The OBR Blog

June 01, 2019 - 06:06 pm Posted in ASCO Conference Coverage Posted in Breast Posted in Lung (includes NSCLC, SCLC, Mesothelioma) Posted in Ovarian Posted in Stomach (Gastric) Cancer comments0 Comments

Several late-breaking studies made a splash today at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting. During the press conference this morning, results from the phase III MONALEESA-7 and KEYNOTE-062 trials were presented as well as long-term survival data from the KEYNOTE-001 trial. In the afternoon, a poster session featured a late-breaking study about the impact of the Affordable Care Act (ACA) in ovarian cancer.

Adding Ribociclib to Endocrine Therapy Improves Survival (Abstract LBA1008)

The addition of ribociclib, an oral CDK 4/6 inhibitor, to frontline endocrine therapy significantly extended overall survival (OS) for premenopausal women with advanced hormone receptor-positive/HER2-negative breast cancer, according to data from the phase III MONALEESA-7 trial.

Participants (N=672) were randomly assigned to received endocrine therapy plus ribociclib or endocrine therapy plus placebo. At a median follow-up of 34.6 months, 35% of patients in the ribociclib arm and 17% in the placebo arm were still receiving the assigned treatment.

The median OS was not yet reached for the ribociclib arm and 40.9 months for the placebo arm, resulting in a 29% relative reduction in risk of death for the ribociclib arm (HR=0.712; 95% CI, 0.535 – 0.948; P=0.00973). At 42 months of follow-up, the estimated OS rate was higher for the ribociclib arm compared with the placebo arm (70.2% vs 46.0%).

“This is the first time a statistically significant improvement in overall survival has been observed with a CDK 4/6 inhibitor in combination with endocrine therapy in patients with hormone receptor-positive advanced disease,” said study presenter Sara A. Hurvitz, MD, Director of the Breast Cancer Clinical Research Program at UCLA Jonsson Comprehensive Cancer Center.

Pembrolizumab in Gastric Cancer May be Safer Than Chemo (Abstract LBA4007)

Compared with chemotherapy, pembrolizumab alone had similar survival and less toxicity in the first-line setting for patients with PD-L1−positive, HER2-negative, advanced gastric or gastroesophageal junction (G/GEJ) cancer in the phase III KEYNOTE-062 trial. A survival benefit with pembrolizumab was seen in patients with tumors that had high PD-L1 expression—defined as a combined positive score of at least 10.

In terms of toxicity, 54.3% of patients who received pembrolizumab had a treatment-related adverse event and 16.9% had a grade 3 or higher adverse event. In contrast, 91.8% of patients who received chemotherapy had a treatment-related adverse event and 69.3% had a grade 3 or higher adverse event.

“For patients with advanced gastric or gastroesophageal cancer, pembrolizumab should really, in many cases, replace chemotherapy as a first-line treatment for this population,” said ASCO Expert Richard L. Schilsky, MD, Senior Vice President and Chief Medical Officer of ASCO.

5-Year Survival Rates for NSCLC Leap Forward with Pembrolizumab (Abstract LBA9015)

Pembrolizumab improved 5-year survival rates for advanced non-small cell lung cancer patients (NSCLC), according to long-term data from the multicohort phase Ib KEYNOTE-001 trial. At 5 years of follow-up, 18% of trial participants (100 of 550) were still alive. By comparison, before the advent of pembrolizumab, the average 5-year survival rate for advanced NSCLC was 5.5%.

Higher PD-L1 tumor proportion score (TPS) was linked to better survival, particularly among treatment-naïve patients—29.6% with a PD-L1 TPS of 50% or greater were still alive 5 years later compared with 15.7% with a PD-L1 TPS between 1% and 49%.

Among patients who received at least 2 years of pembrolizumab treatment and were still alive at data cutoff (n=46), the 5-year OS rate was 78.6% for treatment-naïve patients and 75.8% for previously treated patients. The objective response rate was 86% for treatment-naïve patients and 91% for previously treated patients.

ACA Linked to Better Diagnosis and Treatment of Ovarian Cancer (Abstract LBA5563)

After the implementation of the ACA in 2010, women with ovarian cancer had an increased likelihood of being diagnosed at an early stage and receiving treatment within 30 days of diagnosis, a poster reported.

