Friday, September 4, 2015

Aspirin could help boost cancer treatment, experts find

'Exciting' study results show anti-inflammatory pain killer suppresses cancer molecule that allows tumours to evade body's immune defences

By , Health Editor
5:00PM BST 03 Sep 2015

Cancer treatment could be more effective when it is combined with aspirin, new research suggests.
The anti-inflammatory pain killer suppresses a cancer molecule that allows tumours to evade the body's immune defences, a study has found.
Experts said the research findings were “exciting”, suggesting that drugs that cost just a few pence could make “a huge difference” helping to save lives.
But they cautioned that the findings would need to be confirmed by further trials before aspirin was routinely given as part of cancer treatment.
Laboratory tests show that skin, breast and bowel cancer cells often generate large amounts of a molecule called prostaglandin E2 (PGE2).
The study found aspirin and other members of the "Cox inhibitor" drug family block its production so that tumours have nowhere to hide. In mice, combining immunotherapy with drugs such as aspirin substantially slowed the growth of bowel and malignant skin cancer.
Professor Caetano Reis e Sousa, who led the team from the Francis Crick Institute in London, said: "We've added to the growing evidence that some cancers produce PGE2 as a way of escaping the immune system.
"If you can take away cancer cells' ability to make PGE2 you effectively lift this protective barrier and unleash the full power of the immune system.
"Giving patients COX inhibitors like aspirin at the same time as immunotherapy could potentially make a huge difference to the benefit they get from treatment.
"It's still early work but this could help make cancer immunotherapy even more effective, delivering life-changing results for patients."
The ability of cancers to manufacture PGE2 may be one reason why some experimental immunotherapy treatments have not lived up to expectations.
Professor Peter Johnson, chief clinician at Cancer Research UK, which funded the study published in the journal Cell, said: "PGE2 acts on many different cells in our body, and this study suggests that one of these actions is to tell our immune system to ignore cancer cells.
"Once you stop the cancer cells from producing it, the immune system switches back to 'kill mode' and attacks the tumour."

Thursday, September 3, 2015

Combination Therapies Continue to Advance in Melanoma with BRAF Inhibitor

Laura Martin @OncEditorLaura
Published Online: Monday, August 31, 2015
Both targeted therapy and immunotherapy regimens, as combinations, have shown significant benefit in the treatment of melanoma.

Combination treatment with the BRAF inhibitor vemurafenib (Zelboraf) and the MEK inhibitor cobimetinib showed promise in patients with BRAFV600-positive advanced melanoma in both the BRIM7 and coBRIM studies.

Follow-up data for BRIM7 presented at the 2015 ASCO Annual Meeting continued to show a response rate of 87% in patients who had not previously received a BRAF inhibitor; however, investigators reported 4 additional complete responses (CRs), raising the CR rate from 10% (n = 6) to 16% (n = 10). Median progression-free survival (PFS) was unchanged at 13.8 months. With extended follow-up, median overall survival (OS) was reached at 28.5 months and 2-year OS was 61%. Despite these additional benefits after extended follow-up, the adverse event frequency and severity remained stable.

Updated results were also presented at ASCO for the phase III coBRIM study, showing a median PFS with the vemurafenib/cobimetinib combination of 12.25 months versus 7.20 months with vemurafenib plus placebo (HR = 0.58; 95% CI, 0.46-0.72). The overall response rate (ORR) was 69.6% versus 50%, respectively. Based on the coBRIM results, the FDA is currently reviewing an application for cobimetinib/vemurafenib for patients with BRAFV600-positive advanced melanoma, with a decision deadline of November 11, 2015.

The frontline checkpoint combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) has also shown promise for patients with advanced melanoma. In data from the phase II CheckMate-069 trial presented at ASCO 2015, ORR was 60% with the combination compared with 11% with ipilimumab alone in patients with BRAF–wild-type disease (P <.0001). There were 12 CRs with nivolumab/ipilimumab versus none with single-agent ipilimumab. Median PFS was 8.9 versus 4.7 months, respectively (= .0012). Similar ORR and PFS results were reported in the BRAF-positive subgroup.

Toxicities were increased with the checkpoint combination, with grade 3/4 adverse events of 51% versus 20% in the control arm.

OncLive sat down with Anna Pavlick, DO, associate professor, Department of Medicine, Ronald O. Perelman Department of Dermatology, assistant director for Clinical Research Education, and co-director of the Melanoma Program at NYU Langone Medical Center, to discuss the future outlook of combination therapies in advanced melanoma and the challenges oncologists should consider regarding them moving forward.

