Sutent | Pharma Strategy Blog

AVEO announces front-line data in renal cell cancer for tivozanib

By MaverickNY on January 3, 2012

A very happy New Year everyone! After shaking off the dust of an extended break over the last two weeks, this morning brought plenty of news to kick start 2012.

The most interesting news was AVEO-Astellas’ announcement regarding their VEGF inhibitor, tivozanib, in advanced renal cell cancer (RCC):

“Tivozanib demonstrated superiority over sorafenib in the primary endpoint of progression-free survival (PFS) in TIVO-1, a global, randomized Phase 3 clinical trial evaluating the efficacy and safety of investigational drug tivozanib compared to sorafenib in 517 patients with advanced renal cell carcinoma (RCC).”

The previous front-line trials with sorafenib (Nexavar) and sunitinib (Sutent) were randomised trials that compared the active drug to placebo and interferon respectively, so this is the first head to head study that compares an investigational agent to an approved VEGF therapy. It was a risky study given that the prior phase II trial in RCC compared tivozanib against placebo, meaning AVEO had no idea whether their had a superior agent or not.

What did the data show?

The TIVO-1 study sought to compare tivozanib versus sorafenib in patients with clear cell renal carcinoma who were treatment naïve, ie they had not received prior therapy with either a VEGF or an mTOR inhibitor. The companies announced the topline results from the DSMC analysis:

Tivozanib demonstrated a statistically significant improvement in PFS with a median PFS of 11.9 months compared to a median PFS of 9.1 months for sorafenib in the overall study population.

Tivozanib demonstrated a statistically significant improvement in PFS with a median PFS of 12.7 months compared to a median PFS of 9.1 months for sorafenib in the pre-specified subpopulation of patients who were treatment naïve (no prior systemic anti-cancer therapy); this subpopulation was approximately 70% of the total study population.

Tivozanib demonstrated a well-tolerated safety profile consistent with the Phase 2 experience; the most commonly reported side effect was hypertension, a well established on-target and manageable effect of VEGFR inhibitors.

The data is being submitted as an abstract to ASCO and an FDA filing will also most likely result this year.

No further information was available at this stage on the second point for the treatment-naive and prior therapy groups. The safety profile was reported on the call to be in-line with prior phase II experience, meaning hypertension, a VEGF class effect, was the most common adverse event.

What do these data mean?

There are several points to note from this topline analysis:

The sorafenib arm did better than expected – based on the PI, we would expect around 5.5 months not 9.1 months.
The sunitinib front-line trial showed a median benefit of ~11.0 months, based on the PI giving 47.3 weeks for PFS.
So while the difference in the TIVO-1 study of ~3 months between the two arms is smaller, the absolute PFS benefit for tivozanib is slightly better than sunitinib, although the caveat is that we cannot really compare them clinically without a head to head trial.
We don’t yet know how well Pfizer’s axitinib (Inlyta) will do in the 1st line setting, as only the second-line topline findings were announced in November:

“Axitinib in previously treated patients with metastatic renal cell carcinoma (mRCC), has met its primary endpoint, demonstrating that axitinib significantly extended progression-free survival (PFS) when compared to sorafenib, in the study population.”

My guess is that at this rate, tivozanib and axitinib may well prove to be more similar than different, as the compounds were fairly close preclinically. By this, I mean that with more selective VEGF inhibitors we are likely to see less toxicities from off-kinase inhibition with perhaps similar efficacy to Sutent, than vast improvements in PFS.

Ultimately, the real winner in a very crowded RCC market is going to be a drug with not only superior PFS, but also a cleaner safety profile. It has been shown previously that combining sunitinib with an mTOR such as everolimus (Afinitor) led to unacceptable toxicities and the concept was thereby abandoned after the phase I trial. However, if either tivozanib or axitinib can be safely combined with an mTOR for additional efficacy, then this would be a big plus for both physicians and patients. At the moment, the count is out on that option.

Currently, physicians typically treat patients with Sutent initially and then consider Nexavar, Afinitor or Torisel as second-line therapy, while reserving Votrient (pazopanib), another VEGF inhibitor, for 3rd line given its adverse event and efficacy profile. Sequencing multiple single agents is therefore very much derigeur in RCC. Whether tivozanib or axitinib can change this is an important consideration for the future.

