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Posts from the ‘Melanoma’ category

Update on RAF resistance in metastatic melanoma

“RAF inhibitors (vemurafenib and dabrafenib) have profound clinical activity in patients with BRAF-mutant melanoma, but their therapeutic effects are limited by the emergence of drug resistance.”

Solit and Rosen (2014)

For today’s post on Science Fridays, I wanted to take a look at an overview paper, published in Cancer Discovery, from two researchers in the metastatic melanoma field who have been looking at multiple mechanisms of resistance.  It’s an important topic because while we have seen incremental improvements in outcomes for this disease, the 5-year survival rate is still rather poor with only 10–20% of metastatic patients still alive by then.  This is not to disparage the efforts of scientists, clinicians or companies working in this space, far from it, but there is is clearly a need for new therapies, strategies and combinations, given the high unmet medical need that exists.

We still have a long way to go in moving the survival needle dramatically.

It wasn’t until I searched for related blog posts to link to this one that I realised how much we have already covered on this topic! Regular readers will recall discussions here on PSB on various combinations such as:

  1. RAF + MEK inhibitors (downstream resistance)
  2. RAF + PI3K-AKT-mTOR inhibitors (cross resistance)
  3. RAF + CTLA–4 checkpoint inhibitors (anti-tumour immunity)

to name a few examples.

We have seen that adding a MEK inhibitor to dabrafenib e.g. trametinib can overcome resistance temporarily and add a few extra months before the resistance sets in again. Similarly for PI3K inhibitors tested to date. Adding ipilimumab, an anti-CTLA–4 checkpoint inhibitor held much promise, but the combination was abandoned with the emergence of unexpected liver toxicity.

Results thus far suggest that something else is acting as an escape route, thereby enabling the tumour to continue driving oncogenic addiction to BRAF.

The $64K questions are what is happening and what can we do about it?

We also need to remember that clinical research advances piecemeal based on evidence from preclinical reseach, so we see the logical evolution of BRAF monotherapy -> combos with downstream (MEK) or upstream (NRAS) targets in same pathway -> combos with diagonal (PI3K) pathways etc.

What Solit and Rosen have done is put a nice summary together of the state of play in this disease and the paper (see References below) is well worth reading.

Their main assertion is interesting, namely:

“The common feature of each of these mechanisms of resistance is that they result in activation of ERK signaling that is insensitive to the RAF inhibitor. Thus, RAF inhibitor resistance is often associated with maintenance of activation of the oncogene-driven pathway.”

Two recent papers are cited in support of this theory from Shi et al., (2014) and Allen et al., (2014) – see References below for additional background reading. Both studies used patient samples to look at clonal evolution and the genetic landscape in advanced melanoma. It’s actually quite amazing what unbiased exome sequencing can uncover at the molecular level, not least are the development of new mutations and other functional alterations.

The Shi et al., (2014) study was briefly summarised by Solit and Rosen:

“Multiple biopsies were obtained at different times or from disparate locations from several patients, and more than a single lesion in the ERK pathway was identifi ed in multiple patients typically within
different tumor biopsies.”

They went to note:

“A detailed phylogenetic analysis of multiple progressive lesions from a subset of these patients suggested branching evolution of tumors in which the development of genetic diversity was not linearly associated with time.”

Previously, a case report found distinct mechanisms of BRAF inhibitor resistance were present in two different progressing lesions from a single patient, so the work of Shi et al., (2014) is consistent with this finding. It blows my mind that different lesions in the same patient might behave completely differently though – imagine trying to devise an appropriate and effective clinical strategy in these cases?!

Allen et al’s (2014) work also involved whole exome sequencing (WES) from patient samples:

“WES was performed on paired pretreatment and progression samples collected from 45 patients, of whom 14 developed resistance soon after initiation of therapy (within 12 weeks). They also detected several resistance mechanisms that had been previously identified to confer RAF inhibitor resistance, including mutations in NRAS , MAP2K1, and NF1 and BRAF amplification.”

A third important study in this area from Wagle et al., (2014) adds to the weight of evidence with new mutations developing. Solit and Rosen continued the story:

“Consistent with the preclinical studies highlighted above demonstrating that MEK1 and MEK2
mutations can confer RAF and MEK inhibitor resistance, a MEK2 Q60P mutation was identifi ed in 1 of 5 patients studied. Of greater surprise to the investigators, one patient had a BRAF splice variant lacking exons 2–10 and a second patient had BRAF amplification.”

By now, you can see the sheer variety of changes and adaptations taking place in different studies around the world in some of the top melanoma labs. What do they have in common though?

“One hypothesis to explain this result is that increased abundance of the oncogenic driver (in this case BRAF) in response to prolonged drug treatment results in increased flux through the ERK pathway and restoration of ERK activity above the threshold required for inhibition of cell proliferation.”

