The OBR Blog

December 12, 2014 - 11:12 am Posted in SABCS Conference Coverage comments0 Comments

Immunotherapy is all the rage these days in oncology, and there is particular interest in those agents that target programmed death 1 (PD-1) and its ligand, PD-L1. In several solid tumors (and hematologic tumors as we saw at ASH last week) there is a race to market for this class of compounds by multiple competitors. Data presented in the past two years in melanoma have been impressive and have led to approvals of Keytruda® (pembrolizumab, Merck; U.S. FDA approval September 2014) and Opdivo® (nivolumab, BMS/Ono; Japanese MHLW approval July 2014 ) in advanced/metastatic disease and will likely lead to approvals in other indications in the near future (non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) are nearest term). Robust research in this area continues to push into additional indications, including breast cancer. In general, breast cancer is seen as less responsive to immunotherapy, and there has been some skepticism about the ability of immunotherapy to deliver.  In particular, mutant proteins that serve as “neo-antigens” to the immune system are very low in breast cancer compared to other solid tumors.1 However, high levels of tumor-infiltrating lymphocytes (TILs) do seem to predict pathological complete response (pCR) in breast cancer patients,2 suggesting that the immune system is an important factor in the fight against this disease.

The question as to whether or not immunotherapy can be successful in breast cancer began to be answered Wednesday, December 10, 2014, at the San Antonio Breast Cancer Symposium (SABCS) with two presentations demonstrating early signals of activity for PD-1 and PD-L1 inhibitors in triple-negative breast cancer (TNBC) patients. Wednesday’s oral general session was the venue for the first results of Keytruda in 32 advanced TNBC patients treated in the ongoing Phase Ib KEYNOTE-012 study.3 The trial enrolled heavily pretreated patients (47% had three or more prior lines of chemotherapy) with PD-L1+ disease and treated them with pembrolizumab monotherapy at 10 mg/kg every two weeks. In 27 evaluable patients, the objective response rate (ORR) was 18.5% (1 CR, 4 PR) and median duration of response (DoR) was not reached (range, 15-40+ weeks), with three of five responders remaining on therapy for 11+ months. Adverse events (AEs) were mostly Grade 1/2, including fatigue (18.8%), arthralgia (18.8%), myalgia (15.6%) and nausea (15.6%). Grade 3/4 treatment-related AEs occurred in four patients – anemia, headache, meningitis aseptic, decreased blood fibrinogen and pyrexia – with two patients discontinuing drug due to AEs. There was also one death due to disseminated intravascular coagulation (DIC). Based on this encouraging data, the presenter, Dr. Nanda, disclosed Merck’s plans to start a Phase II trial in TNBC in the first half of 2015 and hinted during the Q&A at plans to pursue the other breast cancer subtypes, such as HER2+ patients, who may also be susceptible to immunotherapy. Small trials, such as PANACEA (NCT02129556), which will examine Keytruda in combination with Herceptin® (trastuzumab, Genentech/Roche/Chugai) in advanced Herceptin-resistant HER2+ breast cancer, should start recruiting soon.

Also on Wednesday, there was a poster presentation of data from a small cohort of 12 patients in the ongoing Phase Ia dose-escalation study of MPDL3280A (anti PD-L1, Genentech/Roche/Chugai), which evaluates doses of 0.3-20 mg/kg every three weeks in previously treated patients with advanced, PD-L1+ TNBC. 4 In nine evaluable patients, ORR was 33% (1 CR, 2 PR); however, there were an additional two responders who were initially pseudo-progressors and were not included in the calculated ORR. Grade 3/4 treatment-related AEs occurred in only one patient, and no dose-limiting toxicities occurred. Further evaluation of MPDL3280A is ongoing in both PD-L1-positive and -negative TNBC patients (NCT01375842).

In both studies, response was measured by RECIST criteria, not immune-related-response criteria that take into account that some patients on immunotherapy initially progress before responding. Had these alternative criteria been used, perhaps the ORR would have been higher. Despite this, the ORR reported in these two studies (19% and 33%) are similar to the ORR reported for PD-1 / PD-L1 inhibitors in other solid tumors ( 31%-34% in melanoma,5,6 17%-21% in NSCLC,7,8,9 20% in RCC and head and neck10,11). Perhaps more important than the response rate is the extent to which the PD-1/PD-L1 inhibitors are able to slow the progression of disease and prolong survival. The duration of response data for Keytruda is the only piece of data that is yet available to guide toward an answer to this question in breast cancer, but it is a promising start – metastatic TNBC has a notoriously poor prognosis, and to see duration of response nearing one year in later lines of therapy is very encouraging. What will be more encouraging is to see an OS benefit extending beyond just those patients who achieve an objective response, as we have come to expect from immunotherapies in many tumors.

