In a six-week span, JosÃ© Baselga, MD, PhD, notched a stunning series of milestones in breast cancer research that could potentially change practice in different subtypes of the disease.
Photo by ©SABCS/Todd Buchanan
José Baselga, MD, PhD, discusses the CLEOPATRA study during the 2011 CTRC-AACR San Antonio Breast Cancer Symposium in December.
In a six-week span, José Baselga, MD, PhD, notched a stunning series of milestones in breast cancer research: the publication of the results of three separate clinical trials with the potential to change practice in different subtypes of the disease.
Baselga is the lead author on: (1) BOLERO-2, which found a significant progression-free survival (PFS) benefit for combining everolimus (Afinitor) with exemestane in postmenopausal women with estrogen receptor-positive, HER2-negative metastatic breast cancer1; (2) CLEOPATRA, which established a PFS benefit for using the novel therapeutic pertuzumab with trastuzumab (Herceptin) as a dual HER2 blockade for HER2-positive patients with late-stage disease2; and (3) NeoALTTO, which found that administering lapatinib (Tykerb) plus trastuzumab in the neoadjuvant setting for HER2-positive patients produced a significant advantage in pathologic complete response.3
It was perhaps a once-in-a-lifetime confluence of events in a lifetime of achievement for an oncology leader who has spent more than 20 years in the field. Baselga built the oncology program at Vall d’Hebron University Hospital in Barcelona, Spain, into an internationally known research institute and served as president of the European Society of Medical Oncology. Earlier in his career, he completed a fellowship in medical oncology at Memorial Sloan-Kettering Cancer Center, New York, New York.
Two years ago, Baselga was named chief of the Division of Hematology/Oncology and associate director of the Massachusetts General Hospital (MGH) Cancer Center in Boston. MGH, which conducts nearly 400 clinical trials annually, has established one of the nation’s most extensive tumor genotyping initiatives.
For much of his career, Baselga has been exploring HER2 gene mutations in breast cancer. His work includes research that led to the development of trastuzumab (Herceptin) for the treatment of HER2-positive disease in the 1990s.
During a recent interview, Baselga couched his latest research highlights in modest terms. “You do multiple things, and to have more than one project coming to the end at the same time and having the three studies positive—that’s never going to happen again,” he said. “It’s just a coincidence.”
On the subject of breast cancer research as a whole, Baselga expressed excitement about the pace of discovery and the implications of recent findings.
“We now have the capacity to interpret much better what’s going on in the tumor and to adopt our therapies based on that,” he said. “This is powerful, and yes, I do believe that we are at a turning point.”
Baselga discussed his own research more extensively in this interview with OncologyLive.
OncologyLive: Is there a theme in these three studies?
Baselga: Yes, in the three cases we have combined new, targeted therapies to whatever was the standard of care. That’s the theme—trying to look for synergistic interactions with targeted therapeutics in breast cancer.
What are the challenges of investigating combination therapies?
Perhaps the most important one is trying to design a clinical trial that will be able to answer the questions that you’re looking for in a way that is error-free and that has good, strong support. It requires a lot of time and efort to do the right and appropriate clinical trial design, and you have to base that on your laboratory data or on data from earlier studies. Trying to model in the clinic what has happened in the lab—that’s the most challenging part of all.
The second challenge is in the case of these newer, more avant-garde, if you wish, clinical trial designs such as NeoALTTO. The challenge there is to set up a whole new set of conditions. The concept of neoadjuvant therapy, and doing clinical trials with neoadjuvant therapy, is not an easy one. On top of that, you want the concept of having a window period of time in which you only administer anti-HER2 therapy without chemotherapy. That gives us yet another level of complexity.
So we need to get the buy-in from investigators and from the patients. You need pathologists to help. You need to build in very complex imaging. This is not easy, I can tell you that.
N = 724
n = 485
n = 239
Clinical benefit rateb
bIncludes complete response, partial response, stable disease >6 months.
*Based on data presented at 2011 CTRC-AACR San Antonio Breast Cancer Symposium, Texas, December 6-10, 2011.