The next challenge is to figure how we can approach better therapeutic index and shutting down of the pathways?

“The results suggest that the early adaptive response of BRAF -mutant cells to ERK pathway inhibition may promote the selection of resistant clones that harbor additional genomic events that
confer higher levels of RAF inhibitor resistance. The data also support combinatorial approaches that attenuate the adaptive response, including the addition of a PI3K or AKT inhibitor to the RAF and MEK (or ERK) inhibitor combination.”

The problem with this approach though, is that the neither the BRAF nor PI3K inhibitors have been able to reach or go beyond the single agent dosing schedules:

“As previous attempts to combine MAPK and PI3K pathway inhibitors have been limited by overlapping toxicities, upfront testing of intermittent treatment schedules should be considered.”

This is the also approach that Das Thakur suggested in her work presented at AACR last year, and subsequently published in Nature, to delay the development of resistance to vemurafenib.

I do think this one area where we may well see new trials evolve in advanced melanoma, so we will have to wait for new data before we can see if the strategy is successful at delaying the emergence of resistant clones. It is good to see the evolution of solid preclinical and translational evidence from patient biopsies helping to inform future clinical trial strategies.

In the meantime, the next major milestone I’m waiting for is on Roche/Genentech’s MEK inhibitor, cobimetinib (GDC–0973), which is due to report combination data with vemurafenib (continuous dosing) later this year. It will be interesting to see if this inhibits MEK more completely than trametinib and whether the combination has a better initial outcome than dabrafenib plus trametinib, which added about two to three months of extra survival over dabrafenib alone.

References:

ResearchBlogging.orgSolit DB, & Rosen N (2014). Towards a Unified Model of RAF Inhibitor Resistance. Cancer discovery, 4 (1), 27–30 PMID: 24402945

Shi H, Hugo W, Kong X, Hong A, Koya RC, Moriceau G, Chodon T, Guo R, Johnson DB, Dahlman KB, Kelley MC, Kefford RF, Chmielowski B, Glaspy JA, Sosman JA, van Baren N, Long GV, Ribas A, & Lo RS (2014). Acquired Resistance and Clonal Evolution in Melanoma during BRAF Inhibitor Therapy. Cancer discovery, 4 (1), 80–93 PMID: 24265155

Van Allen EM, Wagle N, Sucker A, Treacy DJ, Johannessen CM, Goetz EM, Place CS, Taylor-Weiner A, Whittaker S, Kryukov GV, Hodis E, Rosenberg M, McKenna A, Cibulskis K, Farlow D, Zimmer L, Hillen U, Gutzmer R, Goldinger SM, Ugurel S, Gogas HJ, Egberts F, Berking C, Trefzer U, Loquai C, Weide B, Hassel JC, Gabriel SB, Carter SL, Getz G, Garraway LA, Schadendorf D, & Dermatologic Cooperative Oncology Group of Germany (DeCOG) (2014). The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma. Cancer discovery, 4 (1), 94–109 PMID: 24265153

Wagle N, Van Allen EM, Treacy DJ, Frederick DT, Cooper ZA, Taylor-Weiner A, Rosenberg M, Goetz EM, Sullivan RJ, Farlow DN, Friedrich DC, Anderka K, Perrin D, Johannessen CM, McKenna A, Cibulskis K, Kryukov G, Hodis E, Lawrence DP, Fisher S, Getz G, Gabriel SB, Carter SL, Flaherty KT, Wargo JA, & Garraway LA (2014). MAP Kinase Pathway Alterations in BRAF-Mutant Melanoma Patients with Acquired Resistance to Combined RAF/MEK Inhibition. Cancer discovery, 4 (1), 61–8 PMID: 24265154

Das Thakur M, Salangsang F, Landman AS, Sellers WR, Pryer NK, Levesque MP, Dummer R, McMahon M, & Stuart DD (2013). Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature, 494 (7436), 251–5 PMID: 23302800

Overcoming resistance to vemurafenib in metastatic melanoma

One of the interesting themes for that emerged for me at AACR this year was the amount of effort that is being expended on strategies to overcome drug resistance. This was particularly noticeable in metastatic melanoma and non-small cell lung cancer (NSCLC).  More on lung cancer in another post, as today I want to focus on melanoma.

In the advanced melanoma, vemurafenib is given to patients with the BRAFV600E mutation, which occurs in approximately 50% of patients. This oncogene drives activity of the tumour, but inhibition with vemurafenib (Zelboraf) has shown some remarkable effects, as the stunning before and after photos from Levi Garraway’s group demonstrate.

