A four-part VJSession with leading experts Sara Tolaney, Paolo Tarantino, and Sarah Sammons, who offer their perspectives on the exciting developments in the field of breast cancer presented at the San Antonio Breast Cancer Symposium (SABCS) 2023.

Welcome to The Breast Cancer Sessions brought to you by the Video Journal of Oncology (VJOncology).

This exclusive roundtable discussion features leading breast cancer experts Sara Tolaney, Paolo Tarantino, and Sarah Sammons (Dana-Farber Cancer Institute, Boston, MA).

Watch this on-demand feature to learn about updates on the management of HR+/HER2- breast cancer such as the role of CDK4/6 inhibitors as evaluated in MONARCH 3 (NCT02246621) and PARSIFAL trials (NCT02491983), the potential of PIK3CA mutations as described in the INAVO120 trial (NCT04191499), the use of ribociclib and endocrine therapy as adjuvant treatment in HR+/HER2- early breast cancer, and finally neoadjuvant immunotherapy in HR-positive early breast cancer.

Part 1: Updates on CDK4/6 inhibition from MONARCH 3 & PARSIFAL

“We did actually see final overall survival data get presented from MONARCH 3. This is a study that looked at adding abemaciclib to an aromatase inhibitor in the first line setting. And what we saw was that there was not a statistically significant improvement in overall survival from adding abemaciclib to an aromatase inhibitor.”

Sara Tolaney

Part 2: INAVO120: implications of PIK3CA mutations

“And so in my mind, in a patient that recurred on adjuvant CDK or shortly after, I’m not sure if I want to restart immediately a CDK4/6 inhibitor. That said still, for those patients that that meet the criteria of the trial, I really think this is a very active regimen.”

Paolo Tarantino

Part 3: Adjuvant ribociclib and endocrine therapy

On NATALEE it’s wonderful to see that the curves still continue to separate, um, and that there might be, you know, a second option for a larger proportion of patients. I’m not quite there yet with the data presented in terms of risk-benefit ratio. And I think, you know, I’ve examined these hazard ratios for a really long time until I’m cross-eyed. But the reality is, what we talk about patients to, to patients in the clinic are absolute benefits. Are they outweighed or not by the side effect profile? And for the intermediate risk stage II node negative population. I’m just not there yet.”

Sarah Sammons

 

 

Part 4: Neoadjuvant immunotherapy in HR+ early breast cancer

“So then there’s this question that arises, well, who are the patients that actually need immunotherapy. And can we figure out what the biomarkers are to select them. And there were some interesting data presented with regards to this, both from 756 and from 7FL. And the general trend was when you had low ER you tended to have a bigger delta. If you had a higher PD-L1, you tended to have a higher absolute PCR, but also a bigger delta that emerged between the two arms. And so it does seem like there is a trend towards lower ER high PD-L1, sort of driving towards higher benefit”

Sara Tolaney

Full Transcript

Sara Tolaney:

Welcome to the VJSessions with VJOncology. My name is Sarah Tolaney. I’m from Dana-Farber Cancer Institute and I’m joined by two of my esteemed colleagues, Doctor Sarah Salmons and Doctor Paolo Tarantino. So welcome everyone. Today we’re going to be taking you through some of the highlights from San Antonio, specifically focused on some of the interesting new data that emerged focused on hormone receptor positive breast cancer.

So I thought I’d start off with some of the data that we saw regarding first line therapy for metastatic hormone receptor positive disease, where I think we’ve had this debate about what is the optimal CDK4/6 inhibitor to choose in the first line setting. And a lot of this debate has stemmed around overall survival data.

And we did actually see final overall survival data get presented from MONARCH 3. This is a study that looked at adding abemaciclib to an aromatase inhibitor in the first line setting. And what we saw was that there was not a statistically significant improvement in overall survival from adding abemaciclib to an aromatase inhibitor.