What were the goals of the extended follow-up study of BRIM7?

Dr Pavlick: We looked at the 2-year OS of patients who participated in the BRIM7 study. The BRIM7 study examined vemurafenib, which is a BRAF inhibitor, in combination with the MEK
inhibitor cobimetinib. We knew the correct dose of vemurafenib, but we dose escalated the cobimetinib.

We also investigated scheduling. The outcome was that it was safe to administer vemurafenib at a full dose of 960 mg twice daily in combination with 60 mg daily, 21 days on with a 7-day drug-free break during every 28-cycle.

The longer we followed these patients, the more complete responses we were able to see. The time to progression was also extended and the patients were alive for much longer than we had predicted. The toxicities were also very tolerable.

What do you think the impact of these findings will be for patients?

The combination studies have clearly shown that the excitement we had about single-agent BRAF inhibitors was very much quelled when saw all these patients starting to progress after 9 months. However, we are more confident now that we are starting to understand that you can treat patients with combination therapy if they have very aggressive disease; immunotherapy might not be the right choice for them. There is a clear subset of patients who are going to go on and have durable responses from inhibitor therapy, without ever having to receive immunotherapy.

What questions still remain after this analysis?

The phase III study of vemurafenib and cobimetinib [coBRIM] has already been published. Our follow-up analysis confirms the data from almost 7 years ago. However, a few questions remain to be answered. How do we identify the patients that will be the complete responders? How do we better integrate immunotherapy into the inhibitor platform, so that we can give the patients who progress the ability to have longer responses?

Were there any concerning or new toxicities determined in this follow-up?

Toxicities were what we expected for the most part. We actually had fewer toxicities than we predicted. We were very nervous about giving two different targeted therapies at that point, because we did not know what the overlapping toxicity might cause. Our biggest concern was rash, as there were a significant amount of rashes with vemurafenib as well as with cobimetinib. However, the level of rash was actually very tolerable. Interestingly, the combination did not diminish the photosensitivity side effect we had with vemurafenib. However, it did decrease the rate of invasive squamous cell skin cancers that patients might develop.

The CheckMate-069 study also examined a significant combination regimen for patients with previously untreated advanced melanoma. What are your thoughts on the impact of these findings?

Clearly, we have taken a huge stride in combining two immunotherapies. Ipilimumab has a more dynamic toxicity profile than nivolumab, and so we had to tread lightly when we combined the two to make sure we could administer them safely. We found out we can give them safely if we adjust the dose of nivolumab when we combine it with ipilimumab.

Even with this adjustment, we still ran into challenges with managing toxicities. Giving the two drugs together gave at least 50%-60% toxicities that we needed to manage. Most of those toxicities did not preclude us from continuing therapy; however, there were a good number of patients who did need to come off the study right in the beginning of the trial because of toxicity.

The interesting thing about that is, even when patients were never able to get any more combination therapy due to toxicities, many still went on to have strong, durable responses. Because of this, many of us feel very comfortable stating that, if a patient has a toxicity that causes them to discontinue treatment, they may still go on to have a durable response if they received at least 50% of the combination regimen before discontinuing.

What were the most common toxicities found in this trial?

Toxicities include rash, itching, and diarrhea. What we were not expecting to see that we did was an early unset of endocrinopathies, which normally occur with ipilimumab 16 to 20 weeks after starting therapy. In the combination, the endocrinopathies occurred much earlier, at about 6 to 8 weeks after starting therapy. When using these treatments together, we now know to be prepared for that.

What role do you believe this combination will have in the future?

Although the response rate was clearly outstanding, this should not become the standard of care for everyone due to the toxicities. The toxicities can be serious, and they need to be managed promptly and effectively so that patients do not end up in the hospital. Deciding who gets this treatment is really where the art of medicine is going to come into play. Doctors need to look at the patients’ comorbidities, their overall performance status, and the bulk of their disease, and decide if they will be able to withstand the toxicities. The benefit is there, but doctors really need to select the right patients and have the right staff in place to handle this combination.
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Wednesday, September 2, 2015

