Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘Avastin’

Zaltrap – a simple dosing error or not?

By on November 9, 2012

The recent approval of Sanofi/Regeneron’s VEGF targeted monoclonal antibody, ziv-aflibercept (Zaltrap) in combination with FOLFIRI, for the treatment colorectal cancer (CRC) after failure of prior therapy with the FOLFOX regimen has proven to generate quite a controversy.

The efficacy benefit, although modest at 1.4 months extra survival, is similar to that seen with bevacizumab (Avastin) in the same setting.  The pricing, however, was clearly set at a premium at approximately $11,000 a month compared to less than half that for bevacizumab.  I never thought I would be blogging about the price of Avastin actually looking very reasonable!

Unsurprisingly, a consensus that this would be hard to justify was met with a firm reaction from academic thought leaders, including a very strongly worded Op Ed in the NY Times from Drs Peter Bach, Leonard Saltz and Robert Wittes at Memorial Sloan-Kettering Cancer Center (MSKCC), who declared that the price differential was too steep and Zaltrap would not be included in the formulary there.  Dr Saltz is well known for his opposition to high drug prices and the increasing cumulative cost of treating the disease.

Yesterday afternoon a new twist in the tale appeared with a new story in The Cancer Letter (paid subscription required) that Sanofi had halved the price of Zaltrap only two months after the launch in response to public pressure and criticism.  There were several interesting things to note from the article:

  1. The drug’s price was pegged to the 10 mg/kg every two weeks dose of Avastin.
  2. If the company discounts the drug’s price without adjusting the Medicare reimbursement rate, this would create a windfall for prescribing physicians.
  3. Patients’ copayments would continue to be calculated based on the old price.

Based on this, I can’t see MSKCC changing their position, at least until the retail price changes, since there is no benefit to their patients in paying more than they would for Avastin.

Point 2 raised by the Cancer Letter makes me wince slightly.  Although it doesn’t affect Academic physicians, since the Institutions purchase drugs from wholesalers or directly from manufacturers (in this case, Sanofi), in the community setting, oncologists purchase drugs from wholesalers, collect the patient co-pays and claim the reimbursement from the CMS or payers.  In this case, they would make a bigger margin on prescribing Zaltrap over Avastin until the retail price is adjusted.  This would be like going back to the old days of making huge margins on the spread with generics.  Essentially, it offers the oncologists in private practice a large reimbursement incentive in the short term to prescribe Zaltrap over Avastin, at least until the price is changed at the CMS.  The patient, however, is still forced to pay their copays at the original price and get no break from the Sanofi price reduction.

The dosing issue is slightly pertubing though.  It’s well known that the dose of Avastin has usually been 5mg/Kg in colorectal cancer for some years, at least since 2004 from memory, while the dose in other solid tumour was indeed 10mg/Kg.  Sometimes a loading dose of 10mg/Kg is used in patients with a high disease burden followed by the 5mg/Kg maintenance dose.  The actual Avastin PI is very general since the drug was originally approved back in 2003:

“The recommended doses are 5 mg/kg or 10 mg/kg every 2 weeks when used in combination with intravenous 5-FU-based chemotherapy. Administer 5 mg/kg when used in combination with bolus-IFL. Administer 10 mg/kg when used in combination with FOLFOX4.”

Of course, what happens in practice is that drugs are sometimes approved with two different doses based on the trials at the time and clinical practice evolves with experience and knowledge.  In this case, IFL and FOLFOX4 have given way to FOLFIRI and FOLFOX6 as the base regimens to which biologics are added.  It didn’t take the CRC community long to realise that a 5mg/Kg dose worked just as efficaciously as the 10mg/Kg infusion when given with FOLFIRI and FOLFOX6, as well as being more cost effective.

The community practice is reflected in the current NCCN Guidelines, which offer oncologists an overview of the standards for different regimens in different tumour types. You can see the recommended regimens and dosing schedules for colon cancer in the snapshot below:

NCCN Guidelines for Colon Cancer

Bevacizumab dosing in colorectal cancer

This confirms my suspicions and intuition having worked in the colorectal cancer field several times and not seeing much change there since 2004.  Doctors are creatures of habit and safety, unless you give them a compelling (efficacy or reimbursement) reason otherwise.  The NCCN Guidelines are created by a committee of Academic experts based on best practice and are usually followed by oncologists in private practice.