Despite the small cohort of patients and limited data, discussant Dr. Disis was very positive on the results and called for researchers to move ahead and consider combination trials in breast cancer. This is a bit of a departure from typical breast cancer treatment strategies, which tend to focus on sequential monotherapies rather than combination regimens. The immunotherapy field is beginning to explore combination approaches in other solid tumors, so extending that idea to breast cancer isn’t novel. The approach Keytruda is taking (combining with Herceptin) is somewhat expected in breast cancer, although is limited to HER2+ patients. In TNBC patients, however, no targeted therapy options are yet developed with which to combine; chemotherapy thus becomes the de facto combination partner (Celgene is conducting a Phase I trial that includes study of Opdivo with Abraxane® (nab-paclitaxel) in second-line HER2-negative disease (NCT02309177)), although this approach negates the low-toxicity advantage that immunotherapy is meant to afford.  

Breast cancer is the most commonly diagnosed cancer in the U.S. and Europe and is the second most commonly diagnosed cancer globally. Given the large number of patients involved, it is somewhat surprising that the checkpoint inhibitors haven’t been more widely developed in this disease. Perhaps higher unmet need drove early development of PD-1/PD-L1 inhibitors toward other malignancies, but the tides may now be shifting. It seems the immunotherapy wave has finally hit the shores of the breast cancer landscape.


  1. Disis M., Discussant Oral Session 1, SABCS 2014
  2. Loi S., Educational Session: Introduction to Immunotherapy, SABCS 2014
  3. Nanda R., Abstract S1-09, SABCS 2014
  4. Emens L.A., Abstract PD1-06, SABCS 2014
  5. Ribas, Abstract LBA9000, ASCO 2014
  6. Weber, Abstract LBA3, ESMO 2014
  7. Brahmer, Abstract 8030, ASCO 2013
  8. Rizvi, Abstract 8007, ASCO 2014
  9. Spigel, Abstract 8008, ASCO 2013
  10. Motzer, Abstract 5009, ASCO 2014
  11. Seiwert, Abstract 6011, ASCO 2014

By: Stephanie Hawthorne, Ph.D., Senior Director, Clinical and Scientific Assessment, Kantar Health and Mara Jeffress, Ph.D., Associate Consultant, Clinical and Scientific Assessment, Kantar Health

December 13, 2013 - 01:12 pm Posted in SABCS Conference Coverage comments0 Comments

Designing resource efficient development programs to identify drug candidates that should be advanced to late stage development and to determine the most useful trial design and/or target patient population for a Phase III trial are ongoing challenges for drug manufacturers. The I-SPY 2 trial is an innovative “find a winner” trial that aims to address some of these challenges by screening a number of different novel experimental agents in the neoadjuvant setting in combination with a standard chemotherapy regimen of paclitaxel followed by AC compared to standard chemotherapy alone. In this novel trial design, the randomization of patients to treatment arms is adaptive, with randomization probabilities continuing to be updated as the trial progressed. When an experimental treatment arm has enrolled 60-120 patients, an algorithm is used to decide whether that experimental regimen should “graduate.”  Graduating from the trial is defined as having at least an 85% likelihood of success in a randomized Phase III trial in the neoadjuvant setting with a target enrollment of 300 patients and an endpoint of pathological complete response (pCR).  Based on biomarker/subtype testing of patients after enrollment, experimental agents can graduate in a variety of patient segments, such as HER2+/HR-, triple negative disease, and HER2-/HR+.

Multiple pharmaceutical companies are participating in this trial, which to date has been investigating seven different experimental regimens.  Results from the first experimental regimen to graduate, the combination of the PARP inhibitor veliparib (AbbVie) and carboplatin, were presented at 2013 San Antonio Breast Cancer Symposium (SABCS) annual meeting on Friday, December 13.1 Enrollment to the veliparib plus carboplatin experimental arm was only allowed for HER2- patients, making the regimen eligible to graduate in three different patient populations: all HER2- patients, HER2-/HR+ patients, and triple negative patients. A total of 72 patients were randomized to receive veliparib plus carboplatin in combination with standard neoadjuvant chemotherapy, and 44 HER2- patients who were concurrently randomized to receive standard neoadjuvant chemotherapy alone were used as a control.