The study researchers used data from the National Cancer Database and assessed early stage at diagnosis (I/II vs III/IV) and time to treatment (<30 days vs ≥30 days) in women aged 21 to 64 with ovarian cancer (n=72,987) and compared that to women aged 65 or older with ovarian cancer (N=59,499). The study time period defined 2006 to 2009 as before the ACA and 2011 to 2014 as after the ACA.

A difference-in-differences (DD) approach showed a trend toward increased diagnosis among younger women (DD=1.7%; 95% CI, 0.7 – 2.7; P=0.001) and reduction in delays in treatment of 30 days or greater (DD=−1.6%; 95% CI, −0.7 to −2.7; P=0.001) after the ACA was implemented.

“As stage and treatment are major determinants of survival, these gains under the ACA may have long-term impacts on women with ovarian cancer,” concluded the investigators.

Christina Bennett, MS

 

One of biggest challenges in attending an annual ASCO meeting is time management. With over 2,000 abstracts submitted this year and a wide variety of new drugs and therapeutic targets, ASCO 2019 will be no different.

During a webinar last week sponsored by E-Squared Communications (a Conisus company), OBR and three renowned cancer experts helped identify some of the “high impact studies” that are sure to gain a lot of attention at this year’s ASCO Annual Meeting. For those of you who missed this increasingly popular annual webinar, the experts not only covered the important data but also provided some suggestions on where to go if you happen to play hooky for a day at ASCO. Don Sharpe, President and Founder of OBR, moderated the session, and the primary areas of focus included cervical, prostate, pancreatic, breast, lung, and advanced gastric/gastroesophageal junction cancers as well as multiple myeloma and hepatocellular carcinoma (HCC).

Pending its final outcome, the first trial highlighted in the webinar could well be a practice-changing study. This phase 3 Intergroup trial (E3A06) in patients with asymptomatic intermediate- or high-risk smoldering multiple myeloma is the largest randomized trial in this setting to date. The 182 patients who participated in this study were randomized to either receive lenalidomide alone or observation, with progression-free survival (PFS) being the primary endpoint. At a median of 28 months of follow-up, the 3-year PFS rate in the lenalidomide arm seems to be numerically trending in the right direction (91% vs. 66%). This data will be highlighted in an oral abstract (8001) session on Sunday, June 2nd.

Following an interesting review of a phase 2 study highlighting the use of LN-145 tumor infiltrating lymphocytes in patients with cervical cancer, the next phase 3 study highlighted by the experts was a late-breaking abstract. This Australian and New Zealand Urogenital (ANZUP) Cooperative Group trial (ENZAMET) evaluated enzalutamide as first-line androgen-deprivation therapy for metastatic hormone-sensitive prostate cancer. The abstract LBA2 will be presented at the plenary session on Sunday, June 2nd and is sure to draw comparisons to the earlier LATITUDE study of abiraterone in this setting.

Pancreatic cancer seems to be climbing into the spotlight as well this year, as the OBR experts identified the Adjuvant Treatment in Pancreatic Cancer Study (APACT) as an important one to watch. This study evaluated nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with surgically resected pancreatic cancer. With 866 patients enrolled, this large clinical trial had a primary endpoint of disease-free survival; however, the authors noted that the overall survival (OS) results seen in this study may better support the rationale of using this combination in the adjuvant setting, especially for patients who are ineligible for FOLFIRINOX.

The PARP inhibitor olaparib was also discussed in the webinar as a potentially new therapeutic option for patients with pancreatic cancer. The phase 3 POLO trial of olaparib versus placebo as maintenance therapy in patients with germline BRCA-mutated metastatic pancreatic cancer whose disease had not progressed following first-line platinum-based chemotherapy will be highlighted during the plenary session on Sunday, June 2nd (LBA4). This study is the first positive phase 3 trial of any PARP inhibitor in germline BRCA-mutated metastatic pancreatic cancer.

