Major Advances in Breast, Prostate and Colorectal Cancer Treatment Featured at ASCO’s Annual Meeting

– Large Phase III Trials Establish New Standards of Care, Affirm Effectiveness of Commonly Used Targeted Treatment Options –

Article ID: 618667

Released: 1-Jun-2014 10:00 AM EDT

Source Newsroom: American Society of Clinical Oncology (ASCO)

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Newswise — CHICAGO – Findings from four phase III clinical trials in breast, prostate, and colorectal cancers were released today at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO). The studies were presented in ASCO’s Plenary session, which features the meeting’s most important clinical cancer research with the greatest potential to impact patient care.

These pivotal studies reveal new ways to optimize commonly used chemotherapy, hormone therapies, and newer targeted drugs, and answer critical questions about the comparative effectiveness of two common treatment regimens for advanced colorectal cancer. All four trials were supported, at least in part, with federal funding through the U.S. National Institutes of Health.

"Today’s results answer critical questions faced by people with cancer and their doctors every day. There is no doubt that patients will live longer and better because of these studies,” said Clifford A. Hudis, MD, FACP, president of ASCO and chief of the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center. “These major advances – and many others in the history of cancer research – were only possible thanks to our nation’s long-standing commitment to funding clinical cancer research. That commitment must be sustained."

The Plenary studies are:

• Adjuvant exemestane is more effective than tamoxifen when combined with ovarian function suppression in young women with hormone-sensitive, early-stage breast cancer: Post-surgery (adjuvant) exemestane is more effective at preventing breast cancer recurrences than tamoxifen when given with ovarian function suppression in young women with hormone receptor-positive, early breast cancer, reducing the relative risk of developing a recurrent cancer by 28 percent. (Related broadcast quality video available) • Addition of docetaxel to initial hormone therapy substantially improves survival in men with metastatic, hormone-sensitive prostate cancer: The findings suggest inclusion of docetaxel in first-line therapies for men with advanced disease who are healthy enough for chemotherapy, especially those with extensive disease spread. (Related broadcast quality video available)• First-line bevacizumab plus chemotherapy and cetuximab plus chemotherapy provide similar survival benefit for patients with metastatic colorectal cancer: Large U.S.-funded head-to-head comparison trial answers a long-standing question about the relative effectiveness of four common regimens, offering patients and providers new reassurance as they face treatment decisions. • Adding lapatinib to adjuvant trastuzumab does not improve outcomes for women with early-stage HER2-positive breast cancer: Results from the phase III ALTTO study indicate that post-surgery treatment with the two anti-HER2 drugs does not improve disease-free survival compared to standard treatment with trastuzumab alone.

Media Resources:• Online Annual Meeting Media Resource Center: Visit for press releases, press briefing recordings, the press briefing schedule at-a-glance, embargo policies, high-resolution photos, print-friendly downloads, and the Virtual Press Room, an online repository of corporate and institutional press releases from third-party organizations. • CancerProgress.Net: The home of ASCO's 50th Anniversary and a timeline detailing the progress made against 18 of the most common cancers. • Cancer.Net: ASCO's cancer information website, providing doctor-approved information on more than 120 cancer types.The Annual Meeting Media Resource Center will be updated frequently leading up to and throughout the Annual Meeting.

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Plenary Session: Presenting Author: Olivia Pagani, MDSunday, June 1, 2014: 1:45 - 2:00 PM CDT Location: N Hall B1 Institute of Oncology of Southern Switzerland, SAKK & IBCSG, Lugano Viganello, SwitzerlandAdjuvant Exemestane Is More Effective Than Tamoxifen When Combined With Ovarian Function Suppression in Young Women With Hormone-Sensitive, Early-Stage Breast Cancer

A landmark study that was a joint analysis of two phase III trials, TEXT and SOFT, demonstrated that the aromatase inhibitor exemestane more effectively prevents breast cancer recurrences than tamoxifen, when given with ovarian function suppression (OFS), in premenopausal women with hormone-sensitive cancers. In the study, exemestane plus OFS reduced the relative risk of women developing a subsequent invasive cancer by 28 percent, and specifically reduced the relative risk of breast cancer recurrence by 34 percent, compared with tamoxifen plus OFS.

“For years, tamoxifen has been the standard hormone therapy for preventing breast cancer recurrences in young women with hormone-sensitive disease. These results confirm that exemestane with ovarian function suppression constitutes a valid alternative,” said lead study author Olivia Pagani, MD, clinical director of the Breast Unit at the Oncology Institute of Southern Switzerland in Bellinzona, Switzerland. “Our findings indicate that exemestane is better than tamoxifen, when given with ovarian function suppression, but longer follow up of these young women will be important to assess survival, and any long-term side effects and fertility.”