The challenge, however, is that adaptive or acquired resistance can occur in response to treatment and patients sadly find their melanoma returning after approximately 6-9 months on continuous daily therapy.

At last year’s ASCO, we saw that adding a MEK inhibitor such as trametinib to a BRAF inhibitor such as dabrafenib added around an extra 3 months over single agent BRAF therapy before the resistance set in and the disease returned, sometimes with a deadly vengeance.

I’ve written here on this blog about numerous mechanisms of resistance in advanced melanoma from MEK to COT and others (see related posts below for background reading).

The big question at this AACR was how is the field progressing with new research?

Sometimes, we have to go back to the lab to study animal models of resistance before returning to the clinic with new ideas.

Screen Shot 2013-04-15 at 2.54.50 PMThat’s what a young Novartis Postdoctoral fellow from NIBR, Meghna Das Thakur, did. She asked critical questions and attempted to answer them in a series of elegant experiments with mice as well as retrospectively test the concept in patient data. The cool thing is that while many of the oral sessions were taken up by the Major League researchers is that it’s also nice to see up and coming young scientists present some nicely done research.

What Dr Thakur did was really interesting…

Her hypothesis was simple – that resistant tumours are ‘less fit’ than sensitive cells and have a selective disadvantage over sensitive cells in the absence of drug.

If this were true then we would expect to see dependence on drug for growth of resistant tumours in xenografts, much as we do in humans, with vemurafenib. The data clearly showed that vemurafenib resistant tumours were dependent on drug for growth. They also observed that:

1) p-ERK levels increased following withdrawal of vemurafenib in resistant tumours
2) There was a great deal of heterogeneity in the mechanisms of resistance

The key question then becomes how can we use this information to prevent resistance?

One way to explore this is to look at selective pressure, since vemurafenib is usually given continuously…

  • Treating continuously means that selective pressure enriches resistant cells
  • However, withdrawing the drug means that resistant cells suffer a fitness deficit

Essentially, the researchers noted that, “alternating the selective pressure prevents the emergence of a resistant population.”

In comparing continuous vs intermittent dosing, two things could be concluded from the model:

1) Resistant tumours emerge more rapidly under continuous dosing with vemurafenib
2) Intermittent dosing in multiple tumor xenograft models forestalled resistance

What can we learn from retrospective patient data?

What they did next was to look at computed tomography (CT) scans analysed for evidence of vemurafenib-dependence in patients treated with vemurafenib in the BRIM-3 and vemurafenib safety study, which were identified from the clinical trials database at the Royal Marsden Hospital. In particular, they focused on patients who stopped treatment because of progressive disease (PD).

Of 42 patients identified, 19 of these had CT scans performed after cessation of vemurafenib available for review, while 23 patients did not have a CT available for review and in 16 patients this was because of rapid PD.

For each of those 19 patients with a post-vemurafenib CT, the total tumour volume on three consecutive CT scans was recorded:

  • The CT performed prior to stopping vemurafenib
  • The CT performed when progressive disease was diagnosed and vemurafenib stopped
  • The CT performed after vemurafenib was stopped and prior to the initiation of further therapy

They found that 14 of the 19 patients experienced decreased tumour growth rate following cessation of vemurafenib, supporting the hypothesis that resistant tumours emerge more rapidly under continuous dosing with vemurafenib.

In this model, it is clear that intermittent dosing prolongs survival, but what is the underlying mechanism, and what does this mean for future treatment of patients and also clinical trial designs?

From this initial work it was clear that the MOA is not yet fully understood and further bench work will be needed to elucidate the mechanisms involved.  We don’t yet know, as the researchers point out, whether:

“Does resistance come from a clonal population or is it an adaptation or re-wiring of a selected few cells?”

What was clearer though, is that new clinical research will be needed to evaluate the potential for intermittent vs continuous dosing in patients, particularly in combination:

  • Will there be greater selective pressure from BRAF + MEK inhibitor combinations vs BRAF alone?
  • Identify combination partners that could be used during BRAF inhibitor holiday.

Overall…

I thought this was a very nice piece of well thought out research, perhaps one of my favourites from the AACR meeting this year.  Critically, we saw that the preclinical mouse xenograft model predicted a clinically-relevant resistance mechanism. Removal of drug from resistant cells leads to MAPK pathway hyper-activation and resistant cells experience a fitness deficit. Cycling the mice on and off therapy led to better outcomes than if they were dosed continuously, thereby giving us a new strategy to consider in melanoma patients.

The main impact of this preclinical study is that future clinical research in advanced melanoma should investigate the value of intermittent dosing strategies to improve patient outcomes.

The work turns the old concept of continuous dosing 365/24 on its head – suppressing the BRAFV600E oncogene continuously in melanoma may not necessarily be the best strategy in terms of superior outcomes.