The moral of this story for pharma companies is don’t rely on product prescribing information (PI) for setting your pricing as they are often superceded by clinical practice as referenced in NCCN and ASCO Guidelines!

 

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

By 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:

  1. The sorafenib arm did better than expected – based on the PI, we would expect around 5.5 months not 9.1 months.
  2. The sunitinib front-line trial showed a median benefit of ~11.0 months, based on the PI giving 47.3 weeks for PFS.
  3. 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.
  4. 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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ODAC votes unanimously against Genentech and Avastin in metastatic breast cancer

By on June 29, 2011

Finally, we have a result from the public hearing in Washington DC on whether Avastin is a safe and effective drug in first line treatment of metastatic breast cancer after the Oncology Drugs Advisory Committee (ODAC) voted 6-0 against on all three questions (was Avastin effective, safe and should the indication continue to be upheld).

An overwhelming victory for CDER’s case rather than Genentech/Roche’s.

For those of you wondering whether there was any wriggle room for manoeuvre, take a look at the data for yourselves from the original ODAC meeting last year when the FDA reviewed it.  I put together the response rates and survival curves from the RIBBON1 and AVADO trials at the time, based on the publicly available data on the FDA site for all to see.

Essentially, the 5.5 month survival advantage seen in the original trial (E2100) that garnered approval was not confirmed, with the PFS in the follow up trials virtually disappearing.  The systemic side effects of the drug were however, repeated.  It should be noted that none of the three trials showed any improvement in overall survival, so patients sadly did not in fact, live longer on Avastin than with chemotherapy alone.

Like many people, I ardently wish the results were more positive and significantly so – we would at least have better options for women with breast cancer.  Sadly, they are not and the data wasn’t even close.  Had the two additional trials showed a 5 month benefit per the original E2100 trial that was used to support the initial approval, then I don’t think we would have seen the FDA move to suggest withdrawal of Avastin in December.  In fact, it would have been a clear slam dunk the other way.

It’s easy to say that some women benefited (they clearly did) and that some were harmed by the toxicities or did worse (that is equally clear), but as Francis Collins of the NIH recently said, “anecdote is not the plural of data.”

In the absence of any biomarker to help predict response or suggest who is most likely to benefit from treatment with Avastin, we are left with the totality of the aggregated data. This showed no overall benefit from the addition of Avastin to chemotherapy, even though we may sense that there must be something there to indicate who are the responders from the shape of the curve.  Indeed, after two years, the chemotherapy arm actually did better overall in the AVADO trial, as the arms crossed over.

Dr Len

If anyone wants to read the live public Twitter commentary, I highly suggest you check out Dr Len Lichtenfeld’s (American Cancer Society) tweets from the public hearing – a modicum of thoughtful sensitivity and accuracy in his reporting and colour commentary. He also writes a blog that is well worth reading.  Well done, Dr Len!

Finally, rather than suggest yet another confirmatory trial in metastatic breast cancer at the hearing today, I only wish Genentech had made this offer to the FDA last year when there was more flexibility – a public hearing at your request is hardly the best time for negotiation, but rather a review of the existing evidence.

It isn’t often I agree with the FDA 100%, but in the final analysis they called it correctly on this one.  It’s not over yet though, as FDA Commissioner Margaret Hamburg is expected to make the final decision soon.

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European Hematology Association meeting 2011

By on June 8, 2011

Well, after just getting back from the American Society of Clinical Oncology (ASCO) meeting in Chicago, I’m heading off to Europe for the European Hematology Association (EHA) meeting – no rest for the wicked!

ASCO was a rather flat meeting this year – the stars were undoubtedly the imatinib 36 vs 12 month data in adjuvant GIST (clearly superior) and Roche/Plexxikon/Daiichi Sankyo’s vemurafenib in BRAF V600E metastatic melanoma. The ipilimumab data was strangely disappointing in the upfront setting – only 2 months improvement in survival when added to DTIC.

On the Sarcoma front, the catch-all nature of the study came back to haunt Merck with an improvement in PFS but no overall survival benefit for ridaforolimus as maintenance therapy after 1-3 cycles of chemotherapy. That filing will likely result in a highly charged ODAC meeting debating the merits of some awkward results.