The TEXT and SOFT trials were led by the International Breast Cancer Study Group (IBCSG) in collaboration with the Breast International Group (BIG) and the North American Breast Cancer Group (NABCG) as a successful, worldwide collaboration spanning 27 countries and six continents. The trials were partially funded by the U.S. National Cancer Institute.The joint analysis of TEXT and SOFT is the largest study worldwide evaluating adjuvant aromatase inhibitor therapy with OFS in young women with breast cancer, and the first to demonstrate the value of such therapy in women with hormone receptor-positive cancer. Aromatase inhibitors have primarily been used in postmenopausal women, because their use requires that women have a low level of estrogen. In the TEXT and SOFT trials, ovarian function suppression was used in premenopausal women to emulate the low estrogen levels that naturally occur in menopause.

The standard adjuvant endocrine (hormone) therapy for premenopausal women is currently five years of tamoxifen. In some countries, physicians recommend adding OFS to tamoxifen in high-risk younger women. This approach is less common in the United States as the benefit of adding OFS to tamoxifen is uncertain. The SOFT trial also addresses the impact of adding OFS to tamoxifen, and the results will be available in late 2014. The joint analysis of the TEXT and SOFT trials studied the outcomes of 4,690 women, whose average age was 43 years, who were randomized to receive exemestane plus OFS or tamoxifen plus OFS for five years. OFS was achieved through treatment with the drug triptorelin, surgical oophorectomy, or ovarian irradiation. Some women also received adjuvant chemotherapy, as decided with their physician.

The cancer-free survival at five years was 91.1 percent in the exemestane plus OFS group, versus 87.3 percent in the tamoxifen plus OFS group, which was a 28 percent relative reduction in risk. There was a 34 percent relative reduction in breast cancer recurrence risk in the exemestane plus OFS group compared to the tamoxifen plus OFS group and a 22 percent relative reduction in distant recurrence (metastasis) risk. The five-year overall survival rates were high in both groups ─ 95.9 percent in the exemestane plus OFS group and 96.9 percent in the tamoxifen plus OFS group. Longer follow-up is needed to accurately assess the impact of the two treatments on long-term survival.

The side effects were similar to those reported in previous studies comparing adjuvant aromatase inhibitors and tamoxifen in postmenopausal women, and differed depending on the agent. Despite the side effects, only 14 percent of TEXT and SOFT participants completely stopped the protocol-assigned treatments early – an adherence rate that is higher than what is seen in everyday practice. Dr. Pagani stated that this high compliance rate is important information for doctors who wish to propose this treatment to their patients.

The TEXT and SOFT trials were conducted at the same time and in the same general population – premenopausal women with hormone receptor-positive early breast cancer. The original plan was to analyze each trial separately as well as jointly, given the common treatment groups of exemestane plus OFS and tamoxifen plus OFS in both trials. However, by combining the trials in a joint analysis, the results could be presented earlier, giving physicians and patients the possible benefit of acting on the results sooner.

This research was supported in part by Pfizer, Ipsen, the International Breast Cancer Study Group, and the National Cancer Institute, National Institutes of Health.

ASCO Perspective:“Young women with breast cancer have long needed additional treatment options after surgery, and now they may have one,” said ASCO president Clifford A. Hudis, MD, FACP. “Tamoxifen has been a gold standard for decades and has significant benefits. Now, with ovarian suppression, aromatase inhibitors are an option offering a further reduction in the risk of recurrence.”

Relevant Links From Cancer.Net, the oncologist-approved cancer information website from the American Society of Clinical Oncology:• Guide to Breast Cancer• Hormonal Therapy for Early-Stage Hormone Receptor-Positive Breast Cancer• Making Decisions About Cancer Treatment

Relevant links from CancerProgress.Net, the home of ASCO's 50th Anniversary and progress made against 18 of the most common cancers:• Progress Against Breast Cancer Timeline

Abstract #LBA1: Randomized comparison of adjuvant aromatase inhibitor (AI) exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): Joint analysis of IBCSG TEXT and SOFT trials.