This this does NOT mean that ALL tumours will behave in a similar fashion and intermittent dosing should be tested first in clinical trials where there is sufficient scientific evidence to warrant it.  If I were a patient, considering drug holidays without any evidence of effectiveness would NOT be a good idea.

I’m really looking forward to seeing the results of future combination trials with intermittent dosing to see if outcomes are indeed improved beyond would we currently see with continuous dosing either alone or in combination.

 

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ASCO 2012 Update 2: Overcoming resistance in metastatic melanoma

By on June 29, 2012

Photo Credit: Sally Church Pharma Strategy BlogFollowing on from my preview of the 2012 American Society of Clinical Oncology (ASCO) meeting, I am now working through updates on some of the hot topics.

I’m delighted to announce The Chemical & Engineering News blog ‘The Haystack’, have published my second guest post on advances in metastatic melanoma.

This is a devastating disease that has seen very few advances over the last decade since the approval of dacarbazine (DTIC) until last year when the FDA approved two new therapies in vemurafenib (Zelboraf) for patients with the BRAFV600E mutation and ipilumumab (Yervoy), an immunotherapy that targets CTLA4.

Since then, we’ve realised that the inevitable happens – patients tumours become resistant to single agent TKI therapy because adaptive resistance pathways are activated and cross-talk with the MAPK kinase pathway often occurs.  The question of how we can improve on the encouraging results seen so far was explored in new trials in Chicago?

For those of you interested, you read my summary on The Haystack about the new developments in metastatic melanoma from ASCO, which includes dabrafenib, trametinib, anti-PD-1 and others.

For those who missed it, I also wrote a guest post about the ASCO 2012 data on overcoming resistance in non-small cell lung cancer.

May I take this opportunity to wish all my American readers a very enjoyable July 4th Independence Day weekend!

 

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

By 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:

ResearchBlogging.orgFalchook, 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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ASCO 2012 Preview – Highlights of key data emerging from Chicago

By 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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On adaptive mechanisms of crizotinib resistance in ALK-positive lung cancer

By on March 23, 2012

One of the biggest challenges facing cancer research was aptly summarised by Levi Garraway and Pasi Jänne in this month’s Cancer Discovery journal:

“All successful cancer therapies are limited by the development of drug resistance. The increase in the understanding of the molecular and biochemical bases of drug efficacy has also facilitated studies elucidating the mechanism(s) of drug resistance.”

It will therefore come as no surprise to PSB readers that resistance occurs with two drugs approved by the FDA only last year; vemurafenib (BRAFV600E melanoma) and crizotinib (ALK+ lung cancer). We’ve discussed the development of resistance in melanoma here via several potential mechanisms in the past and potential strategies for overcoming them (eg MEK inhibitors), but what about lung cancer?

Two recently published papers have shed some new light on this topic. Doebele et al., (2012) and Katayama et al., (2012) both looked at mechanisms of resistance associated with ALK-rearranged lung cancers.

What did the research show?

Both of these papers were published in March, but in separate journals.

Doebele et al., (2012) examined mechanisms of ALK resistance in EML4-ALK–positive non-small cell lung cancer (NSCLC) patients who had progressed while on crizotinib patients (n=11). The essence of their findings were as follows:

  • Four patients (36%) developed secondary mutations in the tyrosine kinase domain of ALK. Two of the patients exhibited a novel mutation in the ALK domain, encoding a G1269A amino acid substitution that confers resistance to crizotinib in vitro.
  • Two patients, including one with a resistance mutation, exhibited new onset ALK copy number gain (CNG).
  • One patient showed epidermal growth factor receptor (EGFR) mutant activity, without evidence of a persistent ALK gene rearrangement.
  • Two patients had a KRAS mutation, one of which occurred without evidence of persisting ALK gene rearrangement.
  • One patient showed the emergence of an ALK gene fusion–negative tumour with no identifiable alternate driver.
  • Two patients retained ALK positivity, with no identifiable resistance mechanism.

Meanwhile, Katayama et al., (2012) attempted to characterise acquired resistance, i.e. the adaptive resistance that occurs in response to treatment with a TKI. They also took biopsies from patients (n=18) with EML4-ALK–positive (NSCLC) patients who had progressed while on crizotinib. They found that in approximately a a quarter to a third of patients (22% to 36%) multiple mutations were found after sequencing of the ALK kinase domain exons. This resulted in amino-acid substitutions or insertions that are predicted to impair crizotinib binding. When this happens, the drug stops working and patients will relapse on therapy.

More specifically, there were:

  • Five patients (28%) had tumours with alterations in the ALK gene that were the underlying cause of the resistance.
  • There were four different somatic mutations within the ALK gene.
  • One case where the ALK gene was amplified.
  • One ALK mutation was highly resistant to all of the inhibitors examined.