Ovarian cancer data was a mixed bag – olaparib continues to look promising in this setting, although the Avastin OCEANS data caught a few people by surprise – yet another PFS endpoint met but no overall benefit in survival and the expected incidence in bowel perforations. I think this will likely be reserved for high risk women, if used.

There was a lot of interesting/promising data in phase II, which are too numerous to mention right now – check back as I will be adding some notes on some of the emerging compounds that I liked.

Meanwhile, I’m aggregating the tweets from the hematology meeting using the #EHA11 hashtag – you can track them in the widget below if interested in following along remotely. Most of the tweets from me will likely be on leukemias, lymphomas and multiple myeloma.

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Glioblastoma recurrence after VEGF therapy: lack of rebound vascularisation as a mode of escape

By on January 3, 2011

One of my favourite journals, Cancer Research, has a new paper available via open access (i.e. free to the public, thank you AACR), which you can obtain from the link in the Reference section below.

It caught my attention because there was a fascinating symposium on angiogenesis at ESMO this summer with some heavyweight debates from Robert Kerbel (accelerated metastasis) and Lee Ellis (normalisation of tumour vessels) taking different viewpoints on the pros and cons of VEGF inhibition.  I took a few photos of the slides for private study and reflection, as they were going too fast for me to keep up with the key points with unreadable chicken scratch notes, but sadly my iPhone went missing in the exhibit hall less than an hour afterwards before I could download the photos :(.  That said, both sides argued with very compelling data for their perspective that I’m not sure which way I roll on the issue.

In this latest paper, di Tomaso et al., from Boston discuss the concept of recurrent glioblastomas and the tendency to relapse after VEGF therapy.  They noted that there are two current theories for how this might happen:

  1. Switch to VEGF-independent angiogenic pathways
  2. Vessel co-option

They therefore decided to investigate these mechanisms in patients with relapsed glioblastoma using a pan VEGF inhibitor, cediranib.  Now, it should be noted that cediranib (Recentin) is not yet approved and is a small molecule inhibitor, whereas another VEGF inhibitor, bevacizumab (Avastin), is a monoclonal antibody approved for relapsed GBM, so I’m sure why they didn’t use that instead.  It does make extrapolation of the findings a little more tricky though, as you cannot always assume a class effect.

Here are the key findings:

  • Endothelial proliferation and glomeruloid vessels were decreased
  • Vessel diameters and perimeters were reduced to levels comparable to the unaffected contralateral brain hemisphere
  • Tumour endothelial cells expressed molecular markers specific to the blood–brain barrier, indicative of a lack of revascularization despite the discontinuation of therapy
  • Cellular density in the central area of the tumour was lower than in control cases and gradually decreased toward the infiltrating edge, indicative of a change in growth pattern of relapsed GBM after cediranib treatment
  • Cediranib-treated GBMs showed high levels of PDGF-C (platelet-derived growth factor C) and c-Met expression and infiltration by myeloid cells, which may potentially contribute to resistance to anti-VEGF therapy

The authors therefore concluded that:

“rGBMs switch their growth pattern after anti-VEGF therapy—characterized by lower tumor cellularity in the central area, decreased pseudopalisading necrosis, and blood vessels with normal molecular expression and morphology—without a second wave of angiogenesis.”

Commentary:

What intrigued me in particular was not the lack of rebound vascularisation effect but the myeloid component.  Many of you will remember the AACR meeting last September on Molecular Diagnostics in Cancer Therapeutics, where AVEO presented data on their VEGF inhibitor in development and found that the myeloid component acted as a useful biomarker of response for tivozanib in renal cell cancer. You can read more about that here if you missed it.

This raises several interesting questions for me:

  1. Is the myeloid marker that AVEO found with tivozanib actually more useful and applicable to VEGF therapies in general?
  2. Does the myeloid component indicate acute inflammation, as we have seen with respiratory and other diseases?
  3. If PDGF and MET expression rise as resistance sets in, does that suggest logical combination therapies for the treatment of GBM?
  4. How can we better overcome the blood brain barrier, which is a physical impediment to improving outcomes.

Time will tell but clearly the research in relapsed GBM has a-ways to go before we figure out how best to approach it yet.