How Google looks to change the management of diabetes

 Updated Ron Leuty Reporter San Francisco Business Times

Google Inc. and drug developer Sanofi are joining forces to develop and streamline tools for managing diabetes.
The end game: reducing the risk of complications and ultimately lowering the cost of managing type 1 and type 2 diabetes for nearly 30 million patients in the United States and nearly 400 million worldwide.
The move comes as questions swirl about Google's future in health care, following the Mountain View-based company's (NASDAQ: GOOG) decision to move its life sciences unit from the Google X R&D division into a standalone company under the control of its new overarching Alphabet company.
Sanofi (NYSE: SNY), based in Paris, is one of the leading diabetes drug and device sellers.
There is a huge opportunity in diabetes, Google said in a statement. Patients use devices, apps and pieces of paper all try to keep track of food intake, but those methods are largely unintegrated and only a third of patients with type 1 diabetes meet their target blood sugar levels. That can lead to long-term complications, such as heart disease, stroke and nerve damage.
"With new technologies emerging to provide a more continuous and real-time view of a patient's health, we can see the promise for more proactive and effective ways to control diabetes," Andy Conrad, CEO of Google's life sciences team, said in a press release.
Google's highest-profile moonshot to date has come in the aging-related company Calico Life Sciences LLC, led by former Genentech Inc. CEO Art Levinson. But it also is working with Novartis AG on a "smart" contact lens with a miniaturized glucose sensor, a Star Trek-like Tricorder for early detection of disease and Liftware for Parkinson's disease patients who have trouble lifting and controlling utensils.

Friday, August 28, 2015

Histology, Tumor Markers Both Critical in Personalizing Cancer Treatment, Basket Study Shows

 Aug 27, 2015 | Turna Ray

NEW YORK (GenomeWeb) – A team led by Memorial Sloan Kettering Cancer Center researchers has published results from the first basket study demonstrating that such designs may provide clues to which patients with rare cancers are likely to respond to investigational treatment strategies.
The study, published last week in the New England Journal of Medicine, demonstrates that both tumor histology and molecular markers are indispensible factors when crafting precision treatment strategies. Looking specifically at patients with a range of cancers with BRAF V600 mutations, researchers led by MSK's Jose Baselga and David Hyman found that certain tumor types — like lung cancer or Langerhans cell histiocytosis — but not all appear to respond to the BRAF inhibitor Zelboraf (vemurafenib).

In the era of biomarkers and precision medicine, some proponents have predicted a future where patients will receive therapy based on the molecular markers driving their disease — in this case BRAF mutations — instead of the type of tissue or cells their tumors are rooted in (i.e. lungs, colon, etc.) "A lot of people have jumped to that conclusion," said Hyman, acting director of developmental therapeutics at MSK and the first author of the published study.
The work by Hyman's group suggests that tissue characteristics will likely remain an important consideration for personalizing cancer treatments. "A lot of this pertains to the off-label use of approved targeted therapies," he told GenomeWeb. "This is increasingly becoming an issue as we get a wider compendium of targeted therapies for specific indications, which are then commercially available for use in an off-label fashion."

Add to this the fact that more and more people are getting genomic testing through academic centers and a variety of commercial labs. "The issue is how are we going to use that data?" Hyman reflected. "Certainly, we are very enthusiastic about a precision medicine approach, but one of the things that gets lost in extrapolating data in a off-label setting is the relevance of the tumor histology. That clearly has importance."

Meanwhile, increasing understanding of the molecular underpinnings of cancer has disrupted neat histological groupings. Lung cancer is no longer just one disease. A lung tumor can have, for example, ALK rearrangements, EGFR mutations, over-expression of PD-L1, or none of these features. While these tumor features must be attacked using different treatment strategies, the small numbers of patients in these molecularly defined groups make it impossible to conduct traditional randomized-controlled trials.

Enter basket studies. Hyman defined a basket trial as one that enrolls patients regardless of tumor type, based on the presence of a genetic marker, but "with some effort to evaluate the effectiveness [of treatment] on a tumor-specific level." This offers drugmakers a way to quickly detect "early signals" of drug activity across tumor types, and also enable research into how tumor lineage influences response, the researchers wrote in NEJM.

Beyond melanoma

The aim of this study was to gauge whether cancers, other than melanoma, that are characterized by BRAF V600 mutations respond to Roche/Genentech's BRAF inhibitor Zelboraf. The trial steering committee designed the study with a team from Roche, which also provided funding.
Zelboraf is already approved as a treatment for metastatic melanoma patients with BRAF V600E mutations. Approximately half of melanoma patients have BRAF V600 mutations and studies have shown that half of those patients respond to the BRAF inhibitor and many live longer than those without this marker.

BRAF V600 mutations also show up in other cancers, although at much lower rates, making it challenging to explore the efficacy and safety of Zelboraf in other tumor indications. This is precisely what Baselga's team wanted to investigate in their Phase II basket study.