In addition, they observed evidence of alternative mechanisms of resistance evolving, including activation of EGFR and KIT.

What do these results mean?

Firstly, it is striking that there are so many potential escape routes and mechanisms of adaptive resistance to crizotinib therapy.

Secondly, as Garraway and Jänne noted:

“Increased knowledge of drug resistance mechanisms will aid in the development of effective therapies for patients with cancer.”

However, while this is a true and accurate statement, I am left wondering how this might play out in clinical practice? By that, I mean how does a community medical oncologist, who sees the bulk of NSCLC patients go about incorporating this information? For now they can’t, as we are awaiting the results of numerous clinical trial readouts – hopefully there will be some at the annual ASCO meeting in June.

The sheer breadth of the heterogeneity also raises the issue of how will community doctors be able to process all this complex information and select patients for appropriate combination therapies based on numerous potential mechanisms of resistance. Biopsies aren’t always practical in these situations, but perhaps we may see the development of alternative methods of detection evolve in the future.

References:

ResearchBlogging.orgGarraway, L., & Janne, P. (2012). Circumventing Cancer Drug Resistance in the Era of Personalized Medicine Cancer Discovery, 2 (3), 214–226 DOI: 10.1158/2159–8290.CD–12–0012

Doebele, R., Pilling, A., Aisner, D., Kutateladze, T., Le, A., Weickhardt, A., Kondo, K., Linderman, D., Heasley, L., Franklin, W., Varella-Garcia, M., & Camidge, D. (2012). Mechanisms of Resistance to Crizotinib in Patients with ALK Gene Rearranged Non-Small Cell Lung Cancer Clinical Cancer Research, 18 (5), 1472–1482 DOI: 10.1158/1078–0432.CCR–11–2906

Katayama, R., Shaw, A., Khan, T., Mino-Kenudson, M., Solomon, B., Halmos, B., Jessop, N., Wain, J., Yeo, A., Benes, C., Drew, L., Saeh, J., Crosby, K., Sequist, L., Iafrate, A., & Engelman, J. (2012). Mechanisms of Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancers Science Translational Medicine, 4 (120), 120–120 DOI: 10.1126/scitranslmed.3003316

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The importance of metabolism in cancer research

By on March 6, 2012

Cancer metabolism is fast becoming an area to watch out for in R&D.  Last month I tweeted that I was attending a one day meeting at NY Academy of Sciences on Cancer Metabolism with keynote speakers Drs Lou Cantley and Craig Thompson. Jonathan Mandelbaum (@biotechbaumer) responded saying it looked like a dress rehearsal of another related meeting he was attending the following week. That was too good an opportunity to miss, so I invited Jonathan to consider guest posting a summary of the Keystone event he attended here on Pharma Strategy. I’m delighted to say he kindly took me up on the offer and what follows is Jonathan’s synopsis, including some references he chose to illustrate the key points, most of which are open access.

Jonathan has the honour of being the first formal guest post from an industry scientist, although the first informal one went to Al Lalani, Ph.D of Regeneron, who sent in an excellent and very amusing summary of last year’s ASCO abstracts.  The original guest post was from an industry analyst, Adam Bristol, Ph.D.

I hope to post more guest blogs here from scientists going forward, as they add variety and different perspectives on the evolution of the cancer R&D process.

Jonathan Mandelbaum

To give you all some brief background, Jonathan is currently a postdoctoral fellow at Millennium Pharmaceuticals, Inc. based in Cambridge, MA. He received his Ph.D. in Cellular, Molecular and Biophysical Studies from Columbia University. His thesis focused on understanding the functional consequences of recurrent genetic lesions in human diffuse large B-cell lymphoma. Prior to Columbia University, he obtained his Bachelor of Science from McGill University in Montreal, Canada and spent his summers as a research student at the Campbell Family Institute for Breast Cancer Research within the Ontario Cancer Institute.

The 2012 Keystone Symposia on Cancer and Metabolism was a hot meeting, albeit in the cold mountains of Banff, Canada. Research into how cancer cells rewire their metabolism to cope with increased energetic and biosynthetic demands has been reinvigorated in recent years, in large part due to several prominent researchers that were featured at the meeting, such as Craig Thompson, Lou Cantley, Reuben Shaw and David Sabatini.

Talks and posters from Agios Pharmaceuticals, Inc., Novartis, Pfizer and Millennium Pharmaceuticals, Inc., provided additional insight into how industry is thinking of translating these latest findings into novel therapeutics. Without getting into much detail (since much of the data remains unpublished), I will summarize some main themes of the conference and takeaway thoughts on future directions for drug discovery.