However, there was a 13 month improvement in overall survival from the addition of abemaciclib to an AI. And when you specifically looked at the visceral metastases patients, it was about a 15 month delta. So I think clearly a clinically meaningful benefit that was seen. And what was sort of interesting in my mind is if you looked at the updated PFS data and you looked at the six year landmark time point, you actually see almost a quarter of patients are still free of progression in the first line setting. So really just showing you how well some patients can do with CDK4/6 inhibition. But when thinking about why maybe these data did not reach significance, one factor we always have to consider is subsequent lines of therapy. And we do know that more people in the placebo arm did cross over to get a CDK4/6 inhibitor at time of progression than those patients on the abemaciclib arm, so about a third of patients did go on to get a CDK4/6 inhibitor. And certainly this can influence it, as can the multiple other lines of therapy that people got. But one interesting thing I thought that emerged was, you know, the overall survival data we saw was with eight years of follow up.

But when we had looked at the six year time cut at the second interim analysis, it was really about the same time cut that the final OS was presented for MONALEESA-2, so again around six years. And you can see the hazard ratios at that time point were identical at 0.76. But yet now when we get to the eight year data we’re seeing, the hazard ratio went up to 0.8 and no longer significant. And the stats for this trial were a little more complicated because it had a 2 to 1 randomization. They also split their alpha trying to look both at the ITT and the visceral metastases patients.

So I think there is some concern that maybe the statistical design did influence significance. But now when we put this all side by side by all the other trials, I think it makes us consider, you know, what is the optimal CDK4/6 inhibitor to use? We’ve seen OS statistically significant with ribociclib across all their trials in the metastatic setting. And we’ve seen abemaciclib have significance in MONARCH 2 but not MONARCH 3. But yet none of the palbociclib studies reach significance. So I’ll turn to my colleagues here to give their wise thoughts. And so, Sarah, if you see a patient currently in the first line setting, what therapy are you offering them and when you’re choosing a Cdk4 six inhibitor?

Sarah Sammons:

Yeah, thanks. That was a wonderful review, I think. Well, I’m certainly still offering the vast majority of people endocrine therapy and a CDK4/6 inhibitor. There is a small camp of people that that are still not sure that that’s even needed. But I think for most people still offering a CDK4/6 inhibitor in the first line, you know, I think I think the lack of statistical significance, as you pointed out, is somewhat semantics to me.

The numerical improvement in overall survival is very similar. The median overall survival of over 60 months is also wonderful to see, and I hope as the years go by, that line keeps moving further and further down. So the statistical the lack of statistical significance does not bother me. With that being said, I think for the majority of patients, I’m offering them ribociclib, given the consistent overall survival benefits that we’ve seen, across all of the MONALEESA trials. I do like abemaciclib for patients with really heavy visceral disease or patients with CNS metastasis. That’s helpful.

Sara Tolaney:

How about you, Paolo?

Paolo Tarantino:

Hard to add anything about what Sara said. I also agree that in general, the idea of giving first line endocrine treatment and CDK4/6 inhibitors is there and is not influenced by this data and also the agent to prefer in this setting is not really change. I also believe the fact that abemaciclib is beneficial in overall survival, and the lack of statistical significance is probably related to the fact that the trial was not really powered for overall survival. The primary endpoint was progression free survival, and we know there was a significant benefit there. It was striking to see the percentage of patients free from progression at six years, really suggesting that the significant clinical benefit of abemaciclib. But just like NCCN guidelines recommend, I believe that the preferred agent based on both the statistical advantage of survival, but also just the experience of the patient.

We know that the three CDK4/6 inhibitors have got different side effect profiles. I feel that some side effects are more apparent in the in the experience of the patient, some are less. I believe that ribociclib kind of fits well into having both an advantage in PFS and overall survival, and a profile of side effects that is favorable and allows these patients to remain for most of the patients for many years on first line, but I still believe that abemaciclib is beneficial. Palbociclib I think we still struggle to kind of reconcile that the PFS advantage with the lack of even numerical OS advantage, and I still believe that even palbociclib is beneficial and that the missing data about patients in the trial impacted the results. But for the moment, I believe that both ribociclib and abemaciclib are adequate choices in first line with some preference for ribociclib.