The addition of veliparib and carboplatin to standard neoadjuvant chemotherapy improved the estimated pCR in triple negative patients, but not in HER2-/HR+ patients. Although actual pCR rates in the study arms were not calculated because of a concern over bias due to the adaptive randomization in the trial design, a Bayesian model was used to provide estimated pCR rates. In HER2-/HR+ patients, the estimated pCR rate was 14% in the veliparib/carboplatin arm and 19% in the control arm, with a 28% probability that the combination is superior to control. In this patient population, the veliparib/carboplatin arm met the criteria for futility, with a 9% predictive probability of success in a Phase III trial. In contrast, the estimated pCR rate in triple negative patients was 52% in the veliparib/carboplatin arm compared to 26% in the control arm, with a 99% probability that the combination is superior to the control. In this patient population, the veliparib/carboplatin arm met the trial’s criteria for graduation, with a 90% predictive probability of success in a Phase III trial.

While the utility of the I-SPY 2 trial design will not be able to be fully evaluated until after the drug regimens in multiple experimental arms either meet criteria for futility or graduate and are subsequently advanced through successful Phase III programs, these data provide an early signal of the benefits of this novel trial design. With the efficient, collaborative design of this trial, data were able to be provided on the efficacy and potential Phase III success of the veliparib/carboplatin regimen in multiple patient segments based on enrollment of fewer than 100 patients into the experimental arm. Of course, these data are not without caveats; for example, the trial design does not allow for a comparison that could evaluate the relative contributions of the veliparib portion of the regimen and the carboplatin portion of the regimen to the efficacy of the combination. Theoretically, it could be possible that the enhanced efficacy of the regimen is due primarily to the effect of the added carboplatin, and results from an additional trial would be necessary to determine whether or not that is the case. However, for an agent like veliparib, which, if it does enter Phase III development, would be competing with other PARP inhibitors like BMN 673 (BioMarin) and olaparib (AstraZeneca) in a race to be the first agent in this drug class to enter the market for breast cancer, the benefits of this type of collaborative, relatively high throughput type of screening in early stage clinical development will likely provide an important benefit of identifying an appropriate patient population for late stage development, with potentially less time and cost. The results of additional I-SPY 2 experimental arms, as well as the results of late stage development of I-SPY 2 graduates (Puma Biotechnology recently announced the graduation of neratinib in HER2+/HR- patients; Puma press release, December 4, 2013), will be eagerly awaited to see if the potential benefits of this type of innovative trial will be borne out in practice.


  1. Rugo et al., SABCS 2013, Abstract S5-02

By: Stephanie Hawthorne, PhD, Director, Clinical and Scientific Assessment, Kantar Health and Cory Blaiss, PhD, Analyst, Clinical and Scientific Assessment, Kantar Health

December 13, 2013 - 01:12 pm Posted in SABCS Conference Coverage comments2 Comments

There are a variety of known risk factors for developing breast cancer, such as obesity, nulliparity, and age at time of menarche and menopause.1 For patients with a particularly high risk of developing breast cancer, including those who have a family history of the disease or have tested positive for deleterious BRCA1 or BRCA2 mutations, there are several options available for risk reduction. Patients may receive closer breast cancer screening, prophylactic mastectomy or oophorectomy, or treatment with a chemoprevention agent. Currently, two hormonal agents, tamoxifen and raloxifene, are FDA approved to reduce the risk of breast cancer in patients at high risk of developing the disease. Exemestane, an aromatase inhibitor (AI), is another agent available for chemoprevention; although it has not been approved by the FDA for this purpose, it has a Category 1 recommendation in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines.2

At a session on December 12 at the San Antonio Breast Cancer Symposium (SABCS) 2013 annual meeting, results were presented from the Phase III IBIS-II trial that evaluated whether another AI, anastrozole, can prevent the development of breast cancer in women at increased risk of the disease.3 This trial randomized 3,684 post-menopausal women aged 40-70 at increased risk of developing breast cancer to receive either placebo or anastrozole (1 mg/day) for a period of five years. Patients could be classified as high risk based on a variety of factors, such as family history, atypia/LCIS, or increased breast density.

