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Aggregating the 2012 ASCO tweets

By MaverickNY on June 1, 2012

It’s that time of the year – the annual American Society of Clinical Oncology (ASCO) conference in Chicago begins in earnest with Friday being the main travel day for many people before they hit the ground running for the poster sessions this afternoon.

This year, in addition to insights and analysis here on PSB, I’m delighted to announce that I’ll be writing some posts for the Chemical and Engineering News (C&EN) blog, The Haystack after the meeting (links to follow).

For me, one of the key themes emerging from the abstracts is overcoming drug resistance – we know that single agent targeted therapies are not enough, the question is what are the logical combinations needed to shutdown the pathways more comprehensively to improve outcomes. Stay tuned for more on this important topic!

For those of you in town for ASCO, there’s an unofficial Tweetup this evening organized by Adam Feuerstein of The Street and others for anyone interested in joining a mix of people to natter about the hot topics over a beer – check out the details here.

As usual, the aggregated tweets from the event under the #ASCO12 hashtag are posted in the widget below for those who are interested in following along remotely. If you have any questions, please feel free to post them in the Comments below the post and I’ll do my best to answer them:

Update on advanced prostate cancer including enzalutamide (MDV3100) and abiraterone

This month has brought a flurry of regulatory activity in the prostate cancer landscape with several companies seeing noticeable action in the new product development area:

Medivation/Astellas filed enzalutamide (MDV3100) with the FDA in metastatic castration resistant prostate cancer (mCRPC) in the post chemotherapy setting based on the AFFIRM trial
The UK NICE approved abiraterone (Zytiga) in the same setting (except in Scotland), but rejected cabazitaxel (Jevtana)

For this specific post, I want to concentrate on the new trends in advanced prostate cancer, as last weekend I attended the 2012 American Urological Association (AUA) annual meeting, focusing on the basic research sessions hosted by the Society of Basic Urological Research (SBUR) and Society of Urologic Oncology (SUO). It’s hard to ignore the clinical data though, with so much activity in going on in advanced prostate cancer!

While at the oral and poster sessions, I enjoyed informal chats with urologists and researchers. Many of the urologists I spoke to at AUA were very excited about enzalutamide, certainly much more enthusiastic than in the last two years when we saw the arrival of sipuleucel-T (Provenge) and abiraterone (Zytiga) in the pre- and post- chemo settings respectively. The reasons for this were varied, depending on the respondents, ranging from understanding the mechanism of action (MOA) clearly to ease of logistics to lack of concomitant steroid therapy. The fact that the initial overall survival of 4.8 months for enzalutamide in the post-chemo setting, which hints at a more potent and effective therapy, probably helped as well.

With that in mind, I spoke with Dr Neal Shore, one of the AFFIRM trialists about his perspective of the impact of enzalutamide on his patients. Firstly, we discussed the expectations for patients who have received chemotherapy:

“Patients who typically have completed a course of docetaxel have historically a 6-12 month life expectancy depending upon… on how symptomatic or asymptomatic they are.”

Secondly, what was the impact of treatment with enzalutamide?

“In the treatment arm, those who received enzalatumide, they lived at the median 4.8 months longer than patients who received the control placebo.

So in fact their survival extended beyond 18 months. I told you that normally this patient population has a 6-12 month survival expectancy range, that to me is dramatic.

It’s a dramatic life prolongation effect.”

Emphasis mine.

One of the things that makes enzalutamide exciting for me is the ability to target splice variants. This may explain why the agent has slightly better efficacy in the post chemo setting than abiraterone, which demonstrated a 3.9 month overall survival advantage over placebo when it was initially approved. This figure has since improved to 4.7 months with more mature data, suggesting that the initial 4.8 months improvement we see with enzalutamide may also potentially improve further with time.

Previously, I discussed the splice variants with Dr David Hung, the Medivation CEO:

Dr David Hung on Splice Variants:

Another area where we may see changes in mCRPC is sequencing, combinations and different trial designs. While it seems logical that good old fashioned sequencing, as with ADTs in earlier disease, will prolong time to disease progression by managing PSA levels, it should be noted that I don’t think any of those agents have actually shown a significant improvement in overall survival in patients. Unlike oncology, urology tends to have looser endpoints and this is something that we may well see changes in going forward as more rigour is applied in the clinical trial setting.

Combination therapy is something that I think we will also see more of in the future if we are to see real shifts in meaningful outcomes. As Charles Sawyers noted in a previous interview, shutting down the AR pathway more comprehensively with dual inhibition and ‘big guns’ makes solid scientific sense. This doesn’t just mean the obvious though, such as determining whether dual upstream and downstream AR inhibition with enzalutamide plus abiraterone versus either alone would work, but also targeting cross-talk and adaptive resistance pathways such as AR inhibition plus a PI3K inhibitor. Some of these trials are already underway, at least in phase II to see what the safety and efficacy signals looks like.

The arrival of multiple new therapies that change the standard of care also means that once the current crop of new drugs have been approved (abiraterone, enzalutamide and alpharadin) it becomes more difficult to conduct placebo controlled trials with OS any more, as Dr Shore astutely observed:

Dr Shore’s point about surrogate markers of survival in advanced cancer is a highly relevant one given the increasing level of competition in this tumour type.

