The American Society of Clinical Oncology (ASCO) held their annual symposium on Gastrointestinal cancers over the weekend in Fort Lauderdale, FL. I was unable to attend the meeting, but it was interesting to follow it remotely via various people at the event.
In 2008, van Cutsem first presented the interim phase III data from the front line trial of cetuximab
(Erbitux) with FOLFIRI in metastatic colorectal cancer (mCRC) in a plenary session at the ASCO annual meeting. The data demonstrated that biomarker data suggested that the presence of wild type rather than mutant type KRAS predicted response to cetuximab in mCRC.
The updated CRYSTAL data was
probably the most anticipated abstract at this meeting. Here's a snapshot from the abstract:
The data above clearly shows a superior response rate, progression-free survival (PFS) and overall survival (OS) in favour of cetuximab in wild type KRAS.
What was also interesting is that BRAF, another mutation that has been shown to increase resistance to EGFR inhibitors, was not predictive of cetuximab activity, based on pooled data from the CRYSTAL and OPUS trials presented by Prof Kohne.
Overall, these data indicate that testing for KRAS mutational status is a valid way of deciding which patients should receive EGFR inhibitors such as cetuximab for the treatment of metastatic colorectal cancer. Patients with mutant KRAS or BRAF mutations are less likely to do well on such therapy.
It will be interesting to see whether future trials with a RAS/RAF inhibitor such as sorafenib (Nexavar) with cetuximab are being considered in combination to overcome resistance.
{Updated: I should clarify that the wt KRAS effect is an EGFR class effect as you can see from similar data on panitumumab (Vectibix) in the second line setting in this abstract.
The presenter, Peeters, noted that in patients with wild type KRAS:
PFS was 5.9 months for panitumumab plus FOLFIRI
vs. 3.9 months for FOLFIRI alone (HR=0.73).
Median OS was
14.5 months for the study arm vs. 12.5 months for FOLFIRI alone
(HR=0.85).
Response rate for the panitumumab arm was
35% compared with 10% for patients assigned to FOLFIRI alone.
As with cetuximab, there was no difference in PFS, OS or
response rate in patients with mutant KRAS tumours. The study met its primary endpoint, so it will be interesting to see if regulatory approval will be forthcoming in the second line setting for panitumumab.}
Acknowledgement: Many thanks to Kerri Wachter who was at the meeting and provided information and tips that lead to this post.
One of the great things about travelling to scientific conferences around the world, is catching up with old friends, meeting new people, learning new things and also seeing some wonderful sights when least expected.
Here's a quick shot I took at dusk on my 3G iPhone took walking from
the bus stop to the hotel I was staying in for the recent AACR meeting
on molecular origins in lung cancer.
It was nice to get out at the end
of the day for some fresh air, but the sunset was certainly an added bonus and a heartening welcome after the chill of the East coast winter!
Some meetings you can get a decent flavour of what's going on from the press releases and reports coming out from good science writers, reporters and analysts such as Brooke Wang, Kerri Wachter, Mike Huckman and Roxanne Nelson. You can't attend every conference, but you can trust in a few good men (and women) to tell the stories in a straightforward and accurate way.
After a while, I can tell who is actually reporting live from the meeting and who is just rehashing a press release or media briefing – the quality of the reporting and analysis shines through beyond mere data repetition :>}.
One of the biggest things I personally gain from being on the spot is the chance to interact with key opinion leaders and ask them questions. Of course, you can do this by email or phone too, assuming you can track them down in a timely fashion, but checking the nuances on the spot is extremely valuable both for greater understanding and immediacy.
Right now, I'm following the ASCO Gastrointestinal Cancer Symposium from Fort Lauderdale on Twitter via the #GICaSymp hashtag. Kerri is tweeting and reporting from there and several Pharma buddies are also attending and sending updates by email. I'm particularly keen to hear what Dr Eric van Cutsem has to say in his update about KRAS and biomarkers from the CRYSTAL trial in colorectal cancer.
The stunning press release from Amgen today announcing that Vectibix did not meet statistical significance for overall survival (OS) in the 1st line colorectal cancer (CRC) trial with patients who had wild type KRAS mutations was a total shock after it had previously met it's primary endpoint of progression free survival (PFS) earlier this year based on the data presented at the ECCO/ESMO conference.