After seven years of follow-up time, there was a significantly lower incidence of all breast cancer (2.8% vs. 5.6%, HR=0.47, p<0.0001) and estrogen receptor (ER)-positive invasive breast cancer (1.4% vs. 3.3%, HR=0.42, p<0.001) in the anastrozole arm compared to the placebo arm (see Table 1). A subgroup analysis found that this benefit of anastrozole treatment applied to the development of DCIS (HR=0.47) and invasive ER-positive invasive breast cancer (HR=0.42), but there didn’t appear to be a benefit in preventing the development of invasive ER- breast cancer (HR=0.78, confidence interval crossed “1”).

In the chemoprevention setting where a drug is administered to patients who are currently healthy, safety takes on increased importance. Importantly, anastrozole was well-tolerated by patients. There was an increase in musculosketal adverse events (primarily arthralgia, joint stiffness, and carpal tunnel) in the anastrozole arm (63.9% vs. 57.8%), but since there was such a high rate of musculosketal AEs in the placebo arm, most of these AEs are probably not treatment related. There was also a slight and non-significant increase in the incidence of fractures in patients who received anastrozole (8.5% vs. 7.7%), an important consideration since treatment of breast cancer patients with an AI generally results in decreased bone mineral density. Interestingly, Dr. Cuzick, who presented the data, also mentioned that there was a reduction in other (non-breast) cancers in the anastrozole arm, mainly skin cancers, but because that slide was missing from the presentation, the audience was unable to evaluate those data. As would be expected with five years of drug therapy in healthy people, compliance decreased in both arms across the five years of treatment; at the end of treatment, the compliance rate was slightly but significantly lower in the anastrozole arm (68% vs. 72%, HR=0.84, p<0.005).

How do these data from the IBIS-II trial compare to the data for other chemoprevention agents in breast cancer? In the Phase III NSABP P1 trial, the risk ratio of the development of invasive breast cancer with tamoxifen compared to placebo was 0.51 after 69 months of follow-up time.4 During an 81 month (almost 8 years) follow-up of STAR trial comparing raloxifene to tamoxifen in high risk patients, raloxifen was less effective than tamoxifen in reducing the incidence of invasive breast cancer in high risk patients (risk ratio = 1.24).5 Although tamoxifen appears to be more effective than raloxifene, it comes along with a number of toxicities, including increased incidence of invasive endometrial cancers. In the MAP.3 trial, exemestane reduced the incidence of invasive breast cancer compared to placebo with an impressive hazard ratio of 0.33, with a more benign safety profile than tamoxifen.6 From the IBIS-II results, it appears that anastrozole is more effective and less toxic than tamoxifen; compared to exemestane, it appears to be slightly less effective, with a relatively similar safety profile.

Although longer-term follow-up data for anastrozole will likely be necessary to confirm a reasonable safety profile in this setting, the IBIS-II data suggest that anastrozole could be a new option for breast cancer chemoprevention. However, will it be utilized in practice? Although tamoxifen was approved by the FDA 15 years ago to reduce the development of breast cancer in high risk patients, it is rarely utilized in high-risk patients.7,8 This lack of utilization is likely due to the safety profile of tamoxifen; it could be daunting for a generally healthy high-risk patient to consider the prospect of multiple years of a treatment that can be accompanied by non-trivial adverse events. In this setting, a benign safety profile of a drug will likely be critical for utilization.

In addition, competitive landscape in this segment of the market is complicated by the fact that the different available agents for breast cancer chemoprevention are not only competing against each other, but they are competing against other non-drug treatment options, such as prophylactic mastectomy. While this type of prophylactic surgery can certainly have its own downsides, it does have the advantage of taking a shorter amount of time compared to the long five year commitment for treatment with hormone therapies.  It is also probable that patient preferences for the different treatment options available for breast cancer prevention in high risk patients could be influenced by media coverage and popular trends, such as the flood of media coverage of prophylactic mastectomy when actress Angelina Jolie elected to undergo this type of surgery after testing positive for a BRCA mutation. However, for this type of very personal decision, an increasing number of available options can only be a positive development for patients.