In the pre-chemotherapy setting, both abiraterone (302 trial) and enzalatumide (PREVAIL) appear to have progression-free survival (PFS) and OS as co-primary endpoints. It will be interesting to see how the FDA react if only PFS is significant while OS is not, as many commentators suspect from the rather vague and woolly press release that J&J put out for abiraterone. I don’t know what was agreed beforehand with the FDA regarding the study design, but I can see an interesting and highly charged ODAC ahead here as well as much speculation prior to the ASCO presentation of the data in the prostate cancer oral session next month.

OS is a clear, but challenging measure because ultimately, as Dr Shore noted, the endpoint is death. Remember, recent breast cancer trials discussed here on PSB achieved a significant OS of 6 months or more, precisely because crossover wasn’t allowed. These trials had an active arm as a comparator, not placebo, though. We don’t yet know if patients in the placebo arm who relapsed were allowed to crossover to abiraterone early (ie before the IDMC recommendation). If they did, then OS was doomed from the start and the trial design itself was flawed, but we will have to wait for the presentation to see before jumping to conclusions.

I really hope that’s not the case here, because once crossover does occur, it is very hard statistically, to sort out a true survival signal. If the placebo patients didn’t crossover before the IDMC recommended study stoppage, then it’s hard to see why OS wasn’t met (if truly the case) unless the patients had long term compliance and adherence problems as a result of the concomitant steroid therapy. I do find it hard to believe, however, that an IDMC would stop a trial early if a primary registration endpoint was not met, for that would be akin to regulatory hari-kiri!

Overall survival has long been the standard of care in advanced prostate cancer and several drugs have either received approval or will receive approval as a result of meeting that high hurdle. Future entrants will find it very hard to ethically justify using placebo in the comparator arm and will likely need to be compared to sipuleucel-T, docetaxel, cabazitaxel or abiraterone as the currently approved new standards of care and potentially other options will be considered that are seeking approval such alpharadin and enzalutamide in the near future.

This improvement in care raises the bar for companies considering advanced prostate cancer in several ways:

Increased costs (active comparator arm, prolongation of treatment)
Increased time to market (OS takes longer than PFS)

In the end, though, for men with prostate cancer it’s largely all good news as new therapies that clearly prolong life become available and make a difference to their lives, not just in terms of more time with their families, but also in terms of improved quality of life and symptom management.

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Stunning data with dabrafenib (BRAFV600E) in metastatic melanoma and brain metastases

By MaverickNY on May 22, 2012

Sometimes following the progress of cancer drugs can be very depressing given the failure rate, but every now and then something comes along that really brightens the landscape considerably. This week was one of those times.

Eighteen months ago, I posted a note from the 2010 ESMO meeting regarding GSK’s GSK208436 (now known as dabrafenib) in an early phase I/II trial in brain metastases associated with melanoma that was presented by Dr Georgina Long on behalf of an Australian group.

Do check out that original post – it’s well worth reading for some background context in the light of the new data.

At that time, the data and brain scans were quite simply stunning, but the big unanswered question was how durable would the responses be? After all, many of you will know that people with metastatic melanoma generally have a poor prognosis, with a median overall survival of approximately 9–11 months (see Balch et al., 2009).

Originally, the finding that the drug crossed the blood brain barrier was a surprise, as this MD Anderson press release notes:

“The drug’s activity against brain metastases was initially a serendipitous finding at one study site. In one patient, a research PET scan performed just before starting dabrafenib revealed a brain metastasis, but this result was not available until after treatment began.

The institution’s ethics board approved the patient to continue treatment because a follow-up PET scan two weeks later showed decreased metabolic activity in the brain metastasis and subsequent MRIs showed a reduction in its size.”

This week we learned more about the progress of dabrafenib in brain metastases associated with melanoma from a new publication in The Lancet by the same group, in conjunction with researchers from MD Anderson’s Department of Investigational Cancer Therapeutics group (see Falchook et al., 2012). This time, the phase I/II data was reported in incurable patients with brain metastases (n=184, 156 of whom also had metastatic melanoma).

The goals of this study were to determine the safety and tolerability, as well as establish a recommended phase II dose in patients.

The most common side effects were in line which those previously reported for BRAFV600 mutant inhibitors:

“The most common treatment-related adverse events of grade 2 or worse were cutaneous squamous-cell carcinoma (20 patients, 11%), fatigue (14, 8%), and pyrexia (11, 6%).”

For those of you interested in the recommended phase II dose, the group found that 150mg twice daily was the optimal dose for dabrafenib.

At the initial ESMO presentation in 2010, 9 out of 10 of the patients saw reductions in the overall size of their tumours, so I was most interested to see the latest progress with efficacy in a larger cohort of patients. In this study, the shrinkage continued apace:

“Brain metastases in most patients given dabrafenib reduced in size, with four patients’ metastases completely resolving.”

Emphasis mine. Overall, the phase II portion of the trial demonstrated that the responses continue to look rather encouraging:

“At the recommended phase 2 dose in 36 patients with Val600 BRAF-mutant melanoma, responses were reported in 25 (69%) and confirmed responses in 18 (50%). 21 (78%) of 27 patients with Val600Glu BRAF-mutant melanoma responded and 15 (56%) had a confirmed response.

In Val600 BRAF-mutant melanoma, responses were durable, with 17 patients (47%) on treatment for more than 6 months.”