And finally, some observations…

This year’s ASCO is going to be a most interesting meeting for renal cell cancer with data now expected for tivozanib in first and second line expected versus sorafenib, following on from the head to head of axitinib versus sorafenib in second line at last year’s ASCO. I’m not sure when the axitinib front-line data will be available, but it is eagerly awaited given the tivozanib data announcement.

It is interesting that the market is down on the news with AVEO’s shares falling, despite meeting the primary study endpoint. No doubt investors were expecting either a bigger difference between the arms or for the absolute overall PFS value for tivozanib to be greater than 12-12.5 months in the upfront setting.

Part of me would have liked to have seen the safety and efficacy signal of the head to head with sorafenib in a phase 2 trial to see what the real difference between the two was earlier. As it is, the phase 2 was conducted versus placebo, which doesn’t tell us anything about what might be expected in a phase 3 study. It’s always a risk switching horses into the unknown.

Mechanistically though, tivozanib is a VEGF inhibitor in the vein as Sutent, Nexavar, Avastin and Votrient, albeit a more selective one, so there is a limit on what can be expected by blocking a single pathway. Resistance inevitably sets in, so going forward we need to determine what the adaptive resistance pathways to therapy are and then determine what combinations might be feasible to try and overcome them. If this can be done without excessive toxicities, then we can expect the survival to improve further.

Another thing to consider is that previously, AVEO presented some rather promising data on biomarkers of response in their preclinical and phase I RCC data. I’m very keen to see if any subset analysis in the phase III trial will be presented at ASCO and whether the hypothesis stands up in the clinical setting for either the treatment naïve or relapsed patients. If the biomarker can determine who is most likely to respond to tivazanib, then I would expect the PFS to improve in that subset. We must wait and see what, if anything, happens with that.

Finally, for patients moving from 10 to almost 12 months may sound like a small increment in survival, but when we consider the cumulative effect of sequencing multiple drugs, there is no doubt that the efficacy benefits begin to accrue over time. It should not be forgotten than until recently, the choices in RCC were stark. There was either IL-2 (only suitable for a limited number of patients due to severe toxicities) or interferon, which typically had a PFS of approx. 4-5 months.

Since then, in only a few years with several new therapies entering the market, the PFS has already doubled with only single agent therapy; that’s quite an improvement, although we still have a long way to go in understanding the biology of the disease.

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Update on pancreatic Neuroendocrine Tumours (NET)

By MaverickNY on November 10, 2011

Today on 10th November, it’s the Second Annual Worldwide NET (Neuroendocrine Tumor) Cancer Awareness Day. Granted that’s a bit of a mouthful, but it also seems poignant given so many of my news feeds this morning were still full of Steve Jobs, who sadly passed away from the disease last month.

I’ve been meaning to post an update on this rare form of cancer all year, given that we now have targeted therapies now approved by the FDA for treatment, but things were hectic at the office and then with Jobs passing, the timing just seemed tacky and inappropriate.

The idea though, of an Awareness Day for a rare disease such as NET to improve both education and awareness seems an inherently good one to me, especially as there has been some progress clinically in 2011. According to Kulke et al., (2011) NET has an incidence of around 1 per 100,000 individuals. This excellent review covers the key essentials of both the disease and the treatments:

“Patients with pancreatic NET present with diverse symp- toms related to hormonal hypersecretion, tumor bulk, or both. Accurate diagnosis of this condition and differentiation of pancreatic NET from the more common pancreatic adenocarcinomas is a critical first step in developing an appropriate treatment plan.”

It has been quite the landmark year for NET since not one, but two, new therapies were approved by the FDA in May this year with very different mechanisms of action:

Everolimus (Afinitor) from Novartis targets the mammalian target of rapamycin (mTOR), a serine-threonine kinase, downstream of the PI3K/AKT pathway.
Sunitinib (Sutent) from Pfizer is a multikinase inhibitor of VEGF, PDGFR (α and β), KIT, FLT3, RET and CSF-1R.

Both of these drugs are also approved for the treatment of renal cell cancer, which while nearby geographically in the body, is a completely different type of GI cancer. They are now approved for pancreatic neuroendocrine tumours (pNET) that have progressed and cannot be treated with surgery.