  1. Centers for Disease Control,
  2. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Breast Cancer Risk Reduction, Version 1.2013.
  3. Cuzick et al., SABCS 2013, Abstract S3-01.
  4. Fisher et al., J Natl Cancer Inst, 1998.
  5. Vogel et al., Cancer Prev Res, 2010.
  6. Goss et al., N Engl J Med, 2011.
  7. Taylor et al., Ann Fam Med, 2005.
  8. Waters et al., Cancer Epidemiol Biomarkers Prev, 2010.

By: Stephanie Hawthorne, PhD, Director, Clinical and Scientific Assessment, Kantar Health and Cory Blaiss, PhD, Analyst, Clinical and Scientific Assessment, Kantar Health

December 12, 2013 - 02:12 pm Posted in SABCS Conference Coverage comments0 Comments

Endocrine therapy is a mainstay of therapy for breast cancer patients with estrogen receptor (ER) and/or progesterone receptor (PR) positive disease, with use in the adjuvant setting for early stage disease as well as in the metastatic setting.  In the first-line metastatic setting, aromatase inhibitors (AI) can offer clinical benefit in post-menopausal ER+/PR+ patients, with progression-free survival (PFS) in clinical trials ranging from eight to 10 months.1 However, patients will eventually become resistant to endocrine therapy such as AIs, and that point, treatment often needs to shift to use of the more toxic chemotherapy options.

In recent years, as researchers have started to better understand the ER’s interaction with other cellular signaling pathways and the role that cross-talk between these pathways and the ER may play in the development of resistance to endocrine therapy, there has been increasing interest in and investigation of the ability of targeted therapies in combination with endocrine therapy to improve outcomes in ER+ patients, potentially through postponing the development of resistance or “re-sensitizing” patients with acquired resistance.

Sprycel® (dasatinib, Bristol-Myers Squibb) is a multi-targeted tyrosine kinase inhibitor that is currently approved for use in chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia. Sprycel inhibits the Bcr-Abl fusion protein that is present in CML patients. However, it is also known to inhibit c-KIT, PDGFR, Ephrin, and Src kinases.  Because there is evidence that Src interacts with the ER and may potentially play a role in the development of hormonal resistance,2 Sprycel was investigated in ER+ breast cancer patients.

A Phase II trial evaluated the efficacy and safety of first-line Sprycel in combination with the AI letrozole and results were presented at the 2013 San Antonio Breast Cancer Symposium (SABCS) meeting on the morning of Thursday, December 12.3 In this trial, post-menopausal, ER+, HER2- patients with metastatic breast cancer (mBC) who were AI-naïve were randomized to receive either letrozole alone (n=63) or letrozole plus Sprycel (n=57).  Of patients who had received prior therapy in the adjuvant setting, 39% and 48% of patients in the Sprycel plus letrozole and letrozole alone arms, respectively, had received adjuvant chemotherapy; 32% and 37% of patients, respectively, had received adjuvant tamoxifen. A very small minority of patients (2% in Sprycel plus letrozole and 10% in letrozole alone arms) received an AI in the adjuvant setting, but these patients were required to have stopped adjuvant AI therapy at least a year before entry into the study.

The combination of Sprycel plus letrozole showed very promising clinical activity. The median PFS in patients who received Sprycel plus letrozole was 20.1 months, more than double the median PFS of 9.9 months seen in patients who received letrozole alone (see Table 1). This was a non-comparative trial that was not designed for a comparison between treatment arms; however, there was an exploratory PFS hazard ratio of 0.69. In contrast, the Sprycel plus letrozole combination did not appear to offer any major improvement in clinical benefit rate (CBR; objective responses plus stable disease) over letrozole alone (71% vs. 66%). There appeared to be more limited benefit in patients who had received prior letrozole, as patients who crossed over from the letrozole arm to the Sprycel plus letrozole arm upon progression had a clinical benefit rate of 23%.

As would be expected, the addition of Sprycel to letrozole treatment did add some toxicity, and 26% of patients in the Sprycel plus letrozole arm required a Sprycel dose reduction. However, Sprycel was generally well-tolerated and there were no new safety signals compared to the general safety profile that has been observed in CML patients. The most commonly observed adverse events (AEs) were fatigue, rash, nausea, edema, and neutropenia.