References:

ResearchBlogging.org di Tomaso, E., Snuderl, M., Kamoun, W., Duda, D., Auluck, P., Fazlollahi, L., Andronesi, O., Frosch, M., Wen, P., Plotkin, S., Hedley-Whyte, E., Sorensen, A., Batchelor, T., & Jain, R. (2011). Glioblastoma Recurrence after Cediranib Therapy in Patients: Lack of “Rebound” Revascularization as Mode of Escape Cancer Research, 71 (1), 19-28 DOI: 10.1158/0008-5472.CAN-10-2602

FDA moves to withdraw Avastin in breast cancer

By on December 16, 2010

Well, the long awaited decision by the FDA on bevacizumab (Avastin) in breast cancer has finally been published and is probably the least surprising decision by the agency in 2010:

“The Office of New Drugs (OND) recommends withdrawing approval of the breast cancer indication for bevacizumab (Avastin).  This indication was approved on February 22, 2008, under accelerated approval provisions for use in combination with paclitaxel for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer.

As a condition of the accelerated approval, Genentech was required to submit data from two ongoing trials (AVADO and RIBBON1) to provide verification of the treatment effect on progression free survival (PFS) and to provide additional information on the effects on overall survival (OS).  These two trials failed to confirm the magnitude of benefit originally observed in the E2100 study on which accelerated approval was based.  In addition, there was an overall increase in serious adverse events related to bevacizumab.

The modest benefit observed with Avastin together with the substantial adverse reactions observed in breast cancer trials to date fail to provide a favorable risk-benefit profile to support continued marketing of Avastin for a first-line metastatic breast cancer indication.  It is the conclusion of OND that the breast cancer indication for Avastin be withdrawn.”

Source: FDA

This is not a surprising decision following the recent ODAC vote of 12-1 to withdraw the drug for the treatment of breast cancer based on the AVADO and RIBBON1 trial results, which was discussed in detail previously on this blog.  The overall survival data actually showed a slight benefit in favour of the chemotherapy (docetaxel) only arm in AVADO, for example, (31.9 vs. 30.2 months).

Also of interest to many is the more results from the neoadjuvant trial with bevacizumab prior to surgery.   Negative trial results were announced at the San Antonio Breast Cancer Symposium last week, essentially adding another nail in the coffin for a solid rationale for earlier use in breast cancer.

For now, the drug will remain on the market and available in this indication, but the clear intent by the FDA is that they plan on withdrawal following the lack of confirmation for full approval.  The company, Roche/Genentech, have 15 days to request a hearing and judging by the press releases so far, this will be sought.  No doubt significant patient advocacy will also be mobilised in support.

There is no question that some women with breast cancer have benefitted from treatment with bevacizumab, but without a biomarker to determine who is most likely to respond to the therapy, it is difficult to see how it can remain on the market given three overwhelming negative trials demonstrating little overall benefit and some not insignificant risk of systemic side effects.

For me, though, what this body of data consistently shows is that, combined with the negative bevacizumab in adjuvant colorectal cancer, VEGF plays a much clearer role in metastatic disease such as colorectal cancer where the tumours are more vascular and often larger.  In breast cancer, the tumours are typically much smaller by comparison.  It may well be that we learn more about the process of angiogenesis from negative data and how tumours grow.  Angiogenesis is a highly complex process and we still need to learn how other growth factors such as PDGF, angiopoeitins, Tie-2 etc, may play a role in tumour growth.  This has yet to be elucidated but research is ongoing.  The recent post discussing cancer cell seeding teaches us that we have much to learn about the whole process of angiogenesis from early growth to metastasis.  VEGF is clearly not the only target involved.

Meanwhile, this developing story will clearly continue to unfold in 2011.  The New York Times has a different angle on this story, so check it out for yourselves.

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Time for FDA and ODAC to decide on Avastin in breast cancer

By on July 20, 2010

Today I will be out of the office at client meetings, but many of you will be wondering what will happen at the FDA ODAC briefing meeting, which will be discussing the bevacizumab (Avastin) data in breast cancer this morning. You can take a look at the briefing documents here.