I highly encourage reading of the paper for the waterfall plots alone – they are pretty impressive! Overall, nine out of ten patients with brain metastases saw their tumour shrink, as noted in MD Anderson’s press release.

What about the survival curves? So far, the authors have reported the following in the current study:

Non-brain metastases (n=36): median PFS 5·5 months
Brain metastases (n=10): median PFS 4·2 months

The authors speculated the reason for the variability in responses may be due to severity of the disease:

“Differences in progression-free survival in patients with varying lactate dehydrogenase concentrations or ECOG performance status suggest that burden of disease could affect response durability.”

Overall survival data was not provided, presumably because they were not yet met, but these early data are very encouraging signs given that few drugs cross the blood brain barrier, leading the authors to conclude:

“Dabrafenib is the first drug of its class to show activity in treatment of melanoma brain metastases. Clinical trials of melanoma usually exclude patients with brain metastases because of preclinical predictions about drug distribution into the CNS.

We hope that the introduction of drugs that are effective in Val600 BRAF-mutant melanoma metastasised to the brain will result in new trial designs that allow such patients to be included.”

Inevitably, with combination data for BRAF + MEK being presented at this year’s ASCO meeting as highlighted in my preview video, I don’t think it will be long before we see a new trial looking at dabrafenib plus trametinib in this patient population to see whether dual inhibition can overcome the inevitable acquired resistance that develops.

References:

Falchook, G., Long, G., Kurzrock, R., Kim, K., Arkenau, T., Brown, M., Hamid, O., Infante, J., Millward, M., Pavlick, A., O’Day, S., Blackman, S., Curtis, C., Lebowitz, P., Ma, B., Ouellet, D., & Kefford, R. (2012). Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial The Lancet, 379 (9829), 1893–1901 DOI: 10.1016/S0140–6736(12)60398–5

Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, Buzaid AC, Cochran AJ, Coit DG, Ding S, Eggermont AM, Flaherty KT, Gimotty PA, Kirkwood JM, McMasters KM, Mihm MC Jr, Morton DL, Ross MI, Sober AJ, & Sondak VK (2009). Final version of 2009 AJCC melanoma staging and classification. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 27 (36), 6199–206 PMID: 19917835

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Reflections of a Medical Oncologist on AACR 2012

By MaverickNY on May 18, 2012

While thoughts have already turned to the forthcoming ASCO 2012 meeting and today I am off to AUA 2012 in Atlanta, the annual meeting of the American Association Association for Cancer Research (AACR) last month continues to generate insights.

At AACR I was delighted to meet up with Philippe Aftimos, MD, a Clinical Research Fellow at the Jules Bordet Institute in Brussels, Belgium. Philippe is medical coordinator of the Clinical Research Unit and someone who I met through social media (@aftimosp), so it was a pleasure to meet in person.

I was, therefore, thrilled when Philippe agreed to do a guest blog post about what he thought were the highlights of AACR 2012:

A Medical Oncologist at AACR 2012 in Chicago by Philippe Aftimos, MD

As a medical oncologist with recent interest in clinical research, I attended the AACR annual meeting for the first time in Chicago from March 31^st to April 4^th 2012.

At first view, I was impressed by the enormous organization and very large number of participants, which was at least as important as the ASCO annual meeting. However, as a clinician, I only recognized very few familiar faces as the large majority of attendance included basic and translational scientists, as well as representatives of pharma.

Simultaneous sessions took place all over McCormick place and were featured: daily plenary sessions, major symposia, minisymposia, forums, educational sessions, methods workshops, poster sessions, “Current Concepts and Controversies in Organ Site Research” sessions and “Current Concepts and Controversies in Diagnostics, Therapeutics, and Prevention series” sessions. Planning the day’s schedule and navigating between the different sessions was made easy by the well-designed AACR 2012 Annual Meeting app.

My highlights from AACR 2012 can be divided into 3 subjects:

1. Pathways and new drug development

The PI3K-AKT-mTOR pathway was the subject of multiple sessions. It is mutated in tumors such as breast, lung, ovarian, endometrial carcinomas as well as gliomas. Inhibition of TORC1 has been shown to release inhibition of PI3K. Cancer cells harboring low BIM, a pro-apoptotic Bcl-2 family member, are resistant to PI3K inhibitors. PI3K inhibitors can reverse resistance to anti-EGFR tyrosine kinase inhibitors (TKIs) and the combination with MEK inhibitors is active against K-Ras mutant NSCLC. Selective inhibitors of PI3K isoforms are currently in clinical development. BYL-719 is PI3K alpha inhibitor and has shown tumor shrinkage in the phase 1 setting. It is potent against mutated cells and has anti-angiogenic properties. HER-2 amplification and PIK3CA mutation predict sensitivity while PTEN, B-Raf and K-Ras mutations confer resistance. GSK-2636771 is a selective PI3K beta inhibitor potentially inducing synthetic lethality in PTEN deficient mice. Hyperglycemia and hyperinsulinemia are class adverse events of PI3K inhibitors but are seldom seen with GSK-2636771.
ABT-199 is a Bcl-2 inhibitor in phase 1 development with very promising activity starting from the first cohort (starting dose) of chronic lymphocytic leukemia patients. It has also shown synergy when combined with rituximab or combination chemotherapy. Activity is correlated to Bcl-2 expression and specific targeting of Bcl-2 reduces the incidence of thrombocytopenia.
With the discovery of new chemotherapy agents in the treatment of castrate-resistant prostate cancer, interest in anti-hormonal treatments has been renewed. AZD-3514 is a first in class selective androgen receptor downregulator (SARD). It targets the androgen receptor in the nucleus and is currently in phase 1 development.
PD-0332991 is a highly selective inhibitor of CDK4/CDK6 resulting in potent G1 arrest, especially in Rb positive tumors. It showed activity in phase 1 trials with stable disease in breast cancer and liposarcoma. The most impressive results were in the treatment of mantle cell lymphoma with 1 CR in one patient still on-study for 2 years, 2 PR with one patient on study for 30 months and 7 SD out of 16 patients. Main DLT was neutropenia. Thrombocytopenia was also a limiting factor.