Authors: Olivia Pagani, Meredith M. Regan, Barbara Walley, Gini F. Fleming, Marco Colleoni, Istvan Lang, Henry Leonidas Gomez, Carlo Tondini, Harold J. Burstein, Edith A. Perez, Eva Ciruelos, Vered Stearns, Herve R. Bonnefoi, Silvana Martino, Charles E. Geyer Jr., Manuela Rabaglio-Poretti, Alan S. Coates, Richard D. Gelber, Aron Goldhirsch, Prudence A. Francis, SOFT and TEXT Investigators and International Breast Cancer Study Group; Institute of Oncology of Southern Switzerland, SAKK & IBCSG, Lugano Viganello, Switzerland; IBCSG Statistical Center, Dana-Farber Cancer Institute, Boston, MA; NCIC Clinical Trials Group, Kingston, ON; The University of Chicago Medical Center & Alliance, Chicago, IL; European Institute of Oncology & IBCSG, Milan, Italy; National Institute of Oncology, Budapest, Hungary; Instituto Nacional de Enfermedades Neoplásicas & IBCSG, Lima, Peru; Osp. Papa Giovanni XXIII, Bergamo, Italy; Dana-Farber Cancer Institute & Alliance, Boston, MA; Mayo Clinic & Alliance, Jacksonville, FL; University Hospital 12 de Octubre, Madrid, Spain; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and ECOG, Baltimore, MD; Bergonié Institute & EORTC, Bordeaux, France; The Angeles Clinic and Research Institute & SWOG, Santa Monica, CA; Massey Cancer Center, Virginia Commonwealth University School of Medicine & NRG Oncology, Richmond, VA; Institute of Medical Oncology & International Breast Cancer Study Group, Berne, Switzerland; International Breast Cancer Study Group, Berne, Switzerland; IBCSG Statistical Center, Dana Farber Cancer Institute, Boston, MA; Peter MacCallum Cancer Center, ANZBCTG, Melbourne, Australia

Background Adjuvant endocrine therapy with AI vs T improves outcomes in postmenopausal HR+ BC. TEXT and SOFT were designed to test whether adjuvant AI improves outcomes in premenopausal women with HR+ BC treated with OFS (AI question) and to determine the value of OFS in women who remain premenopausal and are suitable for adjuvant T (OFS question). Methods TEXT and SOFT, randomized phase 3 trials, enrolled 5738 premenopausal women with HR+ early BC from Nov03 to Apr11 (2672 TEXT; 3066 SOFT). TEXT randomized women within 12wk of surgery to 5y E+OFS vs T+OFS; chemotherapy (CT) was optional and concurrent with OFS. SOFT randomized women to 5y E+OFS vs T+OFS vs T alone, either within 12wk of surgery if no CT planned, or within 8mo of completing (neo)adjuvant CT. OFS was by choice of 5y triptorelin, oophorectomy or ovarian irradiation. The primary endpoint is disease-free survival (DFS: randomization until invasive local, regional, distant recurrence or contralateral breast; 2nd malignancy; death). Due to low event rates, protocol amendments in 2011 changed the analysis plans to answer the AI question (E+OFS vs T+OFS) by joint analysis of TEXT and SOFT. By Q3’2013 with >5y median follow-up, 436 DFS events were projected, providing 84% power for HR=0.75 with E+OFS vs T+OFS (stratified logrank 2-sided α=0.05). Results At 5.7y median follow-up, 514 (11%) DFS events were reported in the ITT population comparing E+OFS (n=2346) vs T+OFS (n=2344). Patients assigned E+OFS had significantly reduced DFS hazard (HR=0.72; 95% CI, 0.60-0.86; P=0.0002) vs T+OFS; 5y DFS was 91.1% vs 87.3%. Reductions were similar for secondary endpoints of BC-free interval (HR=0.66 (0.55-0.80) 5y BCFI 92.8% vs 88.8%) and distant recurrence-free interval (HR=0.78 (0.62-0.97)), though not overall survival (HR=1.14 (0.86-1.51)) at this early follow-up (194 (4%) deaths). Grade 3-4 targeted AEs were reported in 31% E+OFS vs 29% T+OFS patients. Conclusion In premenopausal women with HR+ BC, adjuvant treatment with E+OFS significantly reduced the risk of recurrence compared to T+OFS.Disclosures: Vered Stearns, Research Funding from Novartis and Pfizer

Research Funding Source: Pfizer, Ipsen, NCI

Plenary Session: Presenting Author: Christopher Sweeney, MBBSSunday, June 1, 2014: 2:15 - 2:30 PM CDT Location: N Hall B1 Dana-Farber Cancer Institute,Boston, MAAddition of Docetaxel to Initial Hormone Therapy Substantially Improves Survival in Men With Metastatic, Hormone-Sensitive Prostate Cancer – Summary contains updated data not included in the abstract –

Findings from a federally funded phase III study, E3805, indicate that adding the chemotherapy drug docetaxel to standard hormone therapy extends survival for men with newly diagnosed hormone-sensitive prostate cancer by roughly 13 months. The survival benefit is even greater for the subset of men with extensive disease spread (high-extent disease).