Background

Avastin was approved to much fanfare because it was basically shown to shrink tumours quite dramatically and the early magnitude of the PFS data suggested benefit in favour of adding Avastin to chemotherapy.  According to the FDA, full approval would be thus debated once the final survival data were available:

“As a condition of the accelerated approval, Genentech was required to submit data from two ongoing, placebo-controlled trials (AVADO and RIBBON1) to provide verification of the treatment effect on PFS and to provide additional information on the effects on overall survival.”

According to the FDA documents:

“The addition of bevacizumab to paclitaxel resulted in a 52% increase in progression-free survival (HR 0.48, 95% CI 0.39, 0.61; p< 0.0001) with an observed 5.5-month difference in median PFS, based on an independent radiographic review.

There was no significant difference in overall survival, a secondary endpoint, between the two treatment arms. The tumor response rate was higher with bevacizumab plus paclitaxel as compared to paclitaxel alone (48.9% versus 22.2%).”

Breast cancer was one of the early tumour types that Genentech tested the drug in but despite promising phase II data, the phase III study was negative and thus they decided to go back to the drawing board with the statisticians and investigate the drugs safety and efficacy in another large scale phase III trial.  Meanwhile, colon cancer overtook breast cancer and became the first approved indication for Avastin instead.

Fast forward to 2010.

The data from AVADO and RIBBON1 is now available in the FDA briefing documents. Here is a quick synopsis from each.  I confess that I found the FDA summary of the data a little confusing, but the tables tell the picture more easily and have included the efficacy data tables from the briefing documents, where appropriate.

AVADO

This study comprised a double-blind, placebo-controlled, three-arm trial of:

  • docetaxel plus placebo
  • docetaxel plus bevacizumab 7.5mg/kg
  • docetaxel plus bevacizumab 15 mg/kg

with all therapies given on a standard three-weekly schedule.

A total of 736 patients with HER-2 neu negative tumors who had not received prior chemotherapy for metastatic breast cancer were enrolled.

Overall the data was summarised as follows:

Picture 3
Source: FDA (pdf link)

The OS Kaplan-Meier curve for the AVADO study looks like this – you can see that they cross over just coming up to two years:

image from img.skitch.comSource: FDA (pdf link)

The FDA went on to describe the tolerability data as thus:

“Safety data showed an increase of grade 3-5 adverse events, serious adverse events and study drug discontinuation with the addition of bevacizumab to docetaxel.  More patients in the bevacizumab-containing arms required interruption/dose reduction or discontinuation of docetaxel due to an adverse event.”

RIBBON1

This was a double-blind, randomized, parallel group study conducted in people with metastatic or locally recurrent HER2-neu negative adenocarcinoma of the breast, who had not received prior chemotherapy for their advanced or metastatic cancer.  A total of 1237 patients were randomized (2:1) to receive anthracycline or taxane-based chemotherapy (n=622) or capecitabine (n=615) in combination with either bevacizumab or placebo.

The efficacy data looks like this:

Picture 4Source: FDA (pdf link)

The FDA also summarised the side effect profile:

“Overall, the incidence of grade 3-5 AEs and serious AEs were almost twice as high in the bevacizumab arms compared to placebo arms in both cohorts. In the taxane/anthracycline cohort, taxane subgroup, there was slightly more deaths in the bevacizumab containing arm than placebo arm (49.8 % versus 43.1 %).

The vast majority of the deaths were attributed to breast cancer. Adverse events known to be caused by bevacizumab were, as expected, increased in the bevacizumab containing arms in both cohorts. The most common AEs associated with bevacizumab were hypertension, bleeding/hemorrhage and febrile neutropenia.”

Essentially though, the incidence of AEs is not significantly different than currently described in the prescribing information.

Overall Conclusions:

In the summing up to the ODAC committee, the FDA briefing document declares:

“AVADO and RIBBON 1 are well conducted, double-blinded trials.  The magnitude of the improvement in PFS observed in these two studies failed to confirm the magnitude of PFS improvement observed in the E2100 trial, the basis for the accelerated approval.

The magnitude of treatment effect is clinically important because it is really a measure of delaying symptoms from tumor progression, which has to be weighed against drug toxicity that is present for the duration of treatment.”

The short answer is that the overall survival data suggested hazard ratios favoring the placebo arms in the AVADO study and the taxane/anthracycline cohort of the RIBBON1 study.  This is important, because it raises the issue of risk:benefit because the women are being exposed to significant toxic side effects with no impact on overall survival.