It has previously been shown that CRC patients with mutated KRAS do not respond to EGFR kinase inhibitors whereas those with wild type mutations do, so one would expect the selected patients to do well and chances of success are increased. However, although the Vectibix arm did better, the result was not significant:
"The prospective analysis of the 203 study showed that Vectibix, when added to a FOLFOX chemotherapy regimen in patients with KRAS wild-type mCRC, resulted in a median overall survival of 23.9 months compared to 19.7 months for patients treated with FOLFOX alone. The median overall survival difference of 4.2 months in the Vectibix arm did not reach statistical significance (HR=0.83, p=0.072)."
Interestingly, according to the newswires some analysts appear to be claiming that regulatory approval and successful sales growth was still possible:
"We believe the positive trend coupled with a robust [progression free survival] benefit will be adequate to support regulatory approval," J.P. Morgan analyst Geoffrey Meacham wrote in a note to clients.
He said that "modest" use of Vectibix in new patients, and an increase in patients who failed previous treatment, could boost his 2012 sales view of $445 million by about $300 million.
Neither Vectibix, nor Erbitux, another EGFR inhibitor from ImClone, are approved for the treatment of newly diagnosed colorectal cancer.
We'll see what the regulatory authorities have to say about the Amgen data. Strategically, however, given that most medical oncologists look at OS as the gold standard that was not met in the patient population most likely to respond, I think it will be hard for Vectibix to gain any real traction in the first-line setting for this disease against Genentech's Avastin even if it is approved, especially when you factor in a more costly therapy and a very nasty rash as a potential side effect.
My own view is that the negative OS result is likely to be more of a death knell in newly diagnosed colorectal cancer for Amgen, but time will tell.
This week I'm snowed under with work, so was unable to attend the ECCO/ESMO conference, but have been following the key updates on Twitter and via press releases. Here are a few snippets of data I found interesting and some analysis/commentary:
1) Bayer announced some updated Phase II data with Nexavar (sorafenib) in breast cancer.
They found that when combined with Roche's capecitabine, it makes a significant difference to the time women live without their disease worsening.
Pfizer's Sutent (sunitinib) also had positive Phase II data in breast cancer in the past, before concluding that the Phase III data was unlikely to show a significant effect. We should therefore probably wait for the phase III sorafenib data before getting over excited.
2) The PI3K pathway might be as a factor in poor response or resistance to HER2-inhibitors such as trastuzumab.
"Of the 8,000 genes tested, we found that only knock down of PTEN conferred resistance to Trastuzumab. Decreased PTEN expression results in hyper activation of the PI3K pathway. Significantly, activating mutations in the gene encoding the p110a catalytic subunit of PI3K (PIK3CA) have been identified in some 25% of primary breast cancers potentially mimicking the effects of PTEN loss. Indeed, overexpression of the breast cancer-derived mutant PIK3CA (H1047R) also conferred resistance to Trastuzumab in cell culture. These findings are consistent with a major role of the PI3K pathway in the development of resistance to trastuzumab."
It makes sense to consider a) predict whether patients are likely to respond to therapy upfront and b) consider multiple therapies to overcome the development of resistance.
3) Impact of microsatellite instability (MSI) positivity and the presence of KRAS and BRAF mutations on colon carcinoma patients.
It has been observed in the past that stage III colon carcinoma patients with the BRAFV600E mutation had a significantly worse prognosis, based on the results of a study that aimed to assess the impact of microsatellite instability (MSI) positivity and the presence of KRAS and BRAF mutations on colon carcinoma patients.
The current study reported on 258 patients with stage III colon cancer who were treated with surgery followed by a 5-fluorouracil-based adjuvant therapy. KRAS mutations in codons 12 and 13 were determined by PCR followed by direct sequencing, and MSI status was determined by typing the BAT 26 marker (positive in 99% of MSI-positive white patients). It was concluded that tumor mutational status should be determined to predict survival more accurately in patients with colon carcinoma.
We will probably hear more about BRAF as a predictive marker in CRC, in addition to the KRAS mutation that was all the rage at ASCO earlier this year. Predicting responses to therapy is one thing, but the real need for patients going forward, is to find new therapies that will overcome the resistance induced by these mutations.
4) Is Iressa (gefitinib) making a comeback in NSCLC?