“Hormone therapy has been a standard treatment for prostate cancer since the 1950s,” said lead study author Christopher Sweeney, MBBS, medical oncologist at the Lank Center of Genitourinary Oncology at the Dana-Farber Cancer Institute in Boston, MA. “This is the first study to identify a strategy that prolongs survival in newly diagnosed metastatic prostate cancer. The benefit is substantial and warrants this being a new standard treatment for men who have high-extent disease and are fit for chemotherapy.”

Androgen hormones fuel prostate cancer growth. Hormonal therapy – also called androgen deprivation therapy (ADT) – alone is the standard first-line treatment for hormone-sensitive prostate cancer. Although ADT is effective, the disease eventually becomes resistant to the therapy in most patients. About 30,000 patients die of hormone-resistant prostate cancer in the United States every year. Chemotherapy is typically initiated only after the disease progresses despite ADT.

In this National Cancer Institute-led study, 790 men with newly diagnosed metastatic prostate cancer were randomly assigned to receive either ADT alone or ADT with docetaxel over a period of 18 weeks. Approximately two-thirds of patients had high-extent disease, meaning that the cancer had spread to major organs and/or the patient had bone metastases. When the disease worsened, 45 patients in the ADT plus docetaxel group received additional docetaxel. In the ADT only group, 123 patients received docetaxel at disease progression.

At a median follow-up of 29 months, there were 136 deaths in the ADT-alone group vs. 101 in the ADT plus docetaxel group. The median overall survival was 44 months in the ADT group and 57.6 months in the ADT plus docetaxel group. The relative improvement in median overall survival was even larger among the 520 patients with high-extent disease (32.2 months vs. 49.2 months). The median overall survival for the subset with low-extent disease takes longer to reach as these patients respond better to ADT, and the median survival has not yet been reached.

Docetaxel also delayed disease progression, assessed by either PSA rise or appearance of new metastases or symptom worsening. At one year, the proportion of patients with PSA levels less than 0.2 ng/mL (a PSA level of less than 0.2 is considered a sign of a better remission) was 11.7 percent in the ADT group vs. 22.7 percent in the ADT plus docetaxel group. The median time to clinical progression (new symptoms or metastases detected on a scan) was 19.8 months in the ADT group vs. 32.7 months in the ADT plus docetaxel group.

This new treatment paradigm will entail earlier, multidisciplinary care involving the collaboration of both urologists and oncologists, who both commonly treat men with prostate cancer, Dr. Sweeney said. Follow-up of patients will continue to assess survival benefits for patients with low-extent disease. Quality-of-life data from this study will be analyzed and reported at a later time.

This research was supported by the National Cancer Institute, National Institutes of Health.

ASCO Perspective:“This study shows a remarkable and meaningful prolongation in survival for advanced prostate cancer. It shows that we can continue to learn more even about older treatments," said ASCO president Clifford A. Hudis, MD, FACP. “Importantly, this study is yet another example of the large impact of the federally funded research system.”

Relevant Links From Cancer.Net, the oncologist-approved cancer information website from the American Society of Clinical Oncology:• Guide to Prostate Cancer• Hormone Therapy for Advanced Prostate Cancer• When the First Treatment Doesn't Work

Relevant links from CancerProgress.Net, the home of ASCO's 50th Anniversary and progress made against 18 of the most common cancers:• Progress Against Prostate Cancer Timeline• Progress in Chemotherapy Timeline

Abstract #LBA2: Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrCa): An ECOG-led phase III randomized trial.