What next?

Looking at the data from the two trials objectively, it is hard to justify treating women with newly diagnosed breast cancer with Avastin, when they would appear to live longer and have less side effects with chemotherapy alone.  The PFS effect seen in E2100 has not been confirmed at all.

Ultimately, I think Roche/Genentech would have a much better case to argue to the FDA and public if they had a biomarker to determine which patients are likely to do better on bevacizumab therapy, just as erlotinib works better in lung cancer patients who are EGFR mutation positive.

I wonder what ODAC will decide?

My educated guess is that one of two scenarios might happen:

  1. Approval remains, but modify the PI language similarly to Iressa to indicate that there is no overall survival advantage associated with adding Avastin to chemotherapy in breast cancer.
  2. Withdrawal of breast cancer indication for Avastin.

Technically, logic would suggest the latter option is more likely given the rules governing accelerated approval, but these panels are a notorious minefield sometimes, very hard to predict and the FDA doesn’t always follow their advice, as the original approval for Avastin in breast cancer demonstrated!

What do you think?

{UPDATE: My educated guess was correct – ODAC voted 12-1 to withdraw Avastin from the market.  The big question now is what will the FDA decide?}

{UPDATE 2: FDA decided to hold a public hearing, now scheduled for Weds June 29th, 2011}

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ASCO 2010 Preview #1

By on May 11, 2010

It's only 3 weeks to go to the Annual ASCO meeting in Chicago so I thought it would be a good time to kick off the annual preview of key data.  One of the things that sets the tone of the meeting is which abstracts are in the plenary session.  Sometimes I don't attend the session if it looks arcane, but this year looks really interesting and worthwhile attending.

The selected abstracts comprise the following:

#LBA1: Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or Fallopian tube cancer (FTC): A Gynecologic Oncology Group study.

#2: Weekly paclitaxel combined with monthly carboplatin versus single-agent therapy in patients age 70 to 89: IFCT-0501 randomized phase III study in advanced non-small cell lung cancer (NSCLC).

#3: Clinical activity of the oral ALK inhibitor, PF-02341066, in ALK-positive patients with non-small cell lung cancer (NSCLC).

#4: A phase III, randomized, double-blind, multicenter study comparing monotherapy with ipilimumab or gp100 peptide vaccine and the combination in patients with previously treated, unresectable stage III or IV melanoma.

Now, three of these trials promise some excitement.  The one I'm surprised about is the French Intergroup study looking at a taxane plus platinum in lung cancer.  In case anyone is wondering, the trial (link) states that:

"It thus seemed to us justified to compare a standard arm, the vinorelbine or the gemcitabine (with the choice of the center) in monotherapy with an experimental arm, association carboplatine + paclitaxel."

Carboplatin plus paclitaxel (with or without bevacizumab) is pretty much standard as first-line treatment for non-small cell lung cancer (NSCLC), so now we know that the doublet is likely more effective than single agent gemcitabine or navelbine in the elderly too, but for me all four are old drugs, likely available as generics and it's all an iteration of what we mostly know already.  I'm particularly interested in new and exciting agents that are coming through or new indications or more recent drugs as we see them expand their utility.

The results are no doubt important, but plenary important?  It could
have well led off an oral lung cancer session and received attention at
Best of ASCO perhaps, but for me, the plenary sessions should be
about groundbreaking new therapies or indications, which the other three
clearly are.

Still, the Korean study in ALK-positive people with NSCLC really gets my attention because we've only heard about a US study in the past, so seeing how this evolves Globally is vitally important.  Pfizer have done a nice job speeding this agent, PF-02341066 (crizotinib), through development having recognised the significance of the rearrangements and then invested significant resources to moving it forward.  They should be commended for that and I sincerely hope the results continue to be positive. 

What is also nice is that I've come across a few new ALK inhibitors at AACR and elsewhere that may work in patients where crivotinib stopped working, perhaps as a reult of new mutations.  This is an exciting area of research, even if it just affects a small subset of patients.  Cancer is a heterogeneous disease so researching and identifying different subtypes that can be then targeted with new therapeutics is critical.