Pembrolizumab was highlighted as well in two studies looking at gastric cancer and GEJ adenocarcinoma (KEYNOTE-062) and advanced HCC (KEYNOTE-240). In KEYNOTE-062, pembrolizumab met its primary endpoint by demonstrating OS noninferiority compared to chemotherapy in the intent-to-treat population. In KEYNOTE-240, pembrolizumab showed positive numerical trends but did not meet statistical significance for its co-primary endpoints of OS and PFS; however, it did show an improved response rate versus placebo (ORR 16.9% vs. 2.2%), and it will be interesting to see what impact this might have going forward.

Another important KEYNOTE study is KEYNOTE-189: Updated OS and progression after the next line of therapy (PFS2) with pembrolizumab (pembro) plus chemo with pemetrexed and platinum vs placebo plus chemo for metastatic nonsquamous NSCLC. KEYNOTE-001 is also a late-breaking abstract looking at 5-year long-term OS for patients with advanced non-small cell lung cancer treated with pembrolizumab.

There are certainly other important abstracts at this year’s ASCO Annual Meeting, but at the very least, this review should help narrow down your choices.

By Adrian Barfield, President, Medallion Healthcare

May 15, 2019 - 10:05 pm Posted in ASCO Conference Coverage Posted in Breast Posted in Multiple Myeloma Posted in Pediatric (includes Adolescents and Young Adults) comments0 Comments

In conjunction with the release of the abstracts for the upcoming 2019 ASCO Annual Meeting, a virtual press cast previewed five noteworthy studies that showcase the range of research that will be presented at the meeting.

Topics included the effect of a low-fat diet on breast cancer mortality, identification of a greater than expected number of targetable molecular alterationsin a pediatric MATCH trial, response of rare pediatric tumors with certain gene fusions to the targeted agent entrectinib, optimization of chemotherapy for frail and/or elderly patients with advanced esophageal cancer, and reduction of progression of smoldering to active multiple myeloma by lenalidomide.

Here are summaries of the key findings.

Low-Fat Diet Associated with Reduced Breast Cancer Mortality (Abstract 520)

Observational studies of the effect of dietary fat on breast cancer have produced equivocal results. To address this, the Women’s Health Initiative (WHI) Dietary Modification (DM) trial, a randomized, controlled study looked at the influence of diet breast cancer incidence and mortality.

The WHI-DM trial (NCT00000611) enrolled 48,835 post-menopausal women age 50 to 79 years who were randomly assigned to dietary intervention (n=19,541) or usual diet (comparison group, n=29,294) from 1993 to 1998. Dietary intervention, which continued for 8.5 years, included reducing fat intake to 20% of calories and increasing intake of vegetables, fruit, and grains, similar to the DASH (dietary approaches to prevent hypertension) diet.

Trial endpoints included deaths from and after breast cancer. Cumulative follow-up data have been collected for a median of 19.6 years. Baseline fat intake was at least 32% of calories. Most women in the diet group increased daily intake of vegetables, fruit, and grains and reduced daily fat consumption to 25% of calories; most did not reach the 20% goal.

In the diet group versus the comparison group, there was a significantly lower risk of death from breast cancer (HR, 0.85; 95% CI, 0.74, 0.96; P=.01) and from any cause after a diagnosis of breast cancer (HR, 0.79; 95% CI, 0.64, 0.96; P=.025).

The authors call this the only study providing randomized clinical trial evidence that an intervention can reduce a woman’s risk of dying from breast cancer, although this analysis was not pre-specified in the original trial design, dietary components were assessed by participant recall, and there was no way to measure adherence to the diet.

At the meeting, the effect of the same dietary modification in a subgroup of women with poor metabolic function, defined as obesity, diabetes, elevated cholesterol, or hypertension, will also be presented (Abstract 1539).

More Actionable Targets than Expected Found in Pediatric MATCH Trial (Abstract 10011)

The NCI-COG (Children’s Oncology Group) Pediatric MATCH (Molecular Analysis for Therapy Choice) trial was designed to address whether a precision oncology approach, i.e., treating tumors with agents selected to target specific genetic alterations, would be useful in the pediatric cancer setting.

NCI-COG Pediatric MATCH will enroll at least 1000 children with tumors that have not responded to standard treatment. The initial step is to screen tumors for potential targets, followed by treatment with therapy matched to alterations found in the tumors independent of tumor type. Treatment is in individual phase 2 clinical trials, of which there are currently 10, one for each current single-agent targeted therapy being tested.