What is the mechanism of action of the combination therapy used in BOLERO-2?
While anti-estrogen therapy is the backbone of therapy in estrogen receptor-positive tumors, hormone resistance either presents up front (primary resistance) or eventually develops (acquired resistance). Taken together, hormonal resistance is clearly one of the largest challenges that we are facing today in the clinic. So we were looking for ways to revert endocrine resistance. Data from multiple labs had shown, over the last few years, that the mTOR pathway that is downstream from the PI3 kinase is one of the most important mediators of endocrine resistance, and it can activate estrogen receptor transcription in a ligand-independent fashion. So even if you are using an aromatase inhibitor [AI], even if you are blocking access of ligand to the estrogen receptor, if you have an abnormally activated mTOR pathway, that estrogen receptor will signal and will be transcriptionally active.
The obvious next approach is to combine an antiestrogen that will interfere with an mTOR inhibitor that will prevent ligand-independent estrogen receptor transcription. And that was the basis for the initial studies. We had done a small pilot neoadjuvant study of the combination of everolimus with an AI, and we had seen a very dramatic improvement in the inhibition of proliferation with everolimus. So we had the clinical data supporting the notion that mTOR inhibitors would revert resistance, and that’s exactly what we saw in BOLERO-2.
What role do you think everolimus will play in this subtype of breast cancer?
I think everolimus is going to be a major addition to therapy. In the patient population that was part of the BOLERO-2 study, the addition of everolimus had very meaningful clinical improvement of patients. I would think that everolimus will become a standard of care in that indication.
Are there broader implications for everolimus in other cancers?
Absolutely. In breast cancer, I think another area that’s extremely important is in tumors that are HER2-positive. We have small phase II studies showing that everolimus can overcome resistance to HER2 therapies, and there are two large randomized trials going on. One is BOLERO-1 and the other is BOLERO-3, which are studying everolimus with trastuzumab and chemotherapy in patients who have failed trastuzumab. If those studies are positive, that means that everolimus will also have a role in therapy of HER2-positive breast cancer.
Now, the data from BOLERO-2 are in second-line therapy. I think a very important question is what’s going to happen in first-line. I think it would be very important to launch, as soon as possible, a study in the adjuvant setting.
I think the data of BOLERO go far beyond the special population or the indication of BOLERO. And what it does is that it opens up the whole field of mTOR and PI3 kinase therapy in breast cancer.
Patients with HER2-positive
breast cancer centrally confirmed
(N = 808)
n = 406
n = 402
(n = 406)
(n = 402)
Objective response rate
Complete response rate
Partial response rate
(n = 336)
(n = 343)
*Based on data presented at 2011 CTRC-AACR San Antonio Breast Cancer Symposium, Texas, December 6-10, 2011.
How was pertuzumab developed?
Pertuzumab was developed at the same time as Herceptin (trastuzumab). If you look at the initial papers by Genentech, they have an antibody called 4D5 that became trastuzumab, and they had another one called 2C4, and that was the murine version of pertuzumab. So that antibody was there from the beginning.
Work by investigators at Genentech showed that pertuzumab was binding to HER2, but it was binding to HER2 in a different site than trastuzumab, and it was preventing a different type of activation than Herceptin did. Now, there were two theories: that pertuzumab may work in breast cancer where HER2 is not overexpressed or that pertuzumab would work together with Herceptin in tumors that overexpress HER2.
I have been involved with pertuzumab for many, many years. I was an early believer in the compound. Pertuzumab in the lab was clearly a better inhibitor of signaling than Herceptin. So I led the phase II study of pertuzumab in breast cancer. That was a beautifully designed study. We had patients who had metastatic disease and they had progressed to Herceptin. Despite having stopped responding to Herceptin, we kept them on Herceptin and we added pertuzumab in these patients, without chemotherapy. We saw that 50% of these patients had either response or stable disease for six months or more. This was remarkable and the turning point in the development of pertuzumab.