After excitedly listening to the BMS R&D Day, I was expecting that ipilimumab might have a chance of a plenary with the melanoma data because the example they gave just took your breath away – this is what we all live for in cancer research – something that really makes a difference to the disease and makes you go, "oh wow!"  You can read more about that commentary here.  Roche and Plexxikon also have a promising compound in development (PLX4032) that targets BRAF.  At Roche's R&D Day, they noted that they planned to present the phase II data later this year at a melanoma meeting.  That's how the timing rolls sometimes.

The bevacizumab (Avastin) data in ovarian cancer was previously announced by Roche earlier this year to be positive, so this is excellent news for women with ovarian cancer.  I really look forward to seeing the results in full.  What's particularly important about this trial is that it is the first positive phase III study of an anti-angiogenic therapy in advanced ovarian cancer.  I think Judah Folkman would be mightily pleased with the progress of angiogenesis inhibitors such as Avastin so far, if he could see them.  It's all too easy to forget the visionaries in research and focus on the results.

For some reason, ovarian cancer always seems to be the poor cousin to breast and lung cancers and regimens that work in either tend to dribble down to ovarian cancer years later, but all three share many similar regimens.

From tomorrow, I'll start an ASCO series taking a look at some of the bionic biotechs with interesting data and a review of some of the big cancers and the potentially interesting data that may be worth highlighting and checking out.

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An overview of Roche's oncology pipeline

By on March 26, 2010

At last weeks investor meeting held by Roche in downtown Wall Street, the Board reviewed the pipeline opportunities in a number of areas.  Earlier this week I wrote about the non-oncology pipeline and today will form an overview of the cancer drugs in development.

One of the things that Roche is renowned for is life cycle management.  They do this better than many in the industry in my opinion and it makes an enormous difference not only to continuity, but also long term revenues and performance. Too many companies take a short term view and do not think ahead to the future. This is a big mistake. Perhaps they get bogged down in classic silos or management do not see it as a priority, but it does make a difference. 

Why?

Well, for starters, think about the basics of marketing. It is much easier to sell new products to existing customers than it is to sell existing products to new customers and even harder to sell new products to completely new customers.  

Thus life cycle management is a smart strategy and done well, enhances the experience for everyone involved whether employees or investors.  I only wish more companies paid closer attention to this important aspect of Pharma marketing.

The other thing I like about Roche's approach to R&D is rigorous and strong proof of concept studies (usually in phase II). Between Roche and Genentech, they both do this particularly well in oncology, it seems to be their signature. This partly explains why they mostly end up with a continuous wall of data across several products including trastuzumab (Herceptin), rituximab (Rituxan) and bevacizumab (Avastin). Of course, negative trials do occur but overall, they seem to have more positive trials than not. This partly explains why they have fewer phase III flops than say, Pfizer, because they spend the time in phase II working things out rather than rushing aggressively ahead on the basis of early evidence.

So what did we learn from the pipeline presentations last week?

There are late stage oncology products in development that look promising.

One example is trastuzumab-DM1, which is basically modified Herceptin with a potent cell killing agent, DM1, bolted on. The goal is to improve the action of Herceptin in metastatic breast cancer, and at the same time invetigate whether the xenograft data in a variety of cancers (breast, ovarian, lymphoma and prostate) with an armed antibody is an effective strategy in people. Recent phase II data from the San Antonio Breast Cancer Symposium in heavily treated women with metastatic breast cancer look encouraging. Phase III trials have already begun and if all goes well, filing is currently anticipated by 2012.

Also potentially strengthening the breast cancer franchise is pertuzumab, a monoclonal antibody that targets HER2. Early phase I trials in several cancer types produced so-so results, but more recent phase II data in breast (combined with Herceptin) and ovarian cancer (in combination with gemcitabine) published this month in JCO look interesting.

Perhaps the most exciting compound though, is PLX4032/RG7204, a BRAF inhibitor being evaluated in malignant melanoma. Currently available data suggests survival is improved by 6 months so the big question is what causes resistance to develop and how this can be overcome. Data on this compound is expected at ASCO, where many are keen to see how it stacks up with ipilimumab (BMS).