There were 422 patients enrolled, from 93 of the 124 COG sites that had the study open, between July 24, 2017 and the data cutoff for this analysis at the end of last year. Tumor samples were received from 92% of enrolled patients and accounted for over 60 different tumor types including central nervous system (CNS) and non-CNS tumors. Turnaround time was 15 days from tumor receipt to treatment assignment.

Study researchers projected a match rate of 10% based on adult data. So far, 24% of screened patients with cancer that did not respond to treatment were eligible for treatment with a targeted agent. Of these, 39 patients (10%) have enrolled in a treatment trial. The trial is ongoing and is expected to add at least four additional single targeted agents. Combination therapies are being considered for future trials.

Rare Pediatric Tumors with Gene Fusions Respond to Entrectinib in Early Trial (Abstract 10009)

Fusions and alterations in intracellular signaling pathways such as TRKA/B/C, ROS1, and ALK genes act as drivers in some tumors by “locking” the pathways in the “on” position. Entrectinib is an oral inhibitor of these pathways and has the additional advantage of being able to cross the blood-brain barrier to enter the CNS.

Pediatric tumors with mutations in TRKA/B/C, ROS1, and ALK genes are rare, and are being identified more frequently as next-generation sequencing is becoming more common. STARTRK-NG (RXDX-101-03) is phase1/1b clinical trial investigating entrectinib in children with recurrent or refractory solid tumors with these gene alterations. Most had undergone prior surgery and radiation.

Of 29 patients enrolled, 16 were in the phase 1 dose-finding part; an additional 13 patients have been enrolled in the ongoing basket phase 1b part at a dose level of 550 mg/m2(initial recommended dose, n=7) or 400 mg/m2for those unable to swallow intact capsules. Diagnoses included primary CNS tumors (n=6), neuroblastoma (n=3), and extracranial solid tumors (n=4). Median patient age is 7 years.

Responses have been seen in all patients whose tumor had a target gene alteration and no responses were seen in patients whose tumors lacked aberrations in target kinases. Therefore, the trial will continue only for patients with target fusions. Presenter Giles W. Robinson, MD, St. Jude Children’s Research Hospital, Memphis, Tennessee, said, “It gives me great pleasure as pediatric brain tumor doctor to show response in CNS tumors” that would otherwise probably have been fatal.

Dose-limiting toxicities included elevated creatinine, dysgeusia, fatigue, and pulmonary edema. Weight gain, problematic for some patients, also occurred as an on-target drug effect. Side effects have resulted in dose reduction to 400 mg/m2.

Dose-Modified Chemotherapy for Frail and/or Elderly Patients with Advanced Gastroesophageal Cancer (Abstract 4006)

Although the average age of patients at the time of diagnosis of advanced, inoperable gastroesophageal cancer is 75 years, and many patients are frail, standard of care chemotherapy has been developed in trials in patients with an average age of 65 years who are generally not frail. This study was motivated by the finding that a survey of oncologists in the UK used reduced dose chemotherapy regimens that were not evidence-based to treat frail and/or elderly patients with gastroesophageal cancer.

A prior phase 2 trial indicated that a 2-drug regimen was preferable to 3-drug or single agent regimens in this setting. The GO2 phase 3 trial was designed to optimize doses of 2-drug chemotherapy regimens and assess benefits and risks.

Patients (n=514) with a median age of about 76 years who were fit for chemotherapy but not for full-dose, 3-drug regimens were enrolled. There were 2 randomization schemes based on whether the patient was considered either certain or likely to benefit from chemotherapy and basic supportive care (BSC) was not appropriate (certain randomization), or would derive uncertain benefit from chemotherapy with BSC possibly appropriate (uncertain randomization). Presenter Peter S Hall, PhD, University of Edinburgh, Edinburgh, UK, discussed the certain randomization option, where patients were randomly assigned to one of 3 dose levels of combinations of oxaliplatin plus capecitabine.

In addition to assessing progression-free survival (PFS), and a non-inferiority boundary agreed upon by a patient focus group and clinicians, the study also determined which dose level resulted in the best “overall treatment utility (OTU),” a novel concept developed in phase 2, which included cancer control, severity of side effects, patient quality of life (QoL), and oncologist’s assessment of benefit.