Then we went on to expand the study in two additional parts. It is unique to have a study with so many parts, but we really wanted to know whether Herceptin was required on top of pertuzumab. The second part of the study involved patients who had progressed on Herceptin. We added pertuzumab alone to see what pertuzumab alone would do. The answer was very little. Pertuzumab alone had minimal response.
So then the next question was part three of the study. Those patients who had not responded to pertuzumab as a single agent we kept on pertuzumab and we added, again, Herceptin. What happened was a very high response rate. I think it’s the first time in oncology in which you have patients who had progressed to two therapies, in this case trastuzumab and pertuzumab, and we put them together and we saw responses. These agents have truly complementary mechanisms of action, and from that the bold move was made to go straight to a first-line phase III registration study. And that was the birth of CLEOPATRA.
The path with pertuzumab has not been easy. It wasn’t clear that pertuzumab was going to be an addition. Initially, there were some concerns about the potential toxicity.
Do the agents work well together because they attack HER2 differently, or because of a cumulative effect?
The two antibodies work together because they have complementary mechanisms of action. One mechanism of HER2 activation is via ligand-independent HER2 activation. That is being blocked by Herceptin. Now, there’s another mechanism of HER2 activation and that’s via the formation of dimers with other members of the HER2 family of receptors and, most importantly, with HER3. HER3 plays a critical role and pertuzumab blocks HER3 from binding to HER2. What happens is that the ligand binds to HER3, HER3 gets close to HER2, they dimerize, and they signal. With trastuzumab and pertuzumab together, you are blocking at the same time the two known mechanisms of HER2 activation. That’s the basis of the effects that we’re seeing.
What role do you expect pertuzumab to play in treatment regimens?
I think pertuzumab will become a standard first-line therapy in HER2-positive disease. We also have started a worldwide adjuvant study with pertuzumab. In the same way that Herceptin has had the biggest impact in the early adjuvant disease setting, it is very likely that pertuzumab will be the same.
Will pertuzumab always be paired with trastuzumab?
It will have to be paired with trastuzumab, or with a trastuzumab-like concept. For example, there is a new compound that is being studied called T-DM1 that has a trastuzumab component, and possibly the combination of T-DM1 and pertuzumab also is going to have a synergistic interaction. Pertuzumab will always need a partner. This is not a solo drug to give.
tumors > 2 cm
(N = 455)
n = 154
n = 149
n = 152
Pathologic complete response (pCR)
cExcluded 15 patients because nodal status
could not be assessed.
†Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2- positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial [published online ahead of print January 17, 2012]. Lancet. 2012;379(9816):633-640.
Please discuss the results of the NeoALTTO trial.
NeoALTTO was a large neoadjuvant study in patients with resectable, HER2-positive breast cancer. The question we were asking is whether the combination of Herceptin and the tyrosine kinase inhibitor lapatinib is better than Herceptin alone. The study also questioned lapatinib alone versus the combination versus trastuzumab.
The way we decided to study that was by having, as a primary endpoint, complete pathological remission. In the field of HER2-positive breast cancer, there are a number of studies, including our own prior study NOAH, that have shown very consistently that pathological complete remission is a good surrogate marker of disease-free survival in the early-disease setting. So we felt that the primary endpoint of pathological complete remission was a solid endpoint.
The study design had six weeks of just biological therapy: in one arm, trastuzumab; in the other, trastuzumab/ lapatinib; and in the third, lapatinib alone. Then at week 6, we would continue with the same biological therapy and we would add paclitaxel weekly for a total of 12 more weeks. So the total duration of therapy was 18 weeks. After surgery, everybody was to receive three cycles of chemotherapy, followed by one year of the HER2 biological therapy that they were getting.
The study had mandatory biopsies on week 2 on everybody and a tumor assessment of response at week 6 at the end of the biological window period. We wanted to know the response rate to biological therapy. So it was a complex clinical trial design that would be able to provide us with many answers.