From 2012 to 2014, researchers enrolled 122 cancer patients with BRAF V600 mutations into several tumor-specific cohorts, and treated them with Zelboraf. The 23 centers where enrollment took place could establish patients' BRAF mutation status by whatever method they chose. Hyman noted that a small number of patients had the Roche Cobas 4800 BRAF V600 mutation test that the US Food and Drug Administration approved to identify melanoma patients who should receive Zelboraf.
The "baskets" included patients with non-small-cell lung cancer, cholangiocarcinoma, Erdheim-Chester disease, Langerhans cell histiocytosis, anaplastic thyroid cancer, multiple myeloma, and other tumor types. Previous case studies had offered hints that a BRAF inhibitor might work well in some, but not all of these cancers.

Based on early signals in the study that colorectal cancer patients weren't responding well to Zelboraf, researchers amended the protocol and decided to give the drug in combination with the anti-EGFR therapy Erbitux (cetuximab). Hyman's team wasn't taking a shot in the dark in deciding to go with this combo, but based it on recent preclinical evidence suggesting that adding an EGFR inhibitor might help colorectal cancer patients overcome resistance to Zelboraf monotherapy.
This demonstrated the speed and flexibility of the basket approach. "This is an example of a very short bench-to-bedside transition," said Hyman, noting that there was a six-month gap between the time that the preclinical studies were published and the basket study was amended for colorectal cancer patients.

Although none of the colorectal cancer patients on Zelboraf monotherapy responded, one patient who received Zelboraf and Erbitux responded and half the patients had some tumor shrinkage.
The researchers noted that the response in this subgroup may have been impacted by the fact that a large proportion of colorectal cancer patients had received treatment with an anti-EGFR antibody. "Given the highly aggressive and chemotherapy-resistant nature of BRAF V600-mutated colorectal cancers, strategies using dual EGFR and BRAF inhibition deserve further evaluation," they wrote in the paper.

NSCLC was one of the biggest "baskets" with 20 patients. The response rate in this cohort was 42 percent, median progression-free survival was 7.3 months, and 66 percent were alive after a year. The median overall survival had not been reached in this cohort at the time of analysis. "This rate compares favorably with the 7 percent response rate reported for standard second-line docetaxel in molecularly unselected patients," Baselga and colleagues wrote in the paper.
Among 14 evaluable patients with Erdheim-Chester disease or Langerhans cell histiocytosis — characterized by the overproduction of a kind of infection-fighting white blood cell — 43 percent responded. The median duration of treatment in this group was around six months, during which time no one progressed.

Adults with these types of rare cancers don't have any approved treatment options. Baselga's group pointed out in the paper that these findings are in line with another recent case series that suggested that a BRAF inhibitor might have activity against Erdheim-Chester disease.
Researchers also reported "anecdotal responses" from patients with pleomorphic xanthoastrocytoma (a type of brain neoplasm), anaplastic thyroid cancer, cholangiocarcinoma (cancer in the bile ducts), salivary-duct cancer, ovarian cancer, and clear-cell sarcoma, and among patients with colorectal cancer who received the Zelboraf/Erbitux combination. Some of these patients treated with Zelboraf experienced tumor shrinkage but not enough to qualify as a response according to measurement criteria.

Three patients with anaplastic thyroid cancer, cholangiocarcinoma, and ovarian cancer had responses that lasted for more than a year. None of the multiple myeloma patients has responded to treatment.
In general, the safety profile of the drug in this trial was similar to studies of Zelboraf in melanoma patients. Around 20 percent of patients experienced common adverse events associated with Zelboraf, which were rash, fatigue, and joint pain.

Options in orphan diseases

"This type of study is great for evaluating rare tumor populations," Hyman said. "It's very clear that the common cancer types are overrepresented in the studies we conduct. You may not be able to get a company interested in doing research in Erdheim–Chester disease." But by doing a basket trial, a drug firm can offer patients a chance to benefit from an investigational treatment.
Since Erdheim-Chester disease was first described in 1930, only a few hundred cases have been reported in the literature. "There's never been a prospective clinical trial in Erdheim-Chester disease," Hyman noted. "One of the things I'm proud of about this study, and I hope we'll start to see more of, is when you look at the tumor types [included] there is a significant representation of very orphan diseases."