The lower doses of chemotherapy were non-inferior to the highest dose for median PFS (4.9 months for the highest dose, 4.1 months for the intermediate dose, and 4.3 months for the lowest dose), as well as for median overall survival (7.5 months, 6.7 months, and 7.6 months, respectively). The lowest dose was associated with the best OTU scores, as a result of fewer side effects and better quality of life (QoL).

Lenalidomide Reduces the Risk of Progression from Smoldering to Active Multiple Myeloma (Abstract 8001)

Smoldering or asymptomatic multiple myeloma (SMM) is a precursor to symptomatic MM. The goal of the phase 2/3 E3A06 trial was to determine if early intervention in intermediate or high risk SMM using low-intensity, single-agent lenalidomide could prevent progression to MM. The primary endpoint was time to develop MM.

In phase 2, the safety of 25 mg daily of lenalidomide for 3 out of every 4 weeks was determined. Phase 3 randomly assigned patients to the same dose of lenalidomide (n=90) or to observation (n=92). Prophylactic aspirin was administered with the lenalidomide.

Time to develop MM was delayed with the use of lenalidomide (2-year PFS probability 0.93; 95% CI, 0.88-0.99) compared with observation (2-year PFD probability 0.76; 95% CI 0.66-0.87). Treatment-related grade 3 and 4 hematologic and non-hematologic adverse events were observed with lenalidomide; 51% of patients in the phase 3 portion discontinued due to toxicity, although there was no difference in QoL reported between the 2 groups.

Three-year PFS was 91% in the lenalidomide group, compared with 66% in the observation group (HR 0.28, P=.0005). Follow-up is too short to determine the effect of treatment on overall survival. The investigators will follow patients who discontinued to see if limited doses of lenalidomide can delay progression of SMM to MM. This study shows early intervention, at least in patients with higher risk SMM, can prevent MM and its associated end organ damage.

By Lynne Lederman, PhD

PS – Don’t forget to sign up for our ASCO ’19 Preview webinar featuring Lee Schwartzberg, MD, Zev Wainberg, MD, and Rich Leff, MD. Register here.

June 05, 2017 - 08:06 pm Posted in ASCO Conference Coverage Posted in Breast comments0 Comments

By Jay Grisolano, PhD and Stephanie Ritz, PhD

Approximately a quarter of breast cancer patients are classified as HER2-positive, according to Kantar Health’s 2016 Treatment Architecture data. 1   Effective targeted agents for the HER2 receptor, such as Herceptin (trastuzumab; Roche) and Perjeta (pertuzumab; Roche), have been developed for this particular patient segment and have greatly improved clinical outcomes for these patients.  Despite these major advances, the need for improved early stage treatments still exists to keep disease from reaching an incurable stage.  Currently, up to one in three early stage HER2+ patients treated with Herceptin in combination with chemotherapy eventually recur.2  In an effort to address this unmet need, Roche is conducting the Phase 3 APHINITY trial (NCT01358877) evaluating the combination of Herceptin, Perjeta, and chemotherapy in the adjuvant setting, hoping to improve upon these outcomes.

The triplet combination of Herceptin, Perjeta, and chemotherapy was initially approved in the HER2+ metastatic setting for first-line patients based on data from the Phase III CLEOPATRA trial, showing addition of Herceptin and Perjeta to chemotherapy improved median progression-free survival (PFS) and median overall survival (OS).3  In addition, the triplet has already demonstrated efficacy in early stage disease.  The Phase II NEOSPHERE study (NCT00545688) compared Herceptin plus docetaxel with or without Perjeta in the neoadjuvant setting.  Results reported at ASCO 2015 and published in Lancet Oncology showed a significantly improved complete response without an increase in cardiotoxicity (Herceptin / docetaxel: pCR 21.5%; Herceptin / docetaxel / Perjeta: pCR 39.3%, p=0.0063).  Additionally, the risk of disease progression or recurrence was reduced by 31% and 40%.4 Based on these data, the triplet neoadjuvant regimen was granted approval in September 2013.