Two interesting abstracts (O9002 and O9003) demonstrated that analysis of four phase III trials comparing gefitinib monotherapy (250 mg orally per day) versus chemotherapy (docetaxel alone or carboplatin/docetaxel) produced marked efficacy of gefitinib in NSCLC patients with EGFR mutations. The benefits of gefitinib in prolonging progression-free survival (PFS) were even greater in Asians with mutations than in non-Asians with mutations.
It is good sense that EGFR testing should be performed in NSCLC patients in order to select for therapy and ensure that those most likely to respond are treated. There is little point in giving a drug to patients who are unlikely to respond, so the value of biomarkers is clearly demonstrated in this setting.
5) Bayer's shows activity in renal cell carcinoma
In addition to sorafenib, Bayer also have an oral multikinase inhibitor, regorafenib (BAY 73-4506), in development, which produced disease regression or stabilization in 81% of patients in 1st-line treatment of patients with metastatic or unresectable RCC
"Of 48 patients evaluable for efficacy, preliminary data indicate a partial response (PR) in 33% (23% confirmed PR) and stable disease in 46% of patients."
Renal cell carcinoma is fast becoming a) a useful tumour type for testing proof of concept for new drugs in development, but that also means that b) that the market is becoming very competitive for such a small indication. I'm not sure what Bayer would usefully gain by having two such products on the market in the same tumour type, since it potentially cannibalises their sorafenib market share.
6) Amgen's motesanib (AMG-706), a VEGF inhibitor looks active in metastatic breast cancer
"Motesanib in combination with P (paclitaxel) or D (docetaxel) appears to be tolerable and shows evidence of antitumor activity in pts with advanced breast cancer. Coadministration with either P or D had no major effect on motesanib PK."
I've been following this agent for a little while as it started cropping up in searches for clinical trials in multiple tumor types. It appears to target VEGF, KIT and PDGF. Poster PD-5029 is a dose finding study, so the emphasis is on adverse events and tolerability rather than efficacy, but 28-29% response rates this early are interesting at this stage. This is one agent I'll be following more closely as more results are published in the future.
There are probably some other interesting abstracts out there, but those are the ones that caught my eye in the news this week. Anyone who saw some other data is welcome to mention or discuss them in the comments below!
The white whales were victims of intestinal cancers caused by industrial pollutants released into the St. Lawrence River by nearby aluminum smelters.
Now research points to environmental pollutants as the cause of deadly cancers in several wildlife populations around the world. Normally rare in wildlife, cancers in California sea lions, North Sea flounder and Great Lakes catfish seem to have been triggered or accelerated by environmental contaminants.
Other animals, including Tasmanian Devils, sea turtles, woodchucks, eels and sperm whales, also have been stricken with cancers, although they appear to stem from natural causes, including viruses, spontaneous tumors, or genetic factors.
In some cases, the survival of a species and the stability and biodiversity of an ecosystem is jeopardized. The cancers also highlight the dangers that industrial activities pose – not just to animals, but to people in the same areas, exposed to the same compounds.
Cancer is very rare in animals, it's pretty much a man-made disease in various guises.
What then, of the people who worked in the surrounding region in Quebec? Well, it seems people who worked in smelters near the cancer-stricken belugas have reported many cases of lung and bladder cancers linked to coal tar exposure at the factories. Other residents have high rates of digestive tract and breast cancers.
This is an interesting SciAm article worth reading and reflecting on.
That was the lead headline screaming from my intelligence database this morning, from several sources. On checking the Pfizer website, to verify the information, I found the following in a terse press release:
"Pfizer Inc announced today the discontinuation of the SUN 1122 Phase 3
trial that evaluated Sutent® (sunitinib malate) plus FOLFIRI
(irinotecan plus infusional 5-fluorouracil and leucovorin) versus
FOLFIRI alone for the first-line treatment of metastatic colorectal
cancer (CRC). The independent Data Monitoring Committee (DMC) found that
the addition of sunitinib to the chemotherapy regimen FOLFIRI would be
unable to demonstrate a statistically significant improvement in the
primary endpoint of progression-free survival (PFS) compared to FOLFIRI
alone, in this study. No new safety issues were identified."
It would therefore seem that small molecule TKI's are not the way to go with this disease given that Novartis' vatalanib also failed in phase III trials of a similar nature. Genentech's Avastin acts differently, targeting the outside of the receptor as a monoclonal antibody.