Central to the conference is the observation known as the Warburg effect, identified by Otto Warbug in 1924. Essentially, Warburg saw that cancer cells, despite being flush with oxygen, rely on aerobic glycolysis for their energy needs, resulting in an excess production of lactate. This phenomenon is common to normal proliferating cells, however, cancer cells have deregulated this process in part through activation of various oncogenic pathways (eg. PI3K, RAS-MAPK) and reliance on the M2 isoform of Pyruvate Kinase (PKM2) (see review by Vander Heiden et al., 2009). Many talks focused on how oncogenic activation of these pathways regulates the activity of different metabolic pathways (eg. glycolysis, the pentose phosphate pathway shunt, amino acid metabolism). For example, it’s known that cells transformed with MYC are dependent on glutamine metabolism for their survival (see Wise et al., 2008).

Is this metabolic rewiring simply an epiphenomenon of oncogene activation or is it truly important for tumorigenesis? Interestingly, mutations in several different metabolic enzymes have been found in certain cancers.  Fumarate Hydratase (FH) and Succinate Dehydrogenase (SDH), enzymes important for the TCA cycle, are inactivated by mutations in rare forms of cancer, implicating mitochondrial dysfunction in these tumors.  Additionally, recurrent gain-of-function mutations in isocitrate dehydrogenase (IDH1/2) have been found in a variety of tumor types, such as glioma and AML.  Most recently, PHGDH, an enzyme important for serine metabolism, was suggested to be the target of a locus recurrently amplified in melanoma (Locasale et al., 2011).

Several talks discussed how these mutations might be important for tumorigenesis. For example, FH-deficient renal tumors have a deregulated anti-oxidant response through activation of the Nrf2 transcription factor (Adam et al., 2011).  The authors suggest that increased fumarate in these cancer cells can promote a post-translational modification of proteins called succination, which can affect protein function.  Gain-of-function mutations in IDH1/2 result in excessive production of the metabolite 2-HG (Dang et al., 2009), which can inhibit the activity of histone demethylases, thus affecting the epigenetic regulation of gene expression (Figueroa et al., 2010).  At least for FH and IDH driven tumors, the common thread appears to be that metabolites can play critical roles in regulating a multitude of cellular processes outside of metabolism itself.

How might this basic research be translated into novel therapeutics?

Two obvious drug targets I mentioned, IDH1/2 and PKM2, are in fact drug programs being pursued by Agios Pharmaceuticals, Inc.  IDH1/2 presents an intriguing opportunity as the mutations are gain-of-function; drugs that can specifically target the mutant protein, akin to imatinib and vemurafinib, might be effective cancer therapeutics.

Although I did not discuss this topic, the autophagy pathway was another focus for several talks at the meeting. As this pathway is important for cells to cope with metabolic stress, and cancer cells face challenges such as hypoxia and nutrient deprivation, targeting autophagy might be a beneficial therapeutic strategy for cancer treatment.

Ultimately, understanding how different genetic dependencies in cancer reprograms cells to be specifically reliant on certain metabolic pathways, might provide synthetic lethal opportunities for drugs that target metabolic enzymes in those pathways.

From a drug discovery perspective, the conference highlighted for me two critical challenges going forward:

  1. What therapeutic window might exist for drugs targeting metabolic pathways? Jeff Rathmell emphasized an important observation that activated lymphocytes are dependent on glycolysis, similar to cancer cells, for their survival. Thus, agents targeting glycolysis might very well have immunological side effects.
  2. Many talks highlighted the plastic and redundant nature of metabolic pathways. Inhibiting one pathway can lead to adaptive flux through another pathway, or even drive metabolic enzymatic reactions in reverse, in order to compensate for that initial block. Understanding and overcoming these pathway redundancies (somewhat similar to the current state of signal transduction drug discovery) will be a key challenge going forward for cancer metabolism translational research.

Jonathan Mandelbaum is currently employed at Millennium Pharmaceuticals, Inc. The views expressed in this article are his own opinion and are not shared by his employer.