It is important to note, that while NET is a rare form of pancreatic cancer, it is not the same thing as the more common pancreatic adenocarcinoma – a fact that the media often got wrong in the case of Steve Jobs and drove me potty at their ignorance and inability to grasp a simple concept. NET is not an adenocarcinoma and has a much larger endocrinology/metabolism component and starts in the hormone-producing cells of the pancreas. There are two types of pancreatic NET:

Functional (overproduce hormones)
Nonfunctional (do not overproduce hormones) and are more common

There are some great resources for patients (and caregivers) want to know more about this disease – here are some examples I came across:

The Pancreatic NET Connections site sponsored by Pfizer gives some great education about the disease
The NET Alliance site is sponsored by Novartis and offers lots of useful information
Pancreatic Cancer Action Network has a nifty Facebook page
The American Cancer Society has information about treatments

Let’s take a look at the new clinical data. Both sunitinib and everolimus were compared to placebo in the phase III trial of refractory patients who were ineligible for surgery and had disease progression.

Here’s what the survival curves look like, based on the data from their respective prescribing information: 1 2

In the case of sunitinib, we can see that the median progression-free survival (PFS) 10.2 months versus 5.4 months for the placebo arm. This difference was highly significant (P 0.000146, HR 0.427):

sunitinib

Looking at the everolimus data, we also see a significant trend in favour of therapy over placebo, i.e. a median PFS of 11.04 months compared with 4.6 months for placebo (P 0.001, HR 0.35):

everolimus

These studies produced very comparable responses from a survival perspective and overall response rates of 9% and 5%, respectively.

While it is good to see some excellent progress on the efficacy front, these new therapies for NET are not without their challenges and side effects though.

In particular, in the phase III study, sunitinib, hypertension was the most common grade 3 event in 10% of patients (a classic function of the VEGF class of drugs) and was also shown to cause cardiac failure leading to death in 2/83 (2%) patients on therapy compared with no patients on placebo.

In contrast, everolimus should be avoided with concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole). The most common grade 3/4 adverse reactions (incidence ≥ 5%) in the phase III pNET trial were stomatitis and diarrhea.

As Kulke et al., observed:

“Surgical resection remains the mainstay of treatment for patients with localized disease.”

However, for patients who are unresectable or have progressed there are at last new options:

“Recent studies have also reported that the tyrosine kinase inhibitor sunitinib and the mTOR inhibitor everolimus improved progression-free survival in patients with pancreatic NET, further expanding the therapeutic arsenal available to patients with this disease.”

In the future, we may well see sequencing studies emerge as well as other targeted therapies to prolong outcomes for patients with this rare disease.

References:

Kulke MH, Bendell J, Kvols L, Picus J, Pommier R, & Yao J (2011). Evolving diagnostic and treatment strategies for pancreatic neuroendocrine tumors. Journal of hematology & oncology, 4 PMID: 21672194

Sunitinib PI accessed ↩
Everolimus PI accessed ↩

More phase III cancer trials flop: Pfizer (Sutent) and Roche (Avastin)

By MaverickNY on March 12, 2010

The last 18 months have seen a lot of failed cancer studies in phase III development after early promising phase II results, teaching us that sometimes rushing full steam ahead without fully understanding the issues is not always the smartest strategy.

Let's start with Pfizer's figitumumab, an IGF-1R antibody, which we have previously discussed in non-small cell lung cancer (NSCLC) (here and here). There was one phase II trial at MD Anderson that led to what many of us thought was a rather cavalier, aggressive and hasty phase III program, without really seeking to understand the underlying biology behind the pathway first. Interestingly, other competitors have taken a much slower and more methodical approach to thinking through the various issues and may well come out ahead as a result.

Given the front-line trial produced a negative response, I think many of us were expecting the 2nd line study to eventually go the same way. The endocrine and biochemical interactions happening around IGF-1R will need more careful reflection before the concept has a real chance of working. There are various things happening around cross-talk between receptors, interaction with the insulin receptor and AKT may well turn out to have an important role to play. All in all, manipulating the biochemistry of the pathways needs a little more sophistication than a mere sledgehammer to crush a grape approach.