For Pfizer, this represents another major setback with Sutent after the recent failure in breast cancer studies. Prior to that, the company terminated two other compounds in phase III development, namely, esreboxetine for fibromyalgia and PD 332,334 for generalized
anxiety disorder (GAD) so 2009 is not turning out to be a stellar year for them.
Chasing blockbusters is clearly not all it is cracked up to be.
Contrast Pfizer's experiences with Novartis approach by following the science rather than the money in a Business Week article. Ilaris, an IL-1 inhibitor, has just been approved by the FDA for a rare autoimmune condition known as Muckle Wells disease. This development follows a similar strategy to that taken by the company with the development of Gleevec, ie focusing on the biology of the disease and finding a targeted drug aimed at the critical mutation. The result? Over 90% of children and adults suffering from the immune disorders
that the drug was designed to treat experienced rapid, sustained
remissions.
After the recent success of Genentech's Avastin (bevacizumab) in metastatic colorectal, lung, breast and brain cancers, it was a little surprising to hear that the adjuvant data in colorectal cancer missed the mark, with the survival data not showing a significant benefit to the Avastin arm. The Genentech press release announced:
"Results from a phase III study of Avastin® (bevacizumab) plus six months of
chemotherapy following surgery in patients with early-stage (adjuvant)
colon cancer (NSABP C-08). The study showed the addition of one year of
Avastin to chemotherapy did not result in a statistically significant
improvement in overall disease-free survival (DFS), the primary
endpoint, compared to chemotherapy alone after surgery. Patients who
received Avastin plus chemotherapy had a lower risk of the cancer
returning during the year of treatment, however, the improvement
diminished over the course of the study. No new safety signals for
Avastin were observed."
At the Genentech ASCO press briefing, the lead investigator, Carmen Allegra noted that six events separated the study from meeting the early-stopping rule at one year. It was that close. The one year data showed plenty of hints of significant survival but by the pre-specified three-year endpoint, when there were 603 events,
disease-free survival had ceased significance. The end result
for Avastin was 77.4% versus 75.5% for standard chemotherapy alone.
The difference between taking a look at the interim data and the final analysis clearly shows the benefit of long term follow up in the adjuvant setting because things may not always be as they seem. It will be interesting to see futher analyses to see if any particular subsets responded better to the combination treatment with Avastin.
Meanwhile, VEGF as a pathway has had a somewhat chequered history since Judah Folkman first elucidated angiogenesis as a potentially important pathway in how tumours grow and survive. Numerous compounds have entered the clinic with great fanfare, but successfully navigating the treacherous R&D waters through to phase III/IV has proved problematic. The latest interesting molecule is AstraZeneca's Zactima (vandetanib, ZD6474), a dual-acting TKI that targets VEGF receptor-2 (KDR) and EGFR. It is currently in phase III development for lung cancer and phase I/II trials are ongoing in colorectal cancer, medullary cancer and others.
The big news with this agent at ASCO earlier this month was the ZODIAC, ZEAL and ZEST trial data in advanced NSCLC.
ZODIAC is a randomised, double-blind, placebo-controlled Phase III
study evaluating the combination of vandetanib 100mg with docetaxel
versus docetaxel alone. The study enrolled 1391 patients previously
treated with one prior anti-cancer therapy for advanced NSCLC. Results presented by Roy Herbst et al., showed that the study met its primary endpoint and the addition of vandetanib to docetaxel resulted in a
statistically significant improvement in progression-free survival
(PFS), the length of time a patient lives without their cancer growing:
PFS 14.0 weeks vs. 17.3 weeks (HR 0.79; P<0.001) in favour of vandetanib.
An update on the survival data is expected be available later this year.
ZEAL (ZACTIMA Efficacy with Alimta in Lung cancer) is a randomised, double-blind, placebo-controlled Phase
III study evaluating the combination of vandetanib 100mg with
pemetrexed versus pemetrexed alone in patients with locally advanced or
metastatic NSCLC, treated with one prior anti-cancer therapy. It
enrolled 534 patients at 160 centres across 23 countries.
The data from ZEAL followed the same trend of ZODIAC, although the primary endpoint
did not reach statistical significance in the study, despite median PFS of 11.9 weeks vs.
17.6 weeks in favour of the vandetanib plus pemetrexed arm (HR 0.86, P=0.108).