The strong efficacy results from this trial could support a move into Phase III development, but BMS’ development plans for Sprycel in this setting are not currently known. If Sprycel does move into Phase III development, it will enter an increasingly competitive corner of the market. Based on the results of the Phase III BOLERO-2 trial,4 the mTOR inhibitor Afinitor® (everolimus, Novartis) was approved in July 2012 in the United States and the European Union for use in post-menopausal ER+/PR+ and HER2- patients who have received prior treatment with an AI (i.e., second-line treatment or later).  The pan-PI3K inhibitor buparlisib (BKM120, Novartis) is also being investigated in two Phase III trials in the second- and third-line settings. The BELLE-2 trial is evaluating Faslodex with or without buparlisib in post-menopausal ER+/HER2- patients who have received prior treatment with an AI, and the BELLE-3 trial is evaluating Faslodex with or without buparlisib in post-menopausal ER+/HER2- patients who have received prior treatment with an AI as well as an mTOR inhibitor (most likely Afinitor).

Both Afinitor and buparlisib are currently positioned for relapsed/refractory metastatic ER+/HER2- patients, and if Sprycel were to enter Phase III development in the first-line metastatic ER+/HER2- setting, it wouldn’t be competing in the same line of therapy as these agents. However, it would be competing directly with palbociclib, the CDK 4/6 inhibitor that has received Breakthrough Therapy status from the U.S. Food and Drug Administration (FDA). Palbociclib is currently being evaluated in combination with letrozole in a Phase III trial in first-line ER+/HER2- metastatic patients.

How does the efficacy data for Sprycel stack up against that for palbociclib? As would be expected considering its Breakthrough Therapy designation, the Phase II data for palbociclib set an extremely high bar for efficacy in this setting, and the initial Phase II results for palbociclib was one of the most-discussed presentation of the 2012 SABCS annual meeting. In this Phase II trial, the addition of palbociclib to letrozole as first-line therapy for post-menopausal ER+/HER2- metastatic patients significantly improved PFS from 7.5 months to 26.1 months, with an impressive hazard ratio of 0.37 (p<0.001).5 In addition, the clinical benefit rate was increased from 44% in the letrozole alone arm to 70% in the palbociclib plus letrozole arm. While the Phase II data presented for Sprycel plus letrozole do not match this high benchmark, the median PFS of 20.1 comes quite close to the remarkable 26.1 month median PFS for palbociclib. While Sprycel would not be likely to outcompete palbociclib on efficacy based on these results alone, it is always possible that the situation could change with results from a Phase III trial, and the promising PFS result for Sprycel certainly provides hope that this strategy for combining hormone therapy with targeted therapies will prove to have a major impact on outcomes for ER+/HER2- patients with metastatic disease.

As hormone therapy generally has a relatively benign safety profile, safety will also be another major factor when physicians are considering whether to add a targeted therapy to hormone therapy in metastatic ER+/HER2- patients.  While Sprycel is clearly well-tolerated enough to be administered to CML patients for relatively long durations, palbociclib was also generally well-tolerated. However, in the Phase II trial, the addition of palbociclib did markedly increase the incidence of Grade 3/4 neutropenia compared to letrozole alone (51% vs. 1%). Therefore, Sprycel could potentially end up with a slight advantage over palbociclib in terms of safety. In this patient population, where physicians attempt to prolong the time on hormone therapy in order to avoid the poor safety profiles of the more toxic chemotherapy regimens, safety will likely play a major role in physicians’ decisions among available agents.

Although the landscape for the treatment of post-menopausal, metastatic ER+/HER2- breast cancer patients is clearly on track to become a crowded market in the future, the increasing number of agents in development offer the hope of significant advances in outcomes for these patients in upcoming years.

By: Stephanie Hawthorne, PhD, Director, Clinical and Scientific Assessment, Kantar Health and Cory Blaiss, PhD, Analyst, Clinical and Scientific Assessment, Kantar Health


  1. Bonneterre, JCO, 2001; Nabholtz, JCO, 2003; Mouridsen, JCO, 2003
  2. Vallabhaneni et al., Breast Cancer Res, 2011; Renoir et al., Biochem Pharmacol, 2013
  3. Paul et al., SABCS 2013, Abstract S3-07
  4. Baselga et al., NEJM, 2012
  5. Finn et al., SABCS 2012, Abstract S1-06
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