However, because few patients with these rare tumor types were enrolled, Baselga and colleagues said their findings should be interpreted with caution. "In the absence of more definitive data, which might not be forthcoming for many diseases owing to logistical impediments, these data present a challenge to clinicians who want to make treatment decisions on the basis of tumor genomic profiling," they wrote in the paper.

Meanwhile, the present basket trial is still enrolling patients. "We've enrolled significantly larger numbers of patients than reported in this manuscript," Hyman said, noting future publications will more definitively describe patients' experiences in larger "baskets."

"We'll see certain themes emerge and this type of study can help tease that out," he added. Pharmaceutical firms can then run with the "themes" or signals, moving quickly into registration studies for a drug in a new tumor type after observing efficacy in a particular "basket" of patients.
Sponsors could, for example, plan from the beginning that after a basket yields a signal, study sites could continue to enroll that cohort until there is more certainty about the drug's efficacy and safety in the subpopulation. "Then, that data could [support market] registration for the companies," Hyman said.

Within pharma and at cancer centers, basket studies are catching on. MSK is currently running between five and 10 basket studies and conducting several in collaboration with industry, Hyman said. "We're opening almost one a month at this point," he said. "It's become very attractive to the [drug] companies."

Ahead of press time, Genentech couldn't make available an expert to discuss how it will proceed based on data from this basket study. However, a company spokesperson said, "Genentech is evaluating the study results to inform future research with the goal of addressing the unmet need of people with rare cancers."

Basket trials are smaller, but they identify cancer patients that derive better-than-average responses to treatments. As a result, companies are investing in basket studies earlier in the drug development process "to search for efficacy over a wider range of tumors," Hyman reflected. "This is the way they want to be developing drugs. They want to set a high bar and there is less and less interest in doing very large studies, looking for incremental benefit to patients."

Monday, August 24, 2015

BRAF V600 Is Targetable in Some Nonmelanoma Cancers

“Efforts by the Cancer Genome Atlas and other initiatives to characterize the genetic landscape of most tumor types have identified BRAF V600 mutations in nonmelanoma cancers, including colorectal cancer, NSCLC, papillary thyroid cancer, diffuse gliomas, cholangiocarcinoma, hairy-cell leukemia, multiple myeloma, Langerhans’-cell histiocytosis and Erdheim-Chester disease”.
In the cancer types with less response, Hyman noted, the BRAF V600 mutation is typically present in fewer than 5 percent of tumors that have resisted conventional therapy and spread, so only those patients would be candidates for the drug.

But the so-called “basket” study from South San Francisco-based Genentech (NYSE: DNA) and its Swiss parent, Roche (SWX: RO), is significant because it is the first completed clinical trial lumping together several genetically similar cancers. Conducted by researchers at the Memorial Sloan Kettering Cancer Center, phase 2 results from a basket trial evaluated the effect of vemurafenib on nonmelanoma BRaf V600-mutated cancers in 122 patients across 23 global centers.

One patient in the study, MaryAnn Anselmo, had been diagnosed with stage 4 glioblastoma in 2013.
Patients with colorectal cancer received oral vemurafenib (960 mg twice daily) alone (n = 10) or with IV cetuximab (Erbitux; Bristol-Myers Squibb, Lilly) at a loading dose of 400 mg/m, followed by a weekly 250-mg/m dose (n = 27). That gene makes a protein that directs cell growth but is mutated in certain cancer patients. “Not only did 40 percent meet strict criteria for response, but almost all of them had improvement in their symptoms and no one progressed while receiving the medicine”, said Dr. Hyman. Secondary endpoints included PFS, OS, duration of response and safety. According to the data, the non-small-cell lung cancer cohort had a response rate of 42%, with a median progression-free survival time of 7.3 months.

The goal was to see if the drug vemurafenib, already approved for metastatic melanoma cases with the BRAF mutation, would work in other tumors with the same mutation.
Forty-three percent (95% CI, 18-71) of patients with ECD or LCH achieved a response. Patients were enrolled in six prespecified cancer cohorts, and patients with all other tumor types were enrolled in the seventh cohort.

In the new study, researchers focused on a mutation known as BRAF V600, which is a defect in a genetic instruction that tells a cell when to die. “We have proven that histology-independent, biomarker-selected basket studies are feasible and can serve as a tool for developing molecularly targeted cancer therapy”, said Dr. Baselga, the study’s senior author. “Confirmation of promising activity identified in basket studies will often necessitate additional studies”.
The study was funded by F. Hoffmann-La Roche/Genentech.
Overall Hyeman stays optimistic about the study’s findings.