What we reported in the journal The Lancet were the results of the primary endpoint, which is the pathological complete remission, but what we observed is that the combination of trastuzumab and lapatinib improved the rate of pathological complete remission. We went from 24% to 52% complete remission, and lapatinib was not that different than trastuzumab in this setting. The important information is the very positive outcome of the study that validates the concept of dual HER2 blockade, and that we also have various tumor samples from all participating patients, so now we have the capacity to investigate biomarker responses.
The NeoALTTO study has a companion study called the ALTTO that is addressing the same questions in the adjuvant setting. It is a huge study with 8000 patients. The study is fully accrued, and we should be getting results soon.
NeoALTTO is the experimental arm of the ALTTO study. We’re looking at the samples and at the tumor biopsies, and we are able to postulate hypotheses that we can then check. It’s a new model in which you have an approach that goes with the neoadjuvant study and an adjuvant study. These two studies are companions, and we can obtain information from both that is meaningful.
What are the implications of the NeoALTTO results?
We were very happy to see these results, and I think they provide support for the concept that dual HER2 blockade is better than single blockade. And also, it gives us a very strong message that it is feasible and appropriate to test new drugs earlier in disease. We have been developing therapies in patients with late-stage cancer, and there’s a level of concern that in that patient population we might be missing some very active compounds. I think that NeoALTTO is a tribute to the possibility of studying new concepts earlier in disease.
What are the potential indications for lapatinib regimens?
The mechanism of action of lapatinib is partially complementary to Herceptin. Lapatinib is a tyrosine kinase inhibitor and a very good signaling inhibitor of HER2.
If the ALTTO study is positive, the new first-line standard of care in the adjuvant setting or in the neoadjuvant setting could be lapatinib plus Herceptin plus chemotherapy. Then the new standard in the first-line setting would be pertuzumab with Herceptin. In a way, they are very similar concepts. Dual HER2 blockade, in both settings, could become the new standard of care.
Things are moving so quickly that if you’re asking me what’s going to be the standard of care two years from now, I could not possibly tell you.
Did the tumors of any participants in the NeoALTTO study disappear with lapatinib, eliminating the need for surgery?
We had a lot of patients who had major responses with the HER2 therapy alone prior to the entry of chemotherapy. We had close to 60% of patients who had a response. In 50% of the cases with the combination, when surgeons go in, they don’t find any tumor left. One could question whether surgery would be indicated. We don’t know the answer.
José Baselga, MD, PhD, in his office at Massachusetts General Hospital Cancer Center in Boston.
Where do you see the need for biomarkers in breast cancer?
I think the need for biomarkers is in every single area of breast cancer. We need to understand which are the HER2-positive tumors that are really sensitive to therapies. Biomarkers and genomics should assist us in making better choices of therapy.
We need to continually connect our efforts to breast cancer up front and to incorporate tumor sequencing early in the game. So, for example, we have here very vibrant clinical trials with PI3 kinase inhibitors. And we know that tumors that harbor PI3 kinase mutations may be more sensitive to PI3 kinase alpha inhibitors. So that’s a marker that we are using to select the right patients for some of our trials.
How is Massachusetts General Hospital Cancer Center researching gene mutations in patients?
This center is one of the pioneers, if not the pioneer in sequencing gene mutations and doing so very efficiently. Last year, we sequenced, in collaboration with pathology, over 2000 tumors from patients that we see in the clinic. For example, the HER2 patients we see here have their tumors sequenced. Within 15 days, we have the results in our system. Those data go into the chart, along with protocols that could help that patient based on the mutation.
Things are moving so quickly that if you’re asking me what’s going to be the standard of care two years from now, I could not possibly tell you.”
We are building a Web-based system that will have, for any given mutation, a layman’s explanation on what that mutation means, and potential clinical trials available here and elsewhere against that mutation. Another area will be for the referring physician; it will be a technical page explaining what the analysis shows, what the implications of that finding are, and then the clinical trials available.
That’s the way we envision the future. That’s one of the ways we need to implement personalized cancer care—by sequencing these tumors and putting the information in the chart so that it’s available to the patient and to the physician so they can make decisions.