Pfizer also announced that two phase III trials with sunitinib (Sutent) also failed to meet their primary endpoint. Sutent is approved for the treatment of renal cell cancer and gastrointestinal stromal tumours (GIST) and as an oral VEGF/KIT inhibitor that was originally developed by Sugen before it was snapped up by Pharmacia, I think it has done pretty well. It is unrealistic to expect every drug to work in every indication and there may be differences between how monoclonal antibodies such as bevacizumab (Avastin) work compared to small molecules such as Sutent and Bayer's sorafenib (Nexavar).

Like Pfizer, Bayer recently announced promising phase II results in breast cancer. Given that Pfizer previously announced last year that a Sutent trial in breast cancer was negative (see previous post), I wasn't expecting the two current trials to be positive. Had they done so, it would have been akin to a miracle.

Roche's Avastin has had a string of good results and also a few setbacks. The original program focused on breast cancer rather than colorectal cancer before the trial was negative. To give Genentech credit though, they went back to the drawing board to figure out what worked and where the issues were before eventually having another success in breast cancer much later. This is probably what Pfizer need to do now too, scientific and clinical reflection is sometimes a necessary part of the pain on the journey.

Avastin has been now approved in colorectal, lung, breast, renal and brain cancers, so a setback in prostate cancer, as Genentech announced this morning, is probably not going to matter too much. This is unfortunate because there really aren't that many options for advanced stage patients who have become hormone resistant. All is not completely lost for men with prostate cancer though, as sanofi-aventis (a client) have reported that their next generation taxane, cabazitaxel, increased survival in this population, so hopefully we will see more of the data at this year's ASCO meeting in June.

One thought we should perhaps reflect on. 'Oncogenic addition' is a phrase bandied around quite a bit these days, and for sure, some approaches have been very successful. We need to remember though, that targeting kinases and enzymes is only going to work if the enzyme is actually critical to the survival of the tumour, which will rarely happen in isolation. The way forward is most likely going to need a more sophisticated approach that combines multiple inhibitors in a logical fashion. To achieve that approach though, will require more iterative phase II trials to really determine exactly what is going on.

Pfizer and Roche/Genentech both have smart scientists and clinicians in their organisations, so my feeling is that they will go back to the drawing board and evaluate these trials and the data very carefully. You can't have a home run every time, but you can sometimes figure out ways to see if an agent can be made to work by tweaking things. Often, we're limited by our knowledge of the biology and sometimes negative trials can actually help us understand things better.

Photo Credit: Stuck in Customs

What price end of life cancer care?

By MaverickNY on March 4, 2010

“After Terence died, Flaherty drew me a picture of a bell curve, showing the range of survival times for kidney cancer sufferers. Terence was way off in the tail on the right-hand side, an indication he had indeed beaten the odds. An explosion of research had made it possible to extend lives for years — enough to keep our quest from having been total madness.

Terence used to tell a story, almost certainly apocryphal, about his Uncle Bob. Climbing aboard a landing craft before the invasion of Normandy, so the story went, Bob’s sergeant told the men that by the end of the day, nine out of 10 would be dead. Said Bob, on hearing that news: “Each one of us looked around and felt so sorry for those other nine poor sonsabitches.”

For me, it was about pushing the bell curve. Knowing that if there was something to be done, we couldn’t not do it. Believing beyond logic that we were going to escape the fate of those other poor sonsabitches.

It is very hard to put a price on that kind of hope.”

Source: Bloomberg

If you don’t do anything else today, please take a few minutes to read the link above about a caregiver’s experience with her husband’s kidney cancer. It describes the hopes, the fears, the process of what people really do go through with end of life cancer.

A powerful story.

One sadly, many people go through, but when is enough, enough? With the current debate raging around healthcare reform, this very human story gives us insight into what people actually go through, not just the treatments and side effect management, but also the billings, the paperwork, the quest for a cure. It makes one realise that any of us could have been there.

For all the pontification by the politicians on both sides of the House, I wish some of them would come to their senses and start thinking about what matters in healthcare reform. Their constituents are people, after all. If they don’t do what we think is fair and reasonable, we can always vote them out until they learn to get it right. There really should be an Amendment that says Congress cannot have a healthcare plan that is not available to everyone else. Only then will the deal get done properly.