References:

ResearchBlogging.orgVander Heiden MG, Cantley LC, & Thompson CB (2009). Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science (New York, N.Y.), 324 (5930), 1029-33 PMID: 19460998

Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, Nissim I, Daikhin E, Yudkoff M, McMahon SB, & Thompson CB (2008). Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proceedings of the National Academy of Sciences of the United States of America, 105 (48), 18782-7 PMID: 19033189

Locasale JW, Grassian AR, Melman T, Lyssiotis CA, Mattaini KR, Bass AJ, Heffron G, Metallo CM, Muranen T, Sharfi H, Sasaki AT, Anastasiou D, Mullarky E, Vokes NI, Sasaki M, Beroukhim R, Stephanopoulos G, Ligon AH, Meyerson M, Richardson AL, Chin L, Wagner G, Asara JM, Brugge JS, Cantley LC, & Vander Heiden MG (2011). Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nature genetics, 43 (9), 869-74 PMID: 21804546

Adam J, Hatipoglu E, O’Flaherty L, Ternette N, Sahgal N, Lockstone H, Baban D, Nye E, Stamp GW, Wolhuter K, Stevens M, Fischer R, Carmeliet P, Maxwell PH, Pugh CW, Frizzell N, Soga T, Kessler BM, El-Bahrawy M, Ratcliffe PJ, & Pollard PJ (2011). Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer cell, 20 (4), 524-37 PMID: 22014577

Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden MG, & Su SM (2009). Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature, 462 (7274), 739-44 PMID: 19935646

Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar A, Fernandez HF, Tallman MS, Sun Z, Wolniak K, Peeters JK, Liu W, Choe SE, Fantin VR, Paietta E, Löwenberg B, Licht JD, Godley LA, Delwel R, Valk PJ, Thompson CB, Levine RL, & Melnick A (2010). Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer cell, 18 (6), 553-67 PMID: 21130701

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A year in the life of Pharma Strategy Blog

By on October 31, 2011

Last week brought the first anniversary of this blog since moving to WordPress as a platform, but as luck would have it, I was snowed under with more work than usual.

Several people have asked about the stats here recently, so it seems a good time as any to do an annual review. Although this blog has been up and running since 2006, it only started on WP on October 24th 2010.

In the last twelve months, PSB has seen the following activity:

  • 614K reads, with around 50-60K reads per month
  • 337K visitors, approx. 30K visitors per month

The busiest day was 6th June, with nearly 5K reads, thanks to a kind link from Matt Herper of Forbes Health.  Ironically, the interim and eagerly anticipated MDV3100 phase III data from Medivation is now due before the end of the year.  More on that when the announcement comes out!

What were the most popular posts? Here’s the Top Ten on Pharma Strategy Blog from the last year based on hits:

  1. PI3K: a hot topic in cancer research
  2. Update on PARP inhibitors
  3. PLX4032 phase III data in metastatic melanoma
  4. Improved survival with ipilimumab in metastatic melanoma
  5. Crizotinib and ALK rearrangements: Ross Camidge interview
  6. Abiraterone/Zytiga FDA approval
  7. Interview with Charles Sawyers
  8. PLX4032 in metastatic melanoma
  9. Update on PI3K from ASCO
  10. Brentuximab Vedotin (SGN-35) for Relapsed CD30-Positive Lymphomas

In some ways, the popularity of these particular posts are no surprise, since if you asked me to name the hot topics in oncology this year, I would have said:

  • ALK in lung cancer
  • BRAF and CTLA4 in melanoma
  • Abiraterone in advanced prostate cancer
  • ADCs and brentuximab

It wasn’t all positive though, as the ongoing PARP story has been notable largely for the negative data. That may change in the future as scientists and clinicians grapple with finding the right targets and sub populations to aim these therapies at.

I was particularly pleased to see that PI3K resonated with the audience as this one of my favourite pathways, although we still have a long way to go to crack the nut with this target.

A big thank you to everyone who read PSB, posted comments, shared articles or the many email exchanges that have taken place; it is much appreciated and I hope that you have enjoyed reading my thoughts and commentary.

Come December, I will post the annual review and predictions for 2012, but in the meantime, normal blog commentary on cancer related topics will resume tomorrow.

When is NICE is not so nice?

By on October 14, 2011

“Ipilimumab is not recommended for the treatment of advanced (unresectable or metastatic) malignant melanoma in people who have received prior therapy.

The Committee was satisfied that ipilimumab meets the criteria for being a life-extending, end-of-life treatment and that the trial evidence presented for this consideration was robust.

The Committee acknowledged that few advances had been made in the treatment of advanced melanoma in recent years and ipilimumab could be considered a significant innovation for a disease with a high unmet clinical need.

Despite the combined value of these factors the Committee considered that the magnitude of additional weight that would need to be assigned to the QALY gains for people with advanced (unresectable or metastatic) melanoma would be too great for ipilimumab to be considered a cost-effective use of NHS resources.”

NHS NICE Guidance

In other words, it’s too expensive and the NHS doesn’t want to pay the £80K ($120K) sticker price. This news is no great surprise given the cost-benefit ratio when considering that there is no way to tell who might benefit most from treatment upfront.

The is, however, a huge difference between hope and false hope, as NPR Shots astutely noted when discussing Avastin in breast cancer earlier this week and in some ways that sentiment applies here too. By this I mean it would be much more compelling to both patients and NICE if an oncologist could talk about a new therapy in specific and useful terms.