2. Immune therapy

The goal is to increase the tail of the curve in the photograph in the right. The approval of ipilimumab in the treatment of metastatic melanoma has inaugurated the new era of anti-cancer immune therapies.

They were very much put in the spotlight at AACR 2012 with a plenary session entitled: Immune Therapies: The Future Is Now. Highlights included: adoptive T-cell therapy, recombinant pox-viral vaccines, intra-tumor injection of vaccines, combination of vaccines and targeted agents in the treatment of melanoma. Characteristics of therapeutic vaccines are: minimal toxicity, indirect effects on tumors, delayed responses that increase over time. Administration in the early course of disease may be better and overall survival is usually the endpoint of clinical trials.

Agents that most caught my attention were monoclonal antibodies targeting the Programmed Death-1 (PD-1) T cell co-receptor and its ligand, B7-H1/PD-L1. Durable responses have been seen, often long-lasting off-therapy. Overall response rates as high as 30% have been demonstrated in renal cell carcinoma and melanoma. Tumor shrinkage was also seen in non-immunogenic cancers such as non-small cell lung cancer. Strong endogenous anti-tumor immune response upregulates PD-L1. For week endogenous anti-tumor immune response, combinations with epigenetic therapies may be key. Agents such as azacytidine can create an inflammatory response. Search for biomarkers such as PD-L1 expression and tumor-infiltrating lymphocytes is ongoing. This reference further explains this pathway: Topalian SL, Drake CG, Pardoll DM. Curr Opin Immunol. 2012 Apr;24(2):207-12.

3. Challenges for the future

With many clinical trials yielding negative results, the necessity for “smarter” trials has become evident. Trials of the future should be biomarker-stratified, enriched and adaptive. Histology-independent, aberration-specific trials should also be considered while being aware of different degrees of functionality and sensitivity of mutations. Combinations of targeted agents are the backbone of recent clinical trials and scientific rationle should be strong:

Supportive and confirmed in vivo and preclinical data
Suitable animal toxicity
Predictable biomarkers
Delivery to patients: number of pills, …

2 challenges remain:

Cooperation between different pharmaceutical patients developing the drugs of the combination
Regulatory-acceptance of mutation-based trials as well as regulations for targeted agents combinations

The session tackling the last issue deserved to feature as a plenary session. A very large crowd attended it with many participants finally sitting on the floor or leaning on walls.

Finally, the 2012 AACR Annual Meeting was yet another example of the rapid development and influence of social media with many scientists, clinicians and pharma representatives tweeting the information live, sharing their opinions, and interacting together.

Bio: Philippe Aftimos, MD

Medical Oncologist, graduate of Saint Joseph University in Beirut, Lebanon and the Free University of Brussels, Belgium. Trained: MD Anderson Cancer Center (Houston, Texas), Memorial Sloan-Kettering Cancer Center (New York City, New York) and Institut Gustave Roussy (Paris, France).

Currently, medical coordinator of the Clinical Research Unit at Institut Jules Bordet Cancer Centre in Brussels, Belgium, investigator for multiple clinical trials. My main interests are new drug development, phase 1 trials and breast cancer.

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ASCO 2012 Preview – Highlights of key data emerging from Chicago

By MaverickNY on May 15, 2012

It’s that time of the year again where we cogitate and contemplate on what might be hot at the annual meeting of the American Society of Clinical Oncology (ASCO) before the abstracts are available (they’re released online tomorrow at 6pm ET).

This year, while interesting early data from up and coming small biotechs is likely to be eagerly presented in poster sessions, the focus is more likely going to be on big Pharma with various phase III and also late phase II trials that are due to report data. Unfortunately, not all of these will produce overwhelmingly positive results though!

What I’m most interested is things that shift the needle meaningfully in terms of survival by six months or more, as we saw from the recent BOLERO2 and CLEOPATRA trials in ER+ and HER2+ breast cancer. There are plenty of agents that offer minor or incremental improvements (colon cancer has long suffered from that syndrome, sadly), but let’s be honest – most of us get excited by the possibility of major shifts in survival.

Please note that I’ve mostly selected some promising agents in development that might achieve that effect, explained why they are different and focused on new data/drugs rather than rehash what I call the ‘middlings’ i.e. minor upgrades to the standard of care.

Without much further ado, here are my ASCO preview highlights for 2012:

Please do check back during the convention both here on PSB, and also on Biotech Strategy, for reports and analysis as the interesting data emerges at ASCO.

If you have any comments or thoughts, please do share them below…

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ASCO 2012 Acronym Mania!