Now Roche is pushing to move their triplet combination into the adjuvant setting with APHINITY, results of which were presented today at the 2017 Annual Meeting of the American Society of Clinical Oncology (ASCO).5  APHINITY is an international, double-blind, placebo-controlled Phase III trial evaluating the efficacy of Herceptin plus chemotherapy with or without Perjeta in the adjuvant setting.  The study enrolled 4,805 patients of lymph-node-positive and -negative status with confirmed HER2 positivity, as defined by IHC3+ or FISH-/CISH-positive.  Patients received 6 to 8 cycles of chemotherapy with Herceptin (8mg/kg) and Perjeta (840 mg)/placebo, followed by Herceptin (6 mg/kg) and Perjeta (420 mg)/placebo alone every 3 weeks for one year (52 weeks) of treatment.  At the time of presentation, the primary endpoint of invasive disease-free survival (IDFS) in the overall population was 92.3% in the triplet arm versus 90.6% seen in the control arm (p=0.045) at four years; however, subgroup analysis suggested that clinical benefit for IDFS appeared to be limited to node-positive and hormone receptor-negative cohorts. The disease-free interval and recurrence-free interval was modestly improved (DFI: 93.4% v. 92.3%, p=0.033; RFI: 95.2% vs. 94.3%, p=0.043); however, the addition of Perjeta did not improve the distant recurrence-free interval.  No difference was noted in median overall survival at first interim analysis (97.7% v. 97.7%, p=0.467), but only one-quarter of data points needed for final analysis had been collected.

The most common Grade 3/4 adverse events associated with the triplet arm included neutropenia in 16.3% of patients (versus 15.7% in the control arm), febrile neutropenia in 12.1% of patients (versus 11.1% in the control arm, anemia in 6.9% of patients (versus 4.7% in the control arm), and diarrhea in 9.8% of patients (versus 3.7% in the control arm), which was predominately observed during the administration of chemotherapy.  Cardiac toxicity was low and similar between the two arms.

Based on these data, it will be interesting to see how physicians adopt the triplet regimen in the adjuvant setting if it gains accelerated approval.  Physician attendees vocalized great concerns during today’s session regarding the financial burden of adding Perjeta for a modest 1.7% IDFS benefit, despite its favorable tolerability profile.  It may be essential for Roche to find specific subsets of patients who benefit most from the triplet in order for physicians to seriously consider integrating the addition of Pejeta into their practice.  Another concern is whether Perjeta retreatment of a patient who recurs with metastatic disease will still be effective.  It was mentioned that trials are being initiated to evaluate retreatment with Perjeta.  Given the modest efficacy of APHINITY and the current absence of data supporting retreatment with the triplet beyond progression, physicians may to choose to save Perjeta until the metastatic setting. These issues may make it difficult to compete with Puma’s HER2 tyrosine kinase inhibitor, neratinib, which already has a PDUFA date set for July.  Data supporting Puma’s application for approval is based on the Phase III ExteNET (NCT02400476) study, which showed a 2% benefit in 2-year DFS (2-year rate: 93.9% vs. 91.6%, p=0.0009) with a relatively well-tolerated toxicity profile.6  Subgroup analysis showed that neratinib may be more effective in ER-positive patients, which could help Puma find its niche in this space should neratinib receive approval.

Nevertheless, APHINITY did meet its primary endpoint showing that addition of Perjeta to Herceptin and chemotherapy as adjuvant treatment achieved a statistically significant improvement in IDFS.  These data suggest that the triplet may become an option for adjuvant treatment of HER2+ early breast cancer.

 

References

  1. Kantar Health’s CancerMPact, Treatment Architecture module, 2017.
  2. Jackisch C, et al. Abstract PD5-01, SABCS 2015; Slamon D, et al. Abstract S5-04, SABCS 2015.
  3. Baselga, J, et al. Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer. N Engl J Med 2012; 366:109-119.
  4. Gianni, L, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. The Lancet Oncology 2016; 17:791–800.
  5. Von Minckwitz, G, et al. APHINITY trial (BIG 4-11): A randomized comparison of chemotherapy (C) plus trastuzumab (T) plus placebo (Pla) versus chemotherapy plus trastuzumab (T) plus pertuzumab (P) as adjuvant therapy in patients (pts) with HER2-positive early breast cancer (EBC). Abstract LBA500, ASCO 2017.
  6. Chan, A, et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Oncology 2016; 17:367 – 377.
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