Secondary endpoints in the ZODIAC and ZEAL studies were also reported. They showed
that addition of vandetanib to chemotherapy significantly improved
objective response rate, a measurement of tumor shrinkage:
ZODIAC: 17.0% vs. 10.0%, P<0.001
ZEAL: 19.1% vs. 7.9%, P<0.001
The studies also demonstrated that adding vandetanib to standard chemotherapy resulted
in a significantly longer time to deterioration of disease related
symptoms:
ZODIAC: HR 0.78, P=0.002
ZEAL:
HR 0.61, P=0.004
Overall survival in both
studies showed a positive trend, although they had not yet reach
statistical significance:
ZODIAC: HR 0.91, P=0.196
ZEAL: HR 0.86, p=0.219
Adverse events reported in both studies was consistent with previous studies with vandetanib in
NSCLC. The most common adverse events associated with vandetanib
included rash, diarrhea and hypertension (ZEAL); rash, diarrhoea and
neutropenia (low white blood cell count) (ZODIAC). Incidence of
protocol-defined QTc prolongation was <2.0 percent in both studies
and was not associated with symptoms.
The ZEST (ZACTIMA Efficacy Study versus Tarceva) trial
is a Phase III randomised, double-blind, multi-centre study to assess
the efficacy of vandetanib 300mg versus erlotinib 150mg in patients with
locally advanced or metastatic NSCLC after failure of at least one
prior anti-cancer therapy. It enrolled 1240 patients at 171 centres
across 22 countries.
Results from the ZEST phase III study were also presented at ASCO. Again, the primary objective of demonstrating a
statistically significant prolongation of PFS for vandetanib was not
met in this study. In a pre-planned non-inferiority analysis,
vandetanib was shown to have similar efficacy to erlotinib for PFS and
OS:
PFS: HR 0.98, P=0.721
OS: HR
1.01, P=0.830.
The objective response rate (ORR) and
symptom control were also similar for both treatments ie ORR was 12% in both arms. The most common adverse events observed in the ZEST study were rash,
diarrhoea and hypertension. Incidence of protocol-defined QTc
prolongation was 5.1 percent in the vandetanib arm.
On the basis of these results, AstraZeneca are expected to file with the FDA in the first half of 2009. Other trials ongoing include ZEPHYR and ZETA. Results from ZEPHYR (300mg monotherapy study in EGFR failures in
advanced NSCLC) and ZETA (300 mg monotherapy in advanced
medullary thyroid cancer) phase III studies are expected be available during
the second half of 2009.
Overall, aside from the Avastin data in glioblastoma following on from the recent FDA approval, I thought this batch of trial results with VEGF inhibitors rather dispiriting, but it may be the almost constant rain in New Jersey over the last 8-10 days that has influenced that sentiment.
After attending the recent annual AACR meeting in Denver, where the weather went on a wild ride from arriving in a snowstorm dumping a foot of snow to 74F and glorious sunshine, I thought it was time to capture a few thoughts on the new trends emerging there. Normally, I would have updated this blog on the conference much earlier, but the demands of client meetings and proposals have intervened somewhat.
It was my first time in Denver and Colorado, so I wasn't really sure what to expect at all but after spending nearly a week there, it's definitely somewhere I would think about visiting again, mainly because every where one went, the people were exceedingly nice and polite, adding to the positive experience.
The organisers were also on Twitter (@aacr) and that helped tremendously with little things like getting the sound up in Hall A or wherever, as the acoustics was rather faint and fuzzy at times. Kudos to their marketing team for their engagement, interaction and responsiveness, they really added to the overall positive experience. More organisations can listen and learn from their approach, because it not having problems that is the issue but how you handle them. AACR handled things with ease and aplomb. Nice one guys, very professional job!
Ok, you're all wondering what about the science and oncology data?
Well, what struck me as general trends and interest was the wealth of information on mTOR, IGF-1R, PI3K/Akt, c-Met and HDACs, plus miRNA seemed to be in just about everything. Sirtuins came up a few times, but the concept is still very early before we can make any conclusions.
Of course, Novartis' mTOR inhibitor, Afinitor, was approved in renal cell carcinoma just before the meeting so there was inevitably a lot of interest in the drug class and where it might be going given that there are now two on the market. Anticipating the concomittant interest a product launch may bring is one bane of conference scheduling – the small room was full to overflowing. I stood outside the double doors and managed to capture a few notes of the session standing up, but some parts of the chicken scratch defy even my interpretation.