Authors: Christopher Sweeney, Yu-Hui Chen, Michael Anthony Carducci, Glenn Liu, David Frasier Jarrard, Mario A. Eisenberger, Yu-Ning Wong, Noah M. Hahn, Manish Kohli, Nicholas J. Vogelzang, Matthew M. Cooney, Robert Dreicer, Joel Picus, Jorge A. Garcia, Robert S. DiPaola; Dana-Farber Cancer Institute, Boston, MA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; University of Wisconsin Carbone Cancer Center, Madison, WI; Fox Chase Cancer Center, Philadelphia, PA; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; Mayo Clinic, Rochester, MN; Comprehensive Cancer Centers of Nevada, Las Vegas, NV; University Hospitals Case Medical Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH; Cleveland Clinic, Cleveland, OH; Division of Oncology, Washington University in St. Louis, St. Louis, MO; Rutgers Biomedical and Health Sciences, New Brunswick, NJBackground: Docetaxel (D) improves OS of men with mPrCa who have progressed on androgen deprivation therapy (ADT). We aimed to assess the benefit of upfront chemohormonal therapy for metastatic PrCa. Methods: 1:1 randomization to ADT alone or ADT + D dosed 75mg/m2 every 3 weeks for 6 cycles within 4 month (mos) of starting ADT. Stratification factors: high volume (HV) vs. low volume (LV) disease (HV: visceral metastases and/or 4 or more bone metastases); Anti-androgen use beyond 30 days; Age ≥70 vs. < 70 years; ECOG PS 0-1 vs. 2; Prior adjuvant ADT > 12 vs. ≤ 12 mos; FDA approved drug for delaying skeletal related events. Key eligibility criteria: suitable organ and neurological function for D; adjuvant ADT ≤ 24 mos and no progression within 12 mos of adjuvant ADT. OS was the primary endpoint and the study was powered to assess for a 33.3% improvement in median OS (80% power and 1-sided alpha=2.5%). Projected median OS for ADT alone: HV-33 mos; LV-67 mos. Results: 790 men were accrued from 7/28/06 to 11/21/2012: ADT N=393; ADT + D: N=397; balanced for demographic, stratification and disease factors. Median age: 63 years (range: 36 to 91); 98% ECOG PS 0 or 1; 89% Caucasian; 24% prior radiotherapy, 24% prior prostatectomy; HV 64% on ADT and 67% on ADT + D. Data released after 4th interim analysis in Sept 2013 when O’Brien Fleming upper boundary was crossed with 53.1% information. This report reflects 1/16/2014 data with median follow-up of 29 mos with 137 deaths on ADT alone vs. 104 deaths on ADT+D. ADT+D: Grade (G) 3/4 Neutropenic fever: 4%/2%; G3 neuropathy: 1% sensory, 1% motor; 1 death due to treatment (no deaths due to treatment on ADT). Efficacy data is in the table below. After disease progression, 123 pts on ADT alone and 45 pts on ADT + D received docetaxel. Conclusions: ADT + D improves OS over ADT alone in men with HV mPrCa. Longer follow-up is needed for men with LV mPrCa.

Intent to treat analysis ADT ADT + D P value Hazard ratio (95%CI*) PSA < 0.2 at 12 mos 9.4% 19.7% <0.0001 Median OS (mos) N=790 N=520-HV N=270-LV 42.3 32.2 NR** 52.7 49.2 NR 0.0006 0.0012 0.0836 0.63 (0.48, 0.82) 0.62 (0.46, 0.83) 0.58 (0.31, 1.08) [footer]* CI: confidence intervals; **NR: not reached.[/footer]

Disclosures: Christopher Sweeney, Consultant or Advisory Role with Sanofi, Honoraria from Sanofi, Research Funding from Sanofi, Other Remuneration from Sanofi; Mario A. Eisenberger, Research Funding from Sanofi; Noah M. Hahn, Consultant or Advisory Role with Sanofi, Honoraria from Sanofi, Research Funding from Sanofi; Jorge A. Garcia, Consultant or Advisory Role with Sanofi, Honoraria from Sanofi, Research Funding from Sanofi; Robert S. DiPaola, Consultant or Advisory Role with Sanofi, Research Funding from Sanofi

Research Funding Source: NIH

Plenary Session: Presenting Author: Alan P. Venook, MDSunday, June 1, 2014: 2:45 - 3:00 PM CDT Location: N Hall B1 University of California,San Francisco, CAFirst-Line Bevacizumab Plus Chemotherapy and Cetuximab Plus Chemotherapy Provide Similar Survival Benefit for Patients With Metastatic Colorectal Cancer

Results from a large federally funded phase III study demonstrate that four common first-line treatment regimens – bevacizumab plus chemotherapy and cetuximab plus chemotherapy – are equally effective for patients with metastatic colorectal cancer and no KRAS mutations. In the study, the median overall survival was roughly 29 months with either approach. The data also suggest that either FOLFOX (oxaliplatin/5-fluorouracil/leucovorin) or FOLFIRI (irinotecan/5-fluorouracil/leucovorin) chemotherapy regimens are acceptable in combination with either of the two targeted drugs.