Examples of doctor-patient conversations about treatment in the near future might look more like this….

Either:

“You have an 70-80% chance of responding to this therapy because you have X (mutation, translocation, biomarker etc), where this drug has been shown to be highly effective and extends life by over 2 years in many of our advanced patients with this disease to date.”

Or:

“This drug may do more harm than good in your case, as it has been shown to effectively target X (mutation, translocation, biomarker etc), which you do not have, and therefore, are unlikely to respond. I believe it would be better to consider these alternatives in your situation… “

We all know about heterogeneity – it’s the very underpining of what makes a cancer survive despite our best efforts to tame it until we can subset into more homogenous and predictable groups.  This means that offering a broad therapy to all patients with a given advanced cancer without any idea of its predictive value is fast becoming a misnomer in today’s world of emerging targeted therapies.  Now, manufacturers (marketers even) might think it’s better not to ‘limit’ their market opportunity, but the reality is many healthcare systems are looking at ways to limit treatments to where it’s needed most, not only for cost reasons, but also to direct resources where they are more likely to work. The current model is not sustainable in the long run.

Of course, if a predictive biomarker was available to determine which patients are more likely to respond to ipilimumab, then the QALY calculation would be considerably different, and possibility even within the realms of the current guidelines.

That’s a whole different ballgame, but hopefully one that will begin to emerge as we have seen with new targeted therapies such as vemurafenib (Zelboraf) in BRAF V600E malignant melanoma, crizotinib (Xalkori) in ALK-positive advanced lung cancers and everolimus (Afinitor) in combination with exemestane in ER/PR+ HER2- breast cancers that have relapsed after initial aromatase inhibitor therapy.

It will be interesting to see how NICE handles all of those situations in the future, since they are all targeted agents showing a significant impact on a patients ability to live longer,with a more precise, and therefore, limited patient definition.  As a Brit and a scientist, I may have reasonable expectations that NICE will make a rational and logical decision in the face of limited resources, but this is also tinted with a large dose of healthy scepticism after the trastuzumab (Herceptin) debacle in HER2-positive breast cancers that lead to the utterly ridiculous and unfair post code lottery in the UK.

We are not talking absolute costs here, but the relative costs of seeing real efficacy benefits of six months or more in those patients most likely to respond, while at the same time giving an offering that truly extends life in a meaningful fashion without exposing too many to the toxic side effects of a given treatment. Dealing with cancer is tough enough without being treated with a regimen that had absolutely no hope of helping people live longer and feel better.

Zelboraf approved by the FDA in BRAF V600E metastatic melanoma

By on August 17, 2011

This morning the FDA approved vemurafenib (Zelboraf), along with it’s companion diagnostic, for the treatment of metastatic melanoma in patients with the BRAF V600E mutation.

This is great news!

The approval has been granted ahead of time, as correctly mentioned in the Reuters article recently. This means we now have two new therapies for the treatment of metastatic melanoma after ipilimumab (Yervoy) was approved in March.

These two new drugs have been rapidly approved within the space of a couple of months following the presentation of the data at the ASCO plenary session in June.

Very little has changed in this landscape since the original approval of dacarbazine (DTIC) many years ago, but the good news is that oncologists now have two new agents to consider for treatment in 2011, which is very much a grand cru year for melanoma.

Zelboraf (link to PDF of the PI) differs from Yervoy in that it is not an immunotherapy to CTLA4, but a small molecule tyrosine kinase inhibitor that targets BRAF and more specifically, one of the mutations driving the disease, V600E.  This mutation is seen in approximately half of patients with metastatic melanoma.  The companion diagnostic (from Roche’s diagnostic division) will enable oncologists to test patients upfront and determine who should receive the therapy since the clinical results have only been demonstrated in those with the mutation.

The hot question is what is the price?

Well, according to Roche/Genentech, the monthly price of Zelboraf will be $9,400 and assumes an average of ~6 months of treatment based on the progression-free survival (PFS) data reported in the phase III BRIM3 (5.3 months) and phase II BRIM2 (6.1 months) studies. The overall survival had not been reached at that time. This means the course of treatment with Zelboraf will be approximately $56,400, but will obviously depend on how long it is taken for.  The comparative cost of treatment for ipilimumab for four infusions is $30K per infusion or $120K per full course.

In addition, the cost of the diagnostic test will likely vary depending upon the laboratory, but it is expected will be determined by the test volume and contract framework established with the laboratory.  The Average Selling Price (ASP) for the cobas BRAF test will be ~$120-150 per test in the US, which is very reasonable.

All in all, news like this will bring a smile to many today – it’s always good to hear of new drugs that make a difference to the lives of cancer patients.

 

 

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