By MaverickNY on May 14, 2012

Many of you will remember PSB reader Dr Al Lalani of Regeneron’s guest blog post around this time last year with a quick summary of the key clinical trials at the American Society of Clinical Oncology (ASCO) meeting based on the study acronyms, which turned out to be highly popular.

Fortunately, Al has kindly sent in a review of this year’s trials in a very creative fashion, as you can see below (PSB: Thanks, Al!).

I strongly suggest that it is of PARAMOUNT importance that you all either check out these key acronyms in the abstracts when they go live on Wednesday to add to your ASCO schedule, or for the more enthusiastic participants, you play acronym bingo as you complete the daily #blisterwalk and make your way round the sessions in Chicago…

The annual ASCO prep work gears up this week in preparation for the online release of full abstracts this week.

You may recall my PSB guest post on the prevalent use of acronyms from last year’s conference.

It seems that some seem to be prepping for ASCO12 in unusual ways:

ASCO 2012 Acronymania, courtesy Dr Al Lalani

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Ribonucleases (RNase) – clinical applications for cancer therapy

By MaverickNY on May 1, 2012

This is the second post of a two-part mini series on RNases with Dr Laura Strong of Quintessence Biosciences. If you haven’t yet read it, check out yesterday’s post, which focused on Ribonucleases (RNase) – what are they and why are they relevant to cancer?

Yesterday, we learned that RNases kill cancer cells by a novel mechanism – destruction of RNA – and may be synergistic with some chemotherapy agents.

In the second part of the mini-series, Laura is going to discuss Quintessence’s progress with moving QBI–139, their lead RNase compound, from precinical research to the clinic. This post focuses on how a small biotech company decided upon the relevant clinical targets they wanted to focus on and reported the initial findings at the American Association for Cancer Research (AACR) meeting last month.

What is the clinical plan for a broadly active agent without a marker?

We took QBI–139 into a first-in-human Phase I trial with the primary objective of understanding the safety profile of the drug in patients with solid tumors. While dose escalating continues, the trial should be complete this year.

In the meantime, we have been refining our strategy for the next stage of clinical development. One of our challenges is the selection of tumor type because the drug showed broad efficacy in the xenograft models. After considering a variety of factors (including markets, competition, regulatory impacts and clinical trial designs), we narrowed our disease focus to non-small cell lung (NSCLC) and ovarian cancers. Despite having single agent activity, we anticipate advancing QBI–139 as part of a combination regimen with a standard of care drug. We have been gathering in vitro and in vivo data to support these approaches and we shared some of our in vitro results at the AACR 2012 annual meeting.

To select the drugs we would combine with QBI–139, the first, second and third line therapies in non-small cell lung and ovarian cancers were evaluated. The diseases are an interesting dichotomy because ovarian cancer is still largely treated as a single disease while non-small cell lung cancer (NSCLC) is transitioning to a collection of diseases divided largely by genetic mutations with some differences based on histology.

First line therapies in ovarian cancer are based on combinations of platinum drugs and taxanes. In contrast, second and third line therapies for ovarian cancer involve a variety of drugs (e.g. topotecan, gemcitabine, vinorelbine), which resulted in selection of cisplatin and docetaxel to explore in combination with QBI–139.

NSCLC patients with changes in EGFR, KRAS and ALK will be treated with targeted agents as first line therapy. The remainder, which is actually the majority, of NSCLC patients, will receive a first line therapy that often includes cisplatin as part of a combination regimen. {Editor’s Note: common NSCLC therapies typically include a platinum (eg cisplatin or carboplatin) and a taxane (eg paclitaxel or docetaxel), or other chemotherapy doublets (eg gemcitabine or pemetrexed with a platinum.)}

A cell viability assay was run to determine the concentration of each single agent that caused a half maximal effect (EC50). The combination studies were then run starting with each drug at the concentration of maximal effect.

Two graphs are provided as examples of the results. The ovarian cancer cell line OVCAR–3 (left) and the NSCLC cell line SK-MES–1 (right) were treated with QBI–139, cisplatin or a combination of the two drugs. The QBI–139 + cisplatin had an additive effect on the OVCAR–3 (ovarian cancer) cells and a synergistic effect on the SK-MES–1 (NSCLC) cells.

QBI-139 Cell Viability courtesy of Laura Strong, Quintessence

The combination index (CI) is then determined using the median effect analysis (This approach is sometimes referred to as the Chou Talalay combination index.). The CI values represent: additive effect (CI = 1), synergy (CI < 1) and antagonism (CI > 1).

What combinations have been evaluated so far?

The QBI–139 combinations showed synergy or additive effects against the ovarian cancer lines tested:

QBI–139 + Cisplatin:

SKOV–3 cells: CI=0.33
OVCAR–3 cells: CI=1

QBI–139 + Docetaxel:

SKOV–3 cells: CI=0.037
IGROV–1 cells: CI=0.05

The QBI–139 + cisplatin combination was synergistic against the non-small cell lung cancer lines tested:

A549 cells: CI=0.714
SK-MES–1 cells: CI=0.4

So what comes next for RNase therapies?

The discovery that naturally occurring RNases could be exploited for potent anti-cancer drugs has provided an alternative approach to RNA as a therapeutic target. Our efforts have advanced a drug with broad activity in xenograft models into the clinic. As we complete the Phase I trial, we are working to best position the drug for the next step on the path to delivering a new tool to help cancer patients.

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Ribonucleases (RNase) what are they and why are they relevant to cancer?