“About 75 percent of patients with metastatic colorectal cancer in the United States initially receive bevacizumab-based therapy, although we know that cetuximab-based therapy is also a good option for a subset of patients,” said lead author Alan P. Venook, MD, the Madden Family Distinguished Professor of Medical Oncology and Translational Research at the University of California in San Francisco, CA. “Our findings clearly show that the two antibodies – with either FOLFOX or FOLFIRI – are both acceptable, and similarly effective. This should reassure doctors and patients facing decisions about treatment selection.”

Each year, about 50,000 Americans are diagnosed with metastatic colorectal cancer. Targeted therapies have played a key part in extending survival, from 10 months 20 years ago to the nearly 2.5 years seen in this study. Bevacizumab targets VEGF, blocking the development of blood vessels that tumors need to grow, while cetuximab targets EGFR, a protein involved in cancer growth and spread. Bevacizumab with FOLFOX is widely used in the United States, while cetuximab-based regimens tend to be used more frequently in Europe.

In the study, 1,137 patients with untreated metastatic colorectal cancer were randomly assigned to receive bevacizumab plus chemotherapy or cetuximab plus chemotherapy. The selection of chemotherapy was based on physician preference (26.6 percent received FOLFIRI, 73.4 percent FOLFOX). The median follow-up was 24 months.

There were no significant differences in either overall or progression-free survival between the treatment groups. In the bevacizumab plus chemotherapy group, the overall and progression-free survival were 29 months and 10.8 months, respectively, and 29.9 months and 10.4 months respectively in the cetuximab plus chemotherapy group.

No new treatment side effects were detected in this study. Common side effects of bevacizumab are high blood pressure, headache, mouth sores, nosebleed, diarrhea, bleeding from the rectum, loss of appetite, fatigue, and weakness, and the most common side effects of cetuximab are acne-like rash, itching, changes in fingernails and toenails, infections, fatigue, and low blood electrolyte levels. Costs of bevacizumab and cetuximab are comparable but side effects are slightly different. FOLFIRI and FOLFOX also differ in side effects ─ FOLIFIRI causes more hair loss and diarrhea but FOLFOX causes neuropathy that often necessitates stopping treatment. Updated analyses show that the overall quality of life for patients on either of the antibodies is similar.

Dr. Venook remarked that this kind of head-to-head comparative clinical trial comparing two agents from different companies with similar indications probably would not have been possible without the nation’s investment in clinical trials led by the National Cancer Institute. “This study shows that we are still doing good, important work, even in the era of reduced funding for cooperative groups,” he said.

Forthcoming analyses from this study will explore benefits of these approaches in different subsets of patients. Genomic profiling will be conducted to identify potential prognostic markers, which might be helpful in selecting optimal treatments for individual patients in the future.

This research was supported in part by the National Cancer Institute, National Institutes of Health; Imclone; Roche; Genentech; BMS; and Eli Lilly.

ASCO Perspective:“With this finding, oncologists and patients have more ways to personalize cancer treatment,” said ASCO president Clifford A. Hudis, MD, FACP. “They can be reassured that two widely used regimens offer good and equivalent survival.”

Relevant Links From Cancer.Net, the oncologist-approved cancer information website from the American Society of Clinical Oncology:• Guide to Colorectal Cancer• Making Decisions About Cancer Treatment• Targeted Treatments• Side Effects of Chemotherapy• Skin Reactions to Targeted Therapies

Relevant links from CancerProgress.Net, the home of ASCO's 50th Anniversary and progress made against 18 of the most common cancers:• Progress in Targeted Therapy• Progress in Chemotherapy• Progress Against Colorectal Cancer

Abstract #LBA3: CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC).

Authors: Alan P. Venook, Donna Niedzwiecki, Heinz-Josef Lenz, Federico Innocenti, Michelle R. Mahoney, Bert H. O'Neil, James Edward Shaw, Blase N. Polite, Howard S. Hochster, James Norman Atkins, Richard M. Goldberg, Robert J. Mayer, Richard L. Schilsky, Monica M. Bertagnolli, Charles David Blanke, Cancer and Leukemia Group B (Alliance), SWOG, and ECOG; University of California, San Francisco, San Francisco, CA; Duke University, Durham, NC; USC Norris Comprehensive Cancer Center, Los Angeles, CA; The University of North Carolina at Chapel Hill, Chapel Hill, NC; Mayo Clinic, Rochester, MN; Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN; Virginia Commonwealth University, Richmond, VA; Pritzker School of Medicine, The University of Chicago, Chicago, IL; Department of Medical Oncology, Yale University School of Medicine, New Haven, CT; Southeast Cancer Control Consortium, CCOP, Goldsboro, NC; The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH; Dana-Farber Cancer Institute, Boston, MA; American Society of Clinical Oncology, Alexandria, VA; Brigham and Women's Hospital, Boston, MA; SWOG and Oregon Health & Science University, Portland, OR