In hematologic malignancies, GA101 or galiximab is being evaluated in non-Hodgkin's Lymphoma (NHL) and chronic lymphocytic leukemia (CLL). It appears to target a different part of the CD20 isotope than rituximab and this may increase it's efficacy. Phase III trials began in 4Q09 thus it will be a little while before we see some results. There is clearly an unmet medical need in the 3rd line refractory disease for more tolerable agents and rituximab is very much the bedrock of treatment for both across multiple lines of therapy either alone or in combination with chemotherapy. A similar agent will likely have good take up with the right approach.

Genentech are investigating various new and improved approaches to angiogenesis, but these are in much earlier development and the bar is very high with bevacizumab (Avastin), even for the company who manufacture it. The list of anti-angiogenesis compounds that didn't make it to market is very long indeed.

I've left the best to last, as hedgehog (Hh) signalling is one of my favourite pathways – it always reminds me of the cheerful cartoon character, Sonic the Hedgehog. RG3616, licensed from Curis, is currently in phase II trials for advanced basal cell carcinoma and trials are also underway for medulloblastoma. If interested, you can find out more about the pathway and the science here.

Overall, the oncology pipeline has a nice mix of follow on compounds to strengthen life cycle management with a raft of monoclonal antibodies with different targets in new cancer types.  Such a strategy should reduce risk and drive the future bottom line if the promise delivers in phase III trials.

ResearchBlogging.org

Baselga, J., Gelmon, K., Verma, S., Wardley, A., Conte, P., Miles, D., Bianchi, G., Cortes, J., McNally, V., Ross, G., Fumoleau, P., & Gianni, L. (2010). Phase II Trial of Pertuzumab and Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer That Progressed During Prior Trastuzumab Therapy Journal of Clinical Oncology, 28 (7), 1138-1144 DOI: 10.1200/JCO.2009.24.2024

Makhija, S., Amler, L., Glenn, D., Ueland, F., Gold, M., Dizon, D., Paton, V., Lin, C., Januario, T., Ng, K., Strauss, A., Kelsey, S., Sliwkowski, M., & Matulonis, U. (2009). Clinical Activity of Gemcitabine Plus Pertuzumab in Platinum-Resistant Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer Journal of Clinical Oncology, 28 (7), 1215-1223 DOI: 10.1200/JCO.2009.22.3354

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Bench to Bedside: How can we speed up cancer drugs to the clinic?

By on March 18, 2010

After yesterday's post about the I-SPY trials in neoadjuvant therapy for breast cancer and how they may speed up the process of bringing new innovative cancer drugs to the clinic faster, I was reflecting on my own experiences with imatinib (Gleevec).   

The Philadelphia Chromosome was first identified in 1960 by Nowell and Hungerford. Gleevec was finally approved by the FDA in May 2001, 41 years later.   

Between 1999, when I arrived in the US and working in New Product Development at Novartis until 2001 when Gleevec was launched, I attended scientific meetings including AACR, ASH and ASCO. Often, Dr Judah Folkman, a scientific researcher from Harvard, would talk about angiogenesis and hypothesised that was the principal mechanism by which tumours grew. I listened to his ideas many times because I was curious and found the concept both fascinating and intuitive. There was a long line of drugs that failed to work though, and every meeting seemed to bring yet more negative results.

Now, Folkman first advanced the angiogenesis theory in 1971 in the New England Journal of Medicine, but it wasn't until 2002, when bevacizumab (Avastin), a VEGF inhibitor that prevented angiogenesis from happening, was finally approved for the treatment of colon cancer.   At that point you go, 'oh wow' and realise that Folkman's theory was indeed proven correct.

Thus a tale of two incredible cancer drugs that both took a relatively long time to evolve from scientific idea to effective treatment in people with cancer.  Or perhaps they were actually relatively 'quick' compared to others, but why it takes this long is something we can surely do better at. 

Last night I was researching ideas for drug development and innovation since the concept of bench to bedside fascinates me and came across this enlightening video from a lunchtime talk that Dr Susan Desmond-Hellmann gave last year at UCSF. Oddly, she seems to have trodden similar thought processes and asked why and how can we speed things up as well. 

The short lecture is well worth listening to for those interested in drug development – the good doctor explains the bench to bedside concept far better than I: 

Sources for scholars and clinical scientists:

The NEJM doesn't appear to go back beyond 1993 online, but the original reference to Folkman's article is at: 

Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182-1186.

A more recent one from 1995, which provides an update is available online at: NEJM

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