By MaverickNY on April 30, 2012

At the recent American Association for Cancer Research (AACR) meeting, I had the pleasure of meeting several interesting young scientists and physicians either in the poster halls or in various scientific sessions. It seemed a great idea to encourage some of them to contribute some guess blog posts here on PSB.

Dr Laura Strong, Photo courtesy of Pieter Droppert, Biotech Strategy Blog

Amongst the people I met was Dr Laura Strong, President and COO of Quintessence Biosciences.

One of the joys of social media is that sometimes you can get to know people a little from online interactions before you actually meet them in real life, making it much easier to walk up and introduce yourself as a ‘warm’ rather than ‘cold’ contact from a conversational standpoint. I’ve been following Laura (@scientre) for a while on Twitter and was keen to learn more about what her early stage biotech company does.

Quintessence Biosciences is, according to it’s website, “a biopharmaceutical company focused on development of novel protein-based therapeutics as anti-cancer agents. The Company’s products are based on the EVade™ Ribonuclease Technology which allows for the engineering of human proteins (ribonucleases) for the treatment of human diseases.”

Essentially, in plain English, this means that “The EVade™ Ribonucleases degrade ribonucleic acids (RNA), resulting in inhibition of protein synthesis and cell death.”

Source: Quintessence Biosciences

Laura was presenting a very interesting poster at the meeting, so I asked her if she was interested in writing a guest post about their work on RNases. She has most kindly agreed, so today and tomorrow we’re running a two-part mini series from Laura on RNases based on Quintessence’s work. For those interested in background research, you can check out more about the company here and also Laura’s blog, The Next Element.

RNases: From Concept to Clinic

At this year’s AACR Annual Meeting, I presented results from in vitro screening of combinations of our clinical stage ribonuclease (RNase). The theme of the meeting, Accelerating Science: Concept to Clinic, captures the serendipitous discovery that started on this course and subsequent development of this innovative and differentiated class of drugs.

Is RNA a good therapeutic target?

RNA has been a validated drug target for decades – from the discovery that various classes of antibiotics target ribosomal RNA to the more recent approaches using modified oligonucleotides to target specific RNA sequences. Vitravene is an oligonucleotide designed to binds a critical cytomegalovirus (CMV) messenger RNA that was approved by the FDA to treat CMV retinitis in immunocompromised patients. Recently a New Drug Application (NDA) was recently filed for another oligonucleotide drug, Kynamro (mipomersen sodium) that targets apolipoprotein-B to treat severe forms of familial hypercholesterolemia. These drugs have another feature in common: they do not target cancer.

In cancer drug development, the development of receptor tyrosine kinase inhibitors (TKIs) provides a potential roadmap for successful development of RNA-based therapies. While the early approved drugs, such as imatinib (targets bcr-abl to treat Philadelphia positive Chronic Myeloid Leukemia (CML)), provided significant benefit to patients, resistance via mutation in the ATP-binding pocket of the kinase domain has become a persistent problem in TKI therapy. This situation has prompted the development of second generation drugs (e.g. dasatinib and nilotinib for CML).

Another important lesson from TKI drug development is the clinical impact of targeting multiple and complementary aberrant signaling pathways. Even if the activity of one component of a pathway is blocked, there are often others that can compensate for the loss. In practice, this has led to development of pan-kinase inhibitors and to combining drugs in clinical trials based on the overlap of pathways. These results suggest that a single target approach may not have enough impact in targeting the RNA in cancer cells.

How do you go after multiple RNA targets?

One approach to target multiple RNA sequences inside a cell is to deliver multiple RNA drugs, such as modified oligonucleotides. Alnylam has taken this approach with their early clinical drug ALN-VSP. The drug uses small interfering RNA (siRNA), which are relatively short (1–22 base pair) RNA duplexes that inhibit messenger RNA once inside cells. In the case of ALN-VSP, two types of siRNA are included in a lipid nanoparticle. ALN-VSP targets two genes involved in liver cancer: kinesin spindle protein and vascular endothelial growth factor. The drug has completed a Phase I dose escalation study.

An alternative approach to attack multiple pieces of RNA in cancer cells is to use a human protein whose function is to degrade RNA, a ribonuclease (RNase). While this alternative may not be immediately obvious, serendipity played a role in bringing this concept to the clinic. In the late 1980s, frog egg extracts were screened for in vitro anti-cancer activity with positive results. The active component turned out to be a frog RNase that is part of the RNase A family.

Professor Ronald Raines at the University of Wisconsin made the connection that bovine RNase A, the prototypical family member, was not toxic to cancer cells and identified a major difference between the frog and bovine RNases. The bovine RNase A binds very tightly to the ribonuclease inhibitor protein found in the cytosol of human cells while the frog RNase does not. Using this information, a variety of bovine RNase A variants were produced with diminished binding to the inhibitor and these RNases were cytotoxic to cancer cells in vitro.

Using the closest human homolog, human RNase I, we first tested the concept of whether certain RNase variants may have anti-tumor activity in preclinical cancer models in mice. Forty human RNase I variants were produced based on data from a crystal structure data of the bound RNase and inhibitor and then tested in xenograft models. The RNases showed a range of activity, highlighting that the activity of the RNase is based on evasion of ribonuclease inhibitor but there are other factors, such as internalization and pharmacokinetics that also contribute to efficacy.