Background: Irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6), combined with bevacizumab (BV) or cetuximab (CET), are first-line treatments for metastatic adenocarcinoma of the colon or rectum (MCRC). The optimal antibody combination is unknown. Methods: Patients (pts) with KRAS wild-type (wt)(codons 12 and 13) MCRC and performance status 0-1 received FOLFIRI or mFOLFOX6 (MD/pt choice at enrollment) and randomized to either CET 400 mg/m2 X 1, then 250 mg/m2 qw or BV 5 mg/kg q2w. The original study included unselected MCRC pts receiving FOLFIRI or mFOLFOX6 and randomized to CET, BV, or both. After 1420 pts accrued the study amended as follows: only pts with KRAS wt tumors (codon 12 and 13) were included and the combination CET + BV arm was deleted. Rx continued until progression, death, unacceptable toxicity, curative surgery; treatment holidays of 4 wks permitted. Subsequent Rx not mandated. Accrual goal was 1,142 pts. One° endpoint was overall survival (OS). Results: Between November 2005 and March 2012, 3,058 unselected pts enrolled, 2,334 KRAS wt pts randomized; final N =1137 (333 pre-amend eligible retrospective KRAS test, 804 post-amend), median f/u = 24 mos; Median age – 59 y; 61% male. Chemo/BV – 559; chemo/CET – 578. FOLFIRI = 26.6%, mFOLFOX6 = 73.4%. OS analysis planned at 849 events; efficacy futility boundary crossed at 10th interim analysis on 1/29/14. OS - chemo/BV v. chemo/CET = 29.04 (25.66 - 31.21) v. 29.93 (27.56 - 31.21) mos; HR = 0.92 (0.78, 1.09) (p value = 0.34). PFS (by investigator): chemo/BV v. chemo/CET: 10.84 (9.86 - 11.4) v. 10.45 (9.66 - 11.33) mos. There were 94 pts free of disease following surgery, median f/u 40 mos (range 8.0 - 86.0). Outcomes similar by gender. On-study toxicity and deaths as expected. Analyses underway: Expanded RAS, FOLFOX v. FOLFIRI, subsequent therapies, long-term survivors, correlates. Conclusions: Chemo/CET and chemo/BV equivalent in OS in pts KRAS wt (codons 12 + 13) MCRC; either is appropriate in first line. Overall OS of 29 + mos and 8% long-term survivors confirms progress in MCRC. The preference for FOLFOX limits chemotherapy comparison. Expanded RAS and other molecular and clinical analyses may identify subsets of pts who get more or less benefit from specific regimens.

Disclosures: Alan P. Venook, Consultant or Advisory Role with Bristol-Myers Squibb and Roche/Genentech, Research Funding from Bristol-Myers Squibb and Roche/Genentech; Bert H. O'Neil, Consultant or Advisory Role with Roche/Genentech; Blase N. Polite, Honoraria from Bayer/Onyx; Howard S. Hochster, Consultant or Advisory Role with Sanofi and Genentech; Richard M. Goldberg, Consultant or Advisory Role with Lilly, Honoraria from Sanofi, Research Funding from Sanofi

Research Funding Source: NIH

Plenary Session: Presenting Author: Edith A. Perez, MDSunday, June 1, 2014: 3:15 - 3:30 PM CDT Location: N Hall B1 Mayo Clinic Cancer Center,Jacksonville, FLAdding Lapatinib to Adjuvant Trastuzumab Does Not Improve Outcomes for Women With Early-Stage HER2-Positive Breast Cancer Findings from a large phase III study, ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation), suggest that post-surgery (adjuvant) treatment using a combination of two HER2-targeted drugs – trastuzumab and lapatinib – is no more effective than standard treatment with trastuzumab alone for women with early HER2-positive breast cancer. In the study, researchers found no statistically significant differences between treatment arms in four-year disease-free survival, which ranged between 86 and 88 percent.