Suffice to say, it was clear that investigators see both mTORi and HDACi as an exciting opportunity to add either drug to standard of care and produce wither an additive effect or possibly reduce the resistance that occurs by blocking an important pathway, thereby making the regimen work more effectively for longer. Merck's HDACi, (vorinostat or Zolinza), was another drug with a similarly bright future in this respect, because while efficacy may be limited as a single agent, it could well be a good drug for multiple combinations. Many of these ideas were discussed at different sessions and checking out clinicaltrials.gov showed over 100 trials already underway or planned with the therapy. That's not bad going for a drug approved for a rare form of lymphoma so far, ie CTCL.
It was interesting that the established medical news reported on some odd things at the meeting such as a urine test to predict smokers risk of lung cancer, drug combinations in pancreatic cancer (a deadly disease) and the impact of the Stimulus Package on cancer research. There was very little on the basic scientific research and progress with biomarkers. Yet virtually every session I went to, including the poster sessions, covered biomarkers in considerable depth.
Biomarkers can be used for different things – as a marker of activity, as a marker of outcome or as a marker for patient selection amongst other things. The field is really only just getting going and will have an increasing impact on healthcare over the next few years. As more targeted agents are developed at great expense, patients, physicians and payers alike want to know which patients are most likely to respond and why? This exciting approach is great news for diagnostic companies such as Nodality, who help pharma companies identify and track critical biomarkers in clinical trials.
Predicting which patients will respond to which therapies will increase the chances of success, reduce costs and improve confidence. The idea of treating everyone with a given cancer to get 10% response rate is old hat now. Why not figure out which 10% are likely to respond to EGFR therapy and just treat those? The ongoing story of the impact of KRAS/BRAF and loss of PTEN in CRC is fascinating; we can now identify 70% of the non-responders and treat those patients more appropriately.
The role of histology is also becoming important in some cancers, especially in NSCLC. For example, it appears that patients with squamous, non-squamous and even non-smoking Asians with adenocarcinoma can each be treated differently. The discussions in the corridors and poster sessions were very much focused on this and more on this topic is expected at ASCO, when Genentech announce the full data for Avastin and Tarceva in first line NSCLC. Alimta also appears to be more effective in non-squamous NSCLC, whereas Avastin is considered for squamous patients to avoid the increased risk of GI bleeds.
All of this information and much more, such as the Erbitux front-line data in CRC will make for a fascinating ASCO later this month.
An interesting pair of papers on tumour suppressor genes in colorectal cancer was just published in PLoS Biology. According to the researchers,
"Our genetic evidence from Drosophila and previous in vitro studies of mammalian Atonal homolog 1Atoh1, (also called Math1 or Hath1) suggest an anti-oncogenic function for the Atonal group of proneural basic helix-loop-helix transcription factors."
What does that mean in reality?
Well, essentially they may have found a master switch and activating a specific gene (Atoh1), which is common to fruit flies, mice and humans, may allow cancer to be "switched off".
Why colorectal cancer, you may ask?
The research demonstrated that colorectal cancer and Merkel cell carcinoma patients show genetic and epigenetic ATOH1 loss-of-function mutations, meaning that switching off the ATOH1 gene function lead to cell differentiation and growth of those tumours. In addition, mice lacking ATOH1 developed bowel cancer, and the gene was also frequently inactivated in human patients with the disease.
Time will tell, but undoubtedly new compounds will be developed targeting the oncogene to re-activate it and slow down tumour progression to determine whether the basic research offers
proof of concept in human cancer. In a few years time, we may even see some therapeutic developments in Pharmaceutical pipelines targeting ATOH1 as a viable and valid target in human colorectal cancer.