Sara Tolaney:

Well, that’s a perfect segue, because you did mention the challenges with interpreting the PALOMA-2 study, given many patients withdrew consent to OS follow up. But we did see this interesting analysis from PARSIFAL-LONG. So this was the study that had compared letrozole to fulvestrant, palbociclib up front and endocrine sensitive patients. It was really trying to address what’s the optimal endocrine backbone. [It] didn’t seem to matter what you chose, whether as an AI or fulvestrant, but now when you follow these patients for a long time with 60 months of follow up, you look at the overall survival and you can see it’s quite robust. And when you actually merge the two arms, you’ll see that the OS is around 65 months. And so if you recollect, we’ve seen initially in PALOMA-2, they reported a 54 month OS, but now 65 months in PARSIFAL-LONG is very similar to what we’re seeing in MONARCH 3 and MONALEESA 2. So does that revive Palbociclib in your minds? I don’t know Sara or Paolo, do you all think?

Paolo Tarantino:

What do you think, Sarah?

Sarah Sammons:

Yeah, that’s a tough one. No, I mean, I do still use palbociclib in some first line patients. I use palbociclib for patients that I’m, you know, worried about the liver. You know, so I’m worried about liver in terms of liver toxicity. Because I worry about that with ribociclib and to a lesser extent, abemaciclib – older patients. You know, I will also consider palbociclib because I do think it’s the best tolerated CDK4/6 personally. I don’t know what to make of this. I really just don’t, and I think if you’re being a purist, you know, you take the randomized trial, against placebo, which is what we have, you know, in the original trials. So I don’t think my mind has changed based on this, but it’s nice to see and it’s nice to see this data again, because it makes me really wonder how these first line oral SERD trials are going to do.

Sara Tolaney:

Yeah, that’s a good point. Given the fulvestrant didn’t outperform the AI in the setting of combination therapy with CDK, I think an excellent point. So we’ll have to see, how it goes. But nice to have choices amongst these drugs upfront. And certainly you can try to individualize it based on the patient in any underlying comorbidities. We did see some other data to think about. Maybe those patients who have early relapse after endocrine therapy and also have a PI3K mutation. This was the INAVO120 study that specifically was for patients who did have early relapse on or within a year of their adjuvant endocrine therapy, and had a PI3K mutation. It was also very specific for patients who did not have diabetes and had a very tightly controlled hemoglobin A-1c under six, and it randomized patients to fulvestrant, palbociclib or fulvestrant palbociclib with anabolism the oral PI3K-alpha inhibitor.

And what they saw was a very dramatic improvement in progression free survival, going from about 7 to 15 months with a hazard ratio of 0.43. While overall survival data is immature, you can see a nice trend there with a hazard ratio of 0.64. And in fact, you also saw more than a doubling an objective response rate favoring the triplet combination over the doublet. However, we do know these PI3K inhibitors are associated with some toxicities, including things like stomatitis, hyperglycemia, diarrhea and rash. And while we do see this was not infrequent in the study, we do see that high grade toxicities were generally low. And so rates of discontinuation in the trial were also reasonably low with the combination. And so I’m curious what you all thought of these data. It was hot off the press, we had just seen a press release a few days prior to the presentation.  Maybe Paolo, I’ll start with you. You know, if this was an approved regimen, would you use it and who would you use it in?

Paolo Tarantino:

I was impressed by this data because the PFS, both as a ratio and numerical advantage is really major, really interesting. The thing that kind of made me think is that it’s a very small population. It’s not that we see that most of our patients recur on endocrine treatment or shortly after, and also have a mutation. And then it was interesting to see that half of the patient in the trial had received tamoxifen as endocrine treatment. That is something that really doesn’t occur much anymore. And finally, among patients that have early recurrence, many of these have got baseline high risk, many positive nodes. And we know that these patients today are treated with adjuvant abemaciclib and probably in the next future adjuvant ribociclib.

And so in my mind, in a patient that recurred on adjuvant CDK or shortly after, I’m not sure if I want to restart immediately a CDK4/6 inhibitor. That said still, for those patients that that meet the criteria of the trial, I really think this is a very active regimen. The toxicities in numerical terms were not infrequent, but at the same time, high grade toxicity and discontinuation were quite favorable. So I do think it is a manageable combination. It is interesting that we’re moving toward triplets. So it’s something we’re not very used to in breast oncology – we’re very few. But I think in these cases of high risk, a patient recurring with very bad prognostic features, I would definitely utilize this triplet in case the patient met the criteria of the trial.

Sara Tolaney:

Yeah. Thanks, Paolo.