Kudos: Thanks to my buddy, Bill Scully of the HCA Group, for sharing the article with me.

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#ASCO Early detection of pancreatic cancer using PAM4 as a biomarker

By MaverickNY on January 22, 2010

"Researchers have developed a novel immunoassay for detecting early-stage pancreatic cancer that identifies and quantifies blood levels of the PAM4 protein – a unique antigen present in almost 90 percent of pancreatic cancers and precancers."

ASCO GI Cancer Symposium, 2010

Wow, that little snippet from the ASCO press releases from the Gastrointestinal symposium in Florida woke me up while sipping coffee this morning!

The reason is that pancreatic cancer is an insidious disease and most patients are diagnosed late, usually in stage IV when there is little that can be done to successfully attentuate the cancer. For years, researchers have struggled with ways of detecting the cancer earlier when treatments are more likely to be effective without confusing cancer from pancreatitis.

Approximately 7% of pancreatic cancer cases are detected at an
early stage, before the cancer has spread to other parts of the body.
The survival rate for early stage pancreatic cancer is around 20%, compared with just 1.8% for those diagnosed when the disease has metastasized.

The PAM4 antibody, also called clivatuzumab, from Immunomedics ($IMMU) used in the assay reacts with a protein produced by pancreatic cancer cells. It appears that the protein is not detectable in normal pancreatic cells and is rarely detected in pancreatitis (inflammation of the pancreas), making it potentially highly specific for pancreatic cancer.

The researchers evaluated an immunoassay for the PAM4 protein in 68 patients who had pancreatic cancer surgery and 19 healthy controls. They found that the test was 62% sensitive for detecting stage 1 pancreatic cancer (disease confined to the pancreas), 86% sensitive for stage 2 disease (disease which has spread to nearby organs) and 91% sensitive for stage 3/4 cancers (local and distant spread). Overall, the assay was 81% sensitive for detecting all stages of pancreatic cancer; while not perfect, it would represent an enormous improvement on current detection rates.

The obvious next step is to validate the test on a larger scale with more patients to determine if it has utility as a diagnostic tool to detect people at risk for pancreatic cancer such as patients with a history of tobacco use, or those with genetic or other medical factors on a yearly basis, to enhance the chance of early detection.

The investigators also suggested that the clivatuzumab antibody may also prove useful for treating the disease by acting as a carrier for agents (such as radioactive isotopes labelled with Y⁹⁰) that can target and kill cancer cells, but this idea is pure supposition at present and as yet, unproven. Immunonomedics have a phase I trial ongoing with clivatuzumab in pancreatic cancer

At the ASCO GI symposium there was, however, some interesting new data in the treatment of pancreatic cancer as Pfizer announced the final results from a randomized Phase III
trial of sunitinib (Sutent) in patients with advanced pancreatic
neuroendocrine tumors, a type of cancer which originates in the
hormone-producing area of the pancreas.

Sunitinib appeared to more than double the
time the patients with lived without
disease progression compared with patients treated with placebo; results showed that median progression-free survival (PFS) was 11.4
months in patients treated with sunitinib compared with 5.5 months in
patients treated in the placebo arm. Overall survival was also prolonged.
Adverse events were similar to those observed in other sunitinib
studies.

The sunitinib results are particularly interesting, not only because they improve survival beyond the six months typically seen with the disease, but also because other VEGF inhibitors such as bevacizumab (Avastin) previously did not appear to be effective in slowing the disease. Sunitinib, though, is a multi-kinase inhibitor that also targets other pathways other than VEGF, including c-KIT, PDGF, FLT3 and RET, suggesting that dual inhibition of perhaps VEGF and PDGF is necessary in this disease.

On the basis of these results, Pfizer filed supplemental applications
for approval in pancreatic neuroendocrine tumours with the US, EU and
Canadian authorities, so help for patients may well be coming sooner than expected.

Two cancer drugs may prevent and reverse Type I diabetes

By MaverickNY on December 5, 2008

Gleevec (imatinib) and Sutent (sunitinib) appear to impact the ability of mice to develop Type I diabetes according to recent research publ;ished in the Proceedings of the National Academy of Sciences (PNAS). The drugs were found to put type 1 diabetes into remission in 80 percent of the test mice and work permanently in 80 percent of those that go into remission.