Wouter Bossuyt, Avedis Kazanjian, Natalie De Geest, Sofie Van Kelst, Gert De Hertogh, Karel Geboes, Greg P. Boivin, Judith Luciani, Francois Fuks, Marinee Chuah, Thierry VandenDriessche, Peter Marynen, Jan Cools, Noah F. Shroyer, Bassem A. Hassan (2009). Atonal homolog 1 Is a Tumor Suppressor Gene PLoS Biology, 7 (2) DOI: 10.1371/journal.pbio.1000039
Wouter Bossuyt, Natalie De Geest, Stein Aerts, Iris Leenaerts, Peter Marynen, Bassem A. Hassan (2009). The Atonal Proneural Transcription Factor Links Differentiation and Tumor Formation in Drosophila PLoS Biology, 7 (2) DOI: 10.1371/journal.pbio.1000040
One of the basic tenets of targeted therapy in cancer treatment is that drugs are developed to target a particular abnormality or aberration that occurs due to the cancer. For example, the breast cancer drug Herceptin targets the HER-2 gene, which occurs in 25-30% of all women with breast cancer. It therefore makes sense to appropriately screen patients prior to treatment to determine which women are most likely to benefit from the therapy.
Similarly, patients with a suspected sarcoma or gastro-intestinal tumour can be tested to see if they are KIT positive, meaning they most likely have a rare form of the disease known as gastro-intestinal stromal tumour or GIST for short. These patients can be selected to receive Gleevec as initial therapy and Sutent should they later become resistant to the treatment. Both drugs target the KIT mutation and have been shown to be effective in inhibiting is activity, which drives the tumour growth.
Gleevec made a major impact on CML by inhibiting BCR-ABL function in Philadelphia positive patients and there are now several other tyrosine kinase inhibitors on the market, namely Sprycel and Tasigna, both of which are able to target some mutations that Gleevec is ineffective against. These additional mutations are not common, but once they develop they can induce resistance to treatment. It would therefore make sense to use these therapies once the mutations develop and allow patients to continue responding to targeted therapies in a very cost effective way. Other agents are also in development for additional mutations that develop, including T315l, which none of the current drugs inhibit. Testing and monitoring CML patients regualrly will allow oncologists to essentially personalise therapy for each patient as necessary.
More recently, therapies have been approved that target the Epithelial Growth Factor Receptor (EGFR) in lung and colorectal cancer. However, in this case, both tumours over express EGFR by some 80-90%, but not all patients respond to targeted treatments. Doctors were baffled to try and determine which patients would most likely benefit since other factors were clearly at play. Eventually, meta analyses confirmed that Tarceva, works very well in female, non-smoking Asians with adenocarcinomas of the lung, for example. Other patients may benefit, but those patients did particularly well with that drug.
In lung cancer, Avastin has been shown to effectively inhibit angiogenesis via the vascular endothelial growth factor receptor. Data emerged that it was not suitable for squamous patients after doctors reported adverse events such as hypertension and bleeding, which is related to the leakage in the tumour vasculature. The drug is therefore approved for use in patients with non-squamous lung histology.
Clearly, histology is becoming important in lung cancer because Alimta, an anti-folate therapy from Lilly has also shown better responses in non-squamous and adenocarcinoma patients compared to squamous ones. The Ciuleanu study reported at ASCO last year compared Alimta as maintenance therapy to best supportive care after induction chemotherapy. The difference may seem small – 4.5 and 4.7 months for non-squamous and adenocarcinoma patients, compared to 2.8 months for squamous cell and 2.6 for best supportive care, but it is a step in the right direction.
The other interesting fact that emerged in lung cancer is that not only is histology important, but also the type of EGFR mutation may predict response to Erbitux and Vectibix, two EGFR inhibitors that have been approved. Previously, it was unclear why some patients responded and others did not; the response rate is in the order of 10-20%. The picture became a little clearer when it was realised in 2005 that another mutation, KRAS, was an important driver of tumour activity, not EGFR, essentially causing resistance to develop:
"Tumor cells from patients in our study who developed secondary
resistance to gefitinib and erlotinib after an initial response on
therapy did not have mutations in KRAS. Rather, these tumor cells had new mutations in EGFR.
This further indicates that secondary resistance is very different from
primary resistance. We are now
trying to figure out other possible reasons why gefitinib or erlotinib
stop working. We also hope to identify mutations in other potential
cancer-causing genes that are critical for lung cancers to survive.
Even though many mutated oncogenes have already been found, the crucial
genes are still unaccounted for in about 50 percent of non-small cell
cancers."