Sarah Sammons:

Yeah, my back of the napkin math is that about a third of patients are going to be endocrine resistant. And then a 40% of them are going to be PI3K-mutated. And then in the US, how many people are going to have an ANC less than 6.0? Probably maybe 60%. So that leads us down to a patient population that may benefit from this strategy of far less than 10%. With that being said, in that specific patient population, I think that this is really promising. I think it’s proof of concept that a triplet like this, can help overcome some resistance, which we’ve seen for a long time in the preclinical data. And I just want to also congratulate, the investigators and the patients for completing the trial. I think it’s, you know, really hard to enroll such a population. And the only other thing I wanted to point out is, you know, the control arm performs so poorly. So this is a really high risk population. But if you look at the PI3K-mutant population of monarch two abemaciclib and fulvestrant, they actually had a median PFS of 16 months. And so I do wonder how other CDKs in a pretreated population would perform outside of a triplet. And I’m not sure what you think about that.

Sara Tolaney:

Yeah. You know, I think it is interesting and certainly it’s true in MONARCH 2 , we did see a very robust, obviously patient populations are a little different though. So while they did allow early relapses to get treated in the first line, they also allowed patients who could have been on a first line AI for a really long time in the metastatic setting. So could have been endocrine sensitive. And so again it is a different patient population. So making it a little tricky to compare. But I think it’s a very valid point. I think some have brought up. Well what about doing sequential therapy. How do you know you really need the triplet? Is it really going to be better. And certainly does add toxicity. But you know, there is robust preclinical data supporting the synergy with these drugs. And I think we do need to figure out the toxicity though, as you were both alluding to. And there is work ongoing, that is planned at least to look at prophylactic measures, to see if we can better control some of these side effects. And so hopefully more to come. But nice to see again that we are sort of moving the needle on improving outcomes for these high risk patients.

So while we’ve talked about up front therapy in the first line metastatic setting, what about thinking about the high risk adjuvant setting. You know, we’ve seen data from monarchE suggesting that using two years of adjuvant abemaciclib significantly reduces adverse events and has become a standard in the high risk population. But now we have a new kid on the block with ribociclib trying to move into the early space. This trial, NATALEE had been designed a little differently than monarchE. It looked at three years of ribociclib, but used a lower dose of ribo than used in the metastatic setting, and it also included an intermediate risk population. And while we saw these data initially presented at ASCO from their second interim, we now see the final primary IDFS data. And so we now we have a little more follow up. So about five and a half more months of follow up time than we had previously seen at ASCO. And so now they’re only about 20% of patients still on their three years of ribo, meaning  you know, most people are having finished their adjuvant ribociclib. There were about a third of patients, though, who did have to discontinue ribociclib early and did not complete the ribociclib.

And so at this time point, now with about 33 months of follow up, we see about a 25% reduction in IDFS events with a 3% absolute difference between the two arms. And we saw a bunch of subset analyzes in this presentation trying to divide out stage two versus three node negative versus node positive. And here you can see the hazard ratios are fairly similar for stage II and III. There are some caveats here. You know the trial did enroll the earlier low intermediate risk patients very quickly in the trial. And so they reached that cap. And so the follow up time is longer in the earlier lower risk patients. So just a caveat when putting these data side by side. And for the node negatives again another caveat. It was only 12% of the population. And so you do see the confidence intervals around that hazard ratio are quite wide. And making that estimate for, you know, this absolute benefit that we’re seeing of around, you know, 2 – 2.5% being again wide. But nonetheless, again, it does seem like there are benefits both in the stage II and III and node negative and node positive. With those caveats, and most of the events that we’re seeing were distant events. Obviously OS at this time point is far too immature. Just 4% of events in each arm. And I think, you know, as we alluded to earlier, some of the toxicities we’re used to with ribociclib are a little bit less because they did lower the dose down to 400mg, a little less in the way of neutropenia than we’re used to seeing, a little less in the way of QTc prolongation. But the issue is not a dose dependent toxicity. And so you did see 8% of patients having high grade elevation of LFTs. And so let’s pretend, uh, ribociclib got an approval in all the patients who were eligible in NATALEE. And would you use ribociclib in all of these patients? Would you prescribe it to the intermediate risk patients, for example? Who would you use it in if it if it was available? And maybe. Sara, I’ll start with you.