The interesting thing is that these two cancer drugs largely inhibit different tyrosine kinases except for KIT and PDGFR, so what is the possible mechanism of action? Gleevec inhibits BCR-ABL, PDGFR and C-KIT. Sutent is a multi kinase inhibitor, but does not affect BCR-ABL. Another inhibitor of KIT only marginally affected the mice, suggesting that PDGFR was the principal mechanism in the non-obese diabetic mice give that:

"… a soluble form of platelet-derived growth factor receptor (PDGFR), PDGFRβIg, rapidly reversed diabetes."

The most common form of diabetes is Type II, often associated with obesity, but few effective options exist for Type I diabetes, which is an autoimmune disease caused by the destruction of insulin-producing cells in the pancreas.

These promising results mean that the scientists will continue to study the effects of PDGFR in type 1 diabetes and have now applied for funding to perform a safety and efficacy clinical trial in patients.

Afinitor extends life for renal cancer patients

By MaverickNY on October 9, 2008

A new drug in development, Afinitor (everolimus, RAD001) appears to extends life without tumour growth by almost 5 months compared to 1.9 months with placebo. In addition, a quarter of the patients in the study remained progression free beyond 10 months of treatment. This is the first therapy to show significant benefit after failure with initial tyrosine kinase therapy (Sutent or Nexavar). It is currently being reviewed by the FDA for treatment of advanced kidney cancer after failure of initial therapy.

Initial therapy with kinase inhibitors has demonstrated signifcant progression free survival (PFS). Nexavar, for example, demonstrated a doubling of median PFS in patients with no prior
cytokine therapy of 25 weeks vs. 12 weeks with placebo. Sutent was compared to interferon-alpha and demonstrated a PFS of 47.3 weeks compared to 22 weeks with interferon-alpha.

What makes Afinitor different and why does it appear to work well, even in patients who have failed stand therapy? Well, the answer lies in it's mechanism of action. Both Sutent and Nexavar are multiple kinase inhibitors, principally of Vascular Endothelial Growth Factor (VEGF), that appears to be important in renal cell cancer. Solid cancers survive by extending their network of tumour vasculature, a process known as angiogenesis. Inhibiting VEGF therefore inhibits the tumours ability to grow. They also inhibit Platelet Derived Growth Factor (PDGF), which is important in cell proliferation.

Afinitor, on the other hand, inhibits the mammalian target of rapamycin (mTOR) is an intracellular protein that
acts as a central regulator of multiple signaling pathways (IGF, EGF,
PDGF, VEGF, amino acids) that mediate abnormal growth, proliferation,
and angiogenesis in cancer. mTOR is a critical component of the PI3K/AKT pathway, a key signaling pathway that is frequently dysregulated in many cancers.

Image courtesy of Novartis Oncology

By targeting a different pathway, the activity of the tumour can be further reduced, even after patients have stopped responding to their initial therapy. This is one of the new key approaches to attacking cancer – find multiple inhibitors of different critical pathways and then determine the best sequencing for the regimens, thereby improving survival.

All three drugs mentioned so far are oral therapies, which are convenient and easy for cancer patients to take each day. Another drug approved for renal cancer is Torisel (temsirolimus), a mTor inhibitor that is given by intravenous infusion over 30-60 minutes on a weekly basis. This drug significantly extended survival in renal cancer patients compared to interferon-alpha treatment (10.9 vs. 7.3 months). When standardised in weeks to enable comparison to Sutent, this means the PFS was approx. 49 weeks compared to 47 for Sutent.

It should be noted that rare bowel perforations are possible with these therapies, a class effect of inhibiting the VEGF pathway. Sutent and Nexavar have also been asssociated with raised blood pressure and hypertension, whereas Torisel may result in hyperglycemia and hyperlipemia. This may result in the need
for an increase in the dose of, or initiation of, insulin and/or oral
hypoglycemic agent therapy and/or lipid-lowering agents, respectively.

Additional new results with these agents are expected at the Annual Society of Clinical Oncology meeting in mid 2009. Afinitor is currently being evaluated by the FDA and EMEA for approval and could be available on the market by March-April 2009.

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