William Pao
At ASCO last year, another piece of the jigsaw puzzle fell into place. Several groups reported that the type of mutation was important, ie whether it was mutated or wild type KRAS. It seemed that the KRAS mutation explained nearly 40% of the non-responders, so those patients who had mutated KRAS were unlikely to respond to Erbitux or Vectibix therapy. It therefore makes sense to test for KRAS upfront to determine eligibility for treatment. This means that the patient will also be spared from taking a drug that is ineffective; false hope does no one any favours nor does wasting money on expensive treatments. A far better use of resources would be to target the drug where it is most likely to work. Researchers are now busy trying to work out what other factors affect efficacy to EGFR inhibitors other than the KRAS mutation status.
{Update} ASCO have just announced that they have released a provisional clinical opinion (PCO) recommending routine KRAS gene testing to guide treatment for metastatic colorectal cancer. You can download the PCO here.
Interestingly, the wild type and mutated type mutations have been seen before – in KIT positive GISTs, where the type of mutation is increasingly dictating whether patients get Gleevec or Sutent as initial therapy, therefore increasing the chances of a positive response and tailoring treatment to the patients most likely to respond. This is much more cost effective than the traditional method of one drug followed by the other drug, when matching the drug to the mutation means that the patients will have a better chance of responding early and for longer.
In breast cancer, gene profiling has been down extensively for some years although the HER-2 mutation has been the only significant way of separating patients so far. It is hoped in the near future that new trials and tests will determine which patients are more likely to respond to different drug regimens, based on the underlying genetic profiling.
All in all, we can clearly see that cancers are increasing being segmented into different subsets based on either the underlying histology or mutational status. These subsets can then be treated as different disease types and therapy tailored according to those drugs most likely to induce the best response at the most efficient cost. In the old world, all patients got chemotherapy regardless and not only does that come with side effects as well as targeting normal cells and cancer cells, but it's also very inefficient.
As we learn more about the science and biology of each tumour type, personalized medicine allows us to reduce side effects by using more targeted drugs with the goal of stopping the particular aberration in the cancer cells as well as increasing the chances of a good response. Things can only get better and that's very good news indeed for cancer patients.
Sources:
William Pao, Theresa Y. Wang, Gregory J. Riely, Vincent A. Miller, Qiulu Pan, Marc Ladanyi, Maureen F. Zakowski, Robert T. Heelan, Mark G. Kris, Harold E. Varmus (2005). KRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib PLoS Medicine, 2 (1) DOI: 10.1371/journal.pmed.0020017
D. A. Eberhard (2005). Mutations in the Epidermal Growth Factor Receptor and in KRAS Are Predictive and Prognostic Indicators in Patients With Non-Small-Cell Lung Cancer Treated With Chemotherapy Alone and in Combination With Erlotinib Journal of Clinical Oncology, 23 (25), 5900-5909 DOI: 10.1200/JCO.2005.02.857
E. Van Cutsem, I. Lang, G. D'haens, V. Moiseyenko, J. Zaluski, G. Folprecht, S. Tejpar, O. Kisker, C. Stroh, P. Rougier (2008). KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. Journal of Clinical Oncology, 26 (25): Abstr.(2)
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(q1w): The EVEREST experience (preliminary data Journal of Clinical Oncology, 26(25): Abstr. (4001)
Michael C Heinrich, Christopher L Corless, Charles Blanke, George D Demetri, Heikki Joensuu, Meg von Mehren, Laura S McGreevey, Cecily L Wait, Diana Griffith, C-J Chen, Andrea Haley, Beate Kiese, Brian Druker, Peter Roberts, Burt Eisenberg,, Sam Singer, Sandra Silberman, Sasa Dimitrijevic, Christopher D Fletcher, Jonathan A Fletcher (2002). KIT mutational status predicts clinical response to STI571 in patients with metastatic gastrointestinal stromal tumors (GISTs) Journal of Clinical Oncology (Abstr. 6)
B. Liegl, J. A. Fletcher, C. L. Corless, C. D. Fletcher, C. P. Raut, R. Donsky, M. M. Bertagnolli, C. Le, G. D. Demetri, M. C. Heinrich (2008). Correlation between KIT mutations and sunitinib (SU) resistance in GIST Journal of Clinical Oncology, 26 (abstr. 92)
T. E. Ciuleanu, T. Brodowicz, C. P. Belani, J. Kim, M. Krzakowski, E. Laack, Y. Wu, P. Peterson, S. Adachi, C. C. Zielinski (2008). Maintenance Pemetrexed Improves Progression-free Survival for NSCLC Journal of Clinical Oncology, 26 (Abstr. 8011)
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