Sarah Sammons:

Yes, thanks. I think, um, it’s wonderful to see that the curves still continue to separate, um, and that there might be, you know, a second option for a larger proportion of patients. I’m not quite there yet with the data presented in terms of risk benefit ratio. And I think, you know, I’ve examined these hazard ratios for a really long time until I’m cross-eyed. But the reality is, what we talk about patients to, to patients in the clinic are absolute benefits. Are they outweighed or not by the side effect profile? And for the intermediate risk stage II node negative population. I’m just not there yet. In prescribing that, I think it looked quite good in the stage three and II and III, but we already, you know, have abemaciclib for those patients. So it could be a great option if they’re intolerant or you don’t think the patient’s a candidate for abemaciclib for the N2 and 3 stage three patients. Not there yet. For the node negative. Stage II patients would love to see them pull out. Maybe a higher risk population. I think the n one population was about 40%. I’d love to see them pull out like a high risk and one population. Because I think there are high risk stage II patients that we want to offer, you know, something like this to our patients. And I just don’t know yet who that is.

Sara Tolaney:

That’s a it’s a good point, Sarah. How about you, Paolo?

Paolo Tarantino:

I couldn’t agree more with Sarah, meaning that it is promising to see these curves diverge. And it kind of reminds us of what happened with monarchE, that we saw the curse progressively diverging and also the benefit increasing in time. But is that enough to prescribe three years of ribociclib for, for instance, for patients with stage two disease for a 1.6% delta in IDFS at three years? Taken into account, of course, the hepatotoxicity of the drug, the potential QTc prolongation and the neutropenia and the financial toxicity, of course, is also relevant for all the all the community and the patient themselves. So I’m not sure that for the moment, for the stage II patients I feel convinced with for stage III, I do feel more convinced. Although if I had the option of abemaciclib, if a patient fitted the monarchE criteria would definitely prefer abemaciclib because the data are more mature for an intermediate patient that does not completely fit the monarchE criteria, or even more for a patient that has to discontinue adjuvant abemaciclib for toxicities and would be willing to try something different, I would feel compelled about utilizing and trying adjuvant ribociclib, although here we are navigating a kind of a data free zone. We don’t know if we can use one after the other. And then in the future, things may become even more complex when new adjuvant immunotherapy comes in the picture. But things are complex enough, so let’s not talk about that probably now. So yes, I believe stage III I’m convinced about the benefit. I think it’s enough for start prescribing it. Stage II I’m not there yet.

Sara Tolaney:

Well, you may have been trying to avoid the immunotherapy discussion. I am going to touch upon it for just one minute, because I do think it was some interesting data that we saw at San Antonio on, adding immunotherapy in the preoperative setting. Although, as you point out, these trials also continued that immunotherapy into the adjuvant setting.

And so these were the designs of the trials that we saw. Keynote-756, which took standard anthracycline taxane chemotherapy with or without pembrolizumab in patients with high grade stage II and III ER-positive disease. And then at time of surgery, if you got pre-op pembro you continued it in the adjuvant setting or if you got placebo, you continued that into the adjuvant setting. And Checkmate-7FL was designed very similarly although with nivolumab being utilized. And unfortunately they did end up closing their study early so that they only ended up enrolling about half of what they planned due to the change in landscape with introduction of CDK4/6 inhibitor inhibitors at that time. And so they are not powered for EFS, whereas 756 is with almost 1300 patients. What we saw, though, was a PCR data, which looks very similar between the two trials. So in this high grade stage II/III ER-positive population, we’re seeing the control arm, you know, have a 14-15% PCR. But then you see this, you know about 9-10% delta between the two arms. So we’re getting a PCR rate in the 24-25% range.

So I think really impressive because traditionally to date we’re not used to seeing that level of PCR. So then there’s this question that arises, well, who are the patients that actually need immunotherapy. And can we figure out what the biomarkers are to select them. And there were some interesting data presented with regards to this, both from 756 and from 7FL. And the general trend was when you had low ER you tended to have a bigger delta. If you had a higher PD-L1, you tended to have a higher absolute PCR, but also a bigger delta that emerged between the two arms. And so it does seem like there is a trend towards lower ER high PD-L1, sort of driving towards higher benefit. And interestingly, in 7 FL we also saw data with regard to TILs suggesting having presence of tilt. Also drove up that PCR rate, although Ki67 did not seem to influence, PCR. And so, you know, again, I think these were very intriguing data and very consistent between the two trials in terms of improvements in PCR data is obviously not mature to have assessed EFS at this time. And so I’m curious what you all think about how to use these data. Would you ever think that a PCR delta of this significance is enough to change practice at this time, or do we need EFS? And what do you think about the biomarker data? Do you think those data are rich enough to suggest PD l one is something we may need to test for in this positive population. So Paolo, what do you think?