QBI–139

We selected QBI–139 as our lead candidate because the drug had the greatest activity across the most tumor types, including breast, colorectal, non-small cell lung, ovarian, prostate and pancreatic cancers. QBI–139 maintains 95% sequence identity to the human RNase I. The efficacy of QBI–139 was similar to chemotherapies and targeted agents when tested in preclinical models. We also did not see the common toxicities associated with chemotherapy (e.g. myelosuppression, alopecia, etc.) in the efficacy models.

The example shown is a xenograft model of prostate cancer (DU145) comparing QBI–139 to the standard of care agent docetaxel as well as the frog RNase. On a once weekly schedule, QBI–139 provides equivalent efficacy as the other two agents with less toxicity. At this dose, QBI–139 did not cause death (as in the docetaxel arm) or weight loss (as in the frog RNase treatment arm).

Do check back PSB tomorrow for the second part of Laura’s synopsis on RNases, which discusses the clinical aspects and where Quintessence are going with this interesting and novel concept.

Highlights of AACR 2012 – Part 3

By MaverickNY on April 23, 2012

Aside from the already published Part 1 and Part 2 blog posts about AACR here on PSB, you can also find some more coverage, including summaries of other topics, on the companion Biotech Strategy Blog, such as the following:

A new development in R&D – hypoxia-activated prodrug (HAP)?

Today I wanted to discuss a completely different subject though. Some data that was eagerly awaited prior to the meeting was the Threshold Pharma data for TH–302 in pancreatic cancer. The concept is an interesting one theoretically – simply described, they sought to develop a compound that is specifically activated under hypoxic conditions – and look for more potent anti-cancer activity.

Now, preclinically, the data looked impressive – see Sun et al., (2011) for a comprehensive overview (reference below, open access) and certainly bore out the hypothesis from a conceptual standpoint, but does this translate into the clinic with patients?

It should be noted that most normal cells in the body thrive under normoxic conditions, whereas tumours tend to grow through angiogenesis under more extreme conditions, with patches of hypoxia and normoxia.

One of the challenges with most existing chemotherapies is getting enough of the drug inside the tumour to cause enough of an effect. Because they are non-specific, they often attack a lot of normal cells in their path too.

Threshold’s theory is essentially based on a pro-drug approach; such bioreductive agents are activated under hypoxic conditions and are not a new concept in cancer research – mitomycin C is a classic one of this genre, for example. They state that:

“After conversion to the active form of the drug, the more resistant hypoxic cells are exposed to high concentrations of released cytotoxic agent, which can also diffuse into the surrounding oxygenated regions of the tumor, exerting what is referred to as a bystander effect.

In this way, TH–302 can kill more of the tumor than can otherwise be accounted for by the hypoxic fraction alone. Because of its selective activation in the hypoxic regions of solid tumors, we believe that TH–302 will be less likely to produce the systemic toxicity caused by most cytotoxic chemotherapies.”

Chemotherapy, however, can also induce a more hypoxic environment and paradoxically induce the production of more cancer stem cells (CSCs), as shown in this excellent graphic published in The Scientist recently by Liu et al., (2012):

Hypoxia is common in cancers, especially solid tumors

Source: The Scientist

As Liu et al., (2012) observed:

“These treatments can create inflammation in the tissue surrounding the tumor as well as hypoxia, or loss of oxygen, which activates Wnt signaling. Inflammatory mediators such as IL–8, IL–6, and Wnt signaling spur CSCs to self-renew or increase in number, thus driving tumor growth.”

Thus while trying to shrink the tumour, there may be some cases where hypoxia induced by chemotherapy can make the tumour more aggressive. This is one of conundrums of cancer chemotherapy. For those of you interested in reading more on CSCs, check out Joan Massaugué’s impressive research for more information.

Ok so far, but what happens in practice?

In this phase IIb trial, patients with advanced pancreatic cancer (n=214), including 77% with distant metastases, were randomised to receive either the standard of care, gemcitabine, TH–302 (240 mg/m2) plus gemcitabine, or TH–302 (340 mg/m2) plus gemcitabine.

Let me state upfront – there were no overall survival (OS) available in the pancreatic study, so we only have progression-free survival (PFS) to go on for now. Surrogate endpoints such as PFS do not always equate to OS, ie patients living longer. With that caveat, the main data can be summarised as thus:

PFS increased from 3.6 months (gemcitabine alone) to 5.6 months (gem + TH–302, either dose).
The hazard ratio comparing the TH–302 combination to gemcitabine alone was 0.61 (p = 0.005).
There was also an increase in tumor response rate from 12% to 22%.
TH–302 related toxicities included myelosuppression, skin and mucosal toxicities, which were dose dependent and consistent with previous trials.

