winfield, Illinois, told Medscape Medical News.

“Now we have a drug that actually enables us to achieve a rapid withdrawal from opioids. When we use lofexidine, we can literally bring in someone using opioids, give them this drug, and they can immediately stop using opioids,” said Alam.

The study was presented at the American Society for Clinical Psychopharmacology (ASCP) 2018.

A Better Alternative

Currently, the standard of care for the treatment of opioid withdrawl is medication-assisted therapy with buprenorphine (multiple brands), but many patients wish to stop using opioids completely, Alam said.

“Buprenorphine is essentially another opioid, albeit a designer opioid, but a number of patients object to clinicians saying that the best evidence is to switch them over to buprenorphine and do buprenorphine for the rest of their life,” he said.

Lofexidine, a selective alpha-2-adrenergic agonist, acts on the central nervous system. Through its effect on the brain stem, it reduces the symptoms of withdrawal to a point at which they become very tolerable.

“We found in our study that you could basically give patients the lofexidine and stop the opiate. In the majority of cases, the withdrawal symptoms at that point were mild,” Alam said.

The researchers enrolled 602 men and women aged 18 years or older who sought treatment for dependence on short-acting opioids. Most were men (71%); the mean age of the patients was 35 years (±11 years).

Most patients (83%) were dependent on heroin.

Participants were randomly assigned to receive placebo, lofexidine 0.6 mg qid (2.4 mg/day), or lofexidine 0.8 mg qid (3.2 mg/day) for 7 days after abrupt opioid discontinuation.

The study assessed the benefit of lofexidine with the Short Opiate Withdrawal Scale–Gossop (SOWS-G), a 10-item inventory of common opioid withdrawal symptoms in which higher scores indicate worse symptoms; by the percentage of participants who completed the study; and by use of the Clinical Opiate Withdrawal Scale (COWS), an 11-item inventory of opioid withdrawal signs and symptoms in which higher scores indicate worse symptoms.

Scores on the SOWS-G were lower for patients treated with lofexidine at both doses compared to patients given placebo (-0.21 for lofexidine 2.4 mg, P = .02; and -0.26 for lofexidine 3.2 mg, P = .003). More patients in the lofexidine-treated group completed the 7-day trial than in the placebo group (41.5% in the 2.4-mg group (odds ratio [OR], 1.85, P = .007), and 39.6% in the 3.2-mg group (OR, 1.71; P = .02), vs 27.8% for placebo.

Mean COWS scores were significantly lower on days 1 to 5 for patients in the lofexidine groups than for patients who received placebo (P < .01).

Good Timing

The most common side effects seen with lofexidine were hypotension, orthostatic hypotension, and bradycardia, but they resulted in few study discontinuations.

The US debut of lofexidine comes at a crucial time. It was recently granted approval by the US Food and Drug Administration (FDA), as reported by Medscape Medical News.

This approval came after 17 years of hard work on the part of the National Institute on Drug Abuse (NIDA).

Dr Ivan Montoya

“Lofexidine has been used for about 25 years in the UK, and it’s widely used, especially for people who are trying to get detoxified, and the experience has been quite positive,” Ivan Montoya, MD, deputy director of NIDA, told Medscape Medical News.

“We tried to use that experience from the UK to bring the compound to the US, but the FDA needed data collected in the US, so we went through the whole submission and review process with a new drug application, and it took us about 17 years to complete the development. It was a very long process,” Montoya said.

The approval came at the right time, he added.

“It was always going to get approved, but right now there is a bigger sense of urgency, and so approval came at the right time. That’s the beauty of it, that now, in the midst of this crisis, we have this medication, which we were working on for 17 years.”

“NIDA made a very significant investment in this compound. Some $27 million were invested, taxpayers’ money,”

Some clinicians feel that clonidine could also be used in this setting, but Montoya pointed out that lofexidine differs from clonidine in two important ways.

“First, lofexidine appears to produce less hypertension than clonidine, so it’s not as bad as clonidine, and the second and most important is that lofexidine is FDA-approved, physicians can prescribe it, it can be in formularies, it can be reimbursed for, so that’s a very big advantage. That’s why NIDA decided to support the development of lofexidine, to be approved by the FDA for that indication,” he said.

Dr Alam has disclosed no relevant financial relationships. Dr Montoya is an employee of the NIDA.

American Society of Clinical Psychopharmacology (ASCP) 2018. Abstract T1, presented May 31, 2018.

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