Paolo Tarantino:

I think these data are impressive. Uh 10% delta in CR with immunotherapy that we know that in most of the prior experiences. But CR benefit translated into an EFS benefit. I do believe that this data will be impactful in the future and may change practice should we already utilize based on past data in the adjuvant immunotherapy? I don’t think so. I think we really want to see survival benefit. And at the same time, in terms of biomarkers, I think, I want to when I think of Keynote 522, when we saw the benefit of adding pembro for triple negative breast cancer in terms of PCR are the first New England publication and presentation. Most of the benefit was in not positive patients. But then in terms of PFS also not negative patients benefit. And so I do believe that even for understanding which patients benefit the most in terms of biomarker, we do need EFS data. So it is hard to wait because we kind of know that these data are impactful, are brilliant. But at the same time, we know that toxicities are there in neoadjuvant immunotherapy can cause also permanent toxicities and sometimes fatal toxicities. And this is the reason why I do believe we need to wait for survival data to balance risks and benefits. But I also believe that these data are great. And it was wonderful to see them both at ESMO and San Antonio.

Sara Tolaney:

No, thanks. Pablo. How about you, Sarah? I know you’ve thought a lot about immunotherapy. What do you think about these data?

Sarah Sammons:

Yeah, I think it’s really promising. I definitely think that there is a small subset of hormonally driven cancers that are high grade, have high gene expression assay risk, um, that may benefit from something like this. And it was actually nice to see both trials present correlates early. Because I do really think that we need to tease out which population is going to benefit. I also think it’s nice to see, you know, the early patients were not included in Keynote 522. And I don’t know about you, but you know, those ER one, two, three patients are patients that you do kind of want to give neoadjuvant immunotherapy. So it’s nice to see that we have some rationale for that now. Um And I think, you know, the pembrolizumab data will be the one that can go for approval if we see an PFS benefit. And I’m really optimistic, and I just really like to see the correlatives continue. In terms of figuring out which population specifically might benefit.

Sara Tolaney:

And I very much agree. It’s nice to see that, you know, there is a big effort being made to try to select patients who really need them, you know, therapy. And as you point out, I think seeing these correlatives correlated with EFS will be really critical to help us figure out who needs it. So hopefully more to come. But sounds like not quite ready for prime time yet. But really, it was an exciting San Antonio. There was so much data that emerged, we only got to touch upon some of the data that came out in the ER-positive space, but it was wonderful, uh, being able to discuss these data with you, Sarah and Paolo. So thank you so much for joining me.

 

The Breast Cancer Channel on VJOncology is supported by Gilead.

These supporters have no influence over the production of the content.

Disclosures

Sara Tolaney

Sara Tolaney reports consulting or advisory role for Novartis, Pfizer, Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, Seattle Genetics, Odonate Therapeutics, CytomX Therapeutics, Daiichi Sankyo, Athenex, Gilead, Mersana, Certara, Ellipses Pharma, 4D Pharma, OncoSec Medical Inc., BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Infinity Therapeutics, Chugai Pharmaceuticals, Myovant, Zetagen, Umoja Biopharma, Menarini/Stemline, Aadi Biopharma, Bayer.

Sara Tolaney reports research funding from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Cyclacel, Nektar, Gilead, Sanofi, Seattle Genetics.

 

Paolo Tarantino

Paolo Tarantino reports AstraZeneca, Daiichi Sankyo and Lilly.

 

Sarah Sammons

Sarah Sammons declares research funding to their institution from Astra Zeneca, Abbvie, Bristol Myers Squibb, Eli Lilly, SEAGEN and Sermonix; and consulting fees from Foundation Medicine, Astra Zeneca, Daichii Sankyo, Eli Lilly, Pfizer, Sermonix and Novartis.