While the study achieved it’s primary endpoint, it should be noted that there are some issues with extrapolating limited phase IIb data to potential success in a phase III trial. For starters, you want to have your groups as carefully balanced as possible or you could be making a leap of faith based on the wrong premise. Malcolm Moore alluded to this fact in his discussion of the data. Looking at the baseline characteristics, I was dismayed to see several areas where the groups weren’t well balanced, which is sloppy research – don’t give people a reason to doubt the data before you start:

Performance status – the TH–302 arms had slightly better PS
The percentage of patients over 65 in the gm +TH–302 240mg/m2 was noticeably less than the other two arms (39% vs 59% and 51%)
The gem alone arm had a higher number of patients with liver mets (67% vs 63 and 57%), which could be argued as more advanced and difficult to treat
Baseline CA19–9 was higher in both TH–302 arms (doubled, why?)
Lower dose arm of TH–302 had less prior systemic treatment in the adjuvant or neoadjuvant setting (8% vs 13% and 11%)
Treatment cycles – the group receiving TH–302 had a median of 2 more cycles and thus longer follow up

Could these factors influence the results? Unfortunately yes, especially when several were weighted in favour of the TH–302 treatment groups. Should they have made a better attempt at balancing them? Absolutely – it’s been a while since I saw so many imbalances and these go both ways making it hard to extrapolate anything much from the efficacy data – it detracts from the study. I wouldn’t like to guess how these might influence a larger, randomised trial in more centres where any efficacy signal seen in phase IIb can rapidly disappear when such bias is removed or significantly reduced.

The bigger challenge, though, as Malcolm Moore pointed out is that the absolute PFS benefit was only 2 months with TH–302 therapy (240mg/m2 dose), which is probably on the limit for moving forwards to a phase III randomised trial.

Overall

I think this is a nice scientific idea that is well worth testing, but TH–302 may not be the one that gets the breakthrough status based on these limited results. Future compounds may be able to induce more potency and efficacy in difficult to treat tumour types – a 2 month absolute benefit in a phase II trial can rapidly disappear in a large scale randomised study, which is something I would be concerned about given some of the imbalances in the patient groups to begin with.

A phase III SPA has been agreed with the FDA in soft-tissue sarcomas (STS), but regular readers will be well aware that I’m not a fan of catch-all studies in unselected patients, especially in broad heteregeneous cancers such as sarcomas and pancreatic cancer. That’s just asking for trouble because the non-responders will lower the overall efficacy, as we saw recently with ridaforolimus, and this sets up a trial for almost certain failure unless smaller subsets with more clearly defined targets can be identified.

References:

Sun, J., Liu, Q., Wang, J., Ahluwalia, D., Ferraro, D., Wang, Y., Duan, J., Ammons, W., Curd, J., Matteucci, M., & Hart, C. (2011). Selective Tumor Hypoxia Targeting by Hypoxia-Activated Prodrug TH–302 Inhibits Tumor Growth in Preclinical Models of Cancer Clinical Cancer Research, 18 (3), 758–770 DOI: 10.1158/1078–0432.CCR–11–1980

Highlights of AACR 2012 – Part 2

By MaverickNY on April 18, 2012

Yesterday, I mentioned that some of the best bits of this year’s American Association for Cancer Research (AACR) meeting were the numerous gems in the poster sessions.

Reuben Sierra, Ming Tsao's Lab (with permission)

One of the coolest such posters I came across was from Ming Tsao’s group.

Specifically, Rafael Sierra (see photo right) was hosting an excellent piece of research entitled: “Overcoming resistance to EGFR-tyrosine kinase inhibitor therapy in non-small cell lung cancer.”

This is an area of much needed research and breakthroughs.

Why?

Well, at the ECCO meeting in Stockholm last September, Tom Lynch was discussing the role of one such EGFR therapy, cetuximab (Erbitux), in lung cancer and wearily declared prior to presenting a negative study,

“If ever there was a drug desperately needing a biomarker, it’s cetuximab”

because while some of the patients responded beautifully to the drug, many others didn’t and at that time, there was no way to determine upfront who might respond before treating.

This is clearly a waste of valuable resources and time because catch-all studies mean that the number of negative responses can balance out the positive responses in too heterogeneous a population. That said, if you know what the potential target(s) or biomarker of response are, then you can select patients more precisely for a study and improve the subsequent overall response rates and OS advantage dramatically.

As Sierra et al., pointed out in their poster at AACR, we do know that:

“Patients that present amplification or activating mutations (L878R or exon 19 deletions) of EGFR, have higher response rates. Selection improved response rates from less than 10% to over 60–80%.”

This is very good progress, but how did their research take this concept further?

In this study, the group reported the preliminary findings from a complex study of genome-wide screenings on EGFR resistant cells to try and identify new genes that might mediate resistance and, importantly, be potentially druggable, unlike say, MYC. This would then offer new logical targets for combination therapies to be tested in the clinic in patients to determine if outcomes could be improved.

At the time of the poster presentation, the group had indeed identified a short list of potential candidates (not named as this would be available in a later publication). Conceptually though, this was an elegant study and I really liked the concept.

This morning, I was delighted to see a news snippet from the 3rd European Lung Cancer Conference in Geneva, Switzerland where the ESMO press release noted that Dr Tsao’s group performed:

“An exploratory analysis on the TORCH patient tumor samples that were available for analysis, looking for molecular biomarkers known to be potential predictors of benefit from EGFR inhibitors.”

Despite the biomarker analysis being pre-planned, however, only a third (36%) of samples were available for analysis. It is always harder to do retrospective mutation analysis on small sample sizes unless rigorously collected as per the BATTLE trials.

I’m looking forward to hearing what targets were identified in Drs Sierra and Ming’s research once published or presented in more detail at a future conference, as this may help us move the field forward in terms of rational combinations to either overcome resistance to EGFR therapy (other than the well known T790M mutation) or prevent resistance from developing early.

Now, that would be very cool and I do hope they alert us to the publication in due course – watch this space!

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