“We were encouraged to see that most patients with HER2-positive early breast cancer are doing well with standard trastuzumab therapy,” said senior study author Edith A. Perez, MD, Deputy Director at Large at the Mayo Clinic Cancer Center in Jacksonville, FL. “But we were surprised that adding lapatinib did not provide further benefit, since the combination of these drugs was promising when given prior to surgery in a smaller study. A key lesson of this trial is that we need robust clinical trials in specific disease settings to fully assess and understand the value of new treatment regimens.”

Post-surgery treatment with trastuzumab and chemotherapy significantly reduces the risk of cancer recurrence and death for women with early-stage HER2-positive breast cancer. However, about 20 percent of patients experience a relapse within 10 years, with the cancer usually appearing in other parts of the body. The goal of this trial was to further reduce the relapse rate by using two drugs that target the HER2 pathway, instead of one.The trial – the largest-ever adjuvant clinical trial in HER2-positive breast cancer – involved 946 medical centers in 44 countries and 8,381 women with newly diagnosed early-stage breast cancer. After surgery, the patients were randomly assigned to treatment with lapatinib plus trastuzumab (concurrent arm), trastuzumab followed by lapatinib (sequential arm), or trastuzumab alone for one year. A majority of these patients (4,613) received these anti-HER2 therapies after completing chemotherapy, and the rest received it both concurrently with chemotherapy and then after. Patients with hormone receptor-positive cancers also received appropriate hormonal therapy.

At a median follow-up of 4.5 years, treatment with lapatinib plus trastuzumab (either sequential or concurrent) was associated with a numerically lower risk of a disease-free survival event – defined as recurrence of invasive breast cancer, development of a second primary cancer, or death from any cause – compared to trastuzumab alone, but the finding was not statistically significant. The four-year disease-free survival rates were similar in the three treatment arms – 86 percent in the trastuzumab arm, 88 percent in the concurrent arm, and 87 percent in the sequential arm.

Compared to trastuzumab alone, the combination treatment was associated with much higher rates of certain side effects, such as diarrhea, skin rash, and liver problems.

Another important finding from this trial was that the rates of serious heart-related side effects were very low. In recent years, many doctors have stopped using anthracycline chemotherapy (such as doxorubicin) due to concerns about heart toxicities and are using the TCH (docetaxel, carboplatin, trastuzumab) regimen instead, even though anthracycline chemotherapy has been more extensively studied. But in ALTTO the rate of congestive heart failure was less than 1 percent, even though 95 percent of women received anthracycline chemotherapy. This safety, along with the patient outcome in terms of breast cancer, provides additional reassurance that using anthracycline-based chemotherapy followed by trastuzumab is safe for women with early-stage HER2-positive breast cancer.

The study was accompanied by a large collection of blood and tissue specimens that will help researchers further understand the biology of breast cancer and provide insight as to why certain patients experience a relapse and others do not.

In a much smaller trial that preceded this study, NeoALTTO, dual treatment with lapatinib and trastuzumab before surgery (called neoadjuvant therapy) doubled the pathological complete response (no evidence of invasive cancer found in the breast or lymph nodes at the time of surgery) rates compared to trastuzumab alone. However, ALTTO did not show that the dual strategy, despite increasing the in-breast response rate, led to better long-term outcome compared to single anti-HER2 therapy with trastuzumab. The ALTTO study will influence the design of future breast cancer clinical trials, as it calls into question the use of in-breast pathological complete response as a surrogate marker of long-term treatment impact when comparing one specific treatment against another.

This research was supported by GlaxoSmithKline and the National Cancer Institute, National Institutes of Health.

ASCO Perspective:“These results illustrate the importance of conducting well-designed clinical trials,” said ASCO president Clifford A. Hudis, MD, FACP. “In this case, the increased in-breast response rate seen for this drug combination when used pre-operatively did not predict improved disease-free survival. Other studies using different drugs could reach different conclusions, but for now this trial provides reassurance that trastuzumab is a safe and potent adjuvant treatment for HER2-positive breast cancer.”

Relevant Links From Cancer.Net, the oncologist-approved cancer information website from the American Society of Clinical Oncology:• Guide to Breast Cancer• Targeted Treatments• HER2 Testing for Breast Cancer

Relevant links from CancerProgress.Net, the home of ASCO's 50th Anniversary and progress made against 18 of the most common cancers:• Progress Against Breast Cancer Timeline• Progress in Targeted Therapy• Progress in Chemotherapy

Abstract #LBA4: First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC).

Authors: Martine J. Piccart-Gebhart, Andrew Peter Holmes, Jose Baselga, Evandro De Azambuja, Amylou C. Dueck, Giuseppe Viale, Jo Anne Zujewski, Aron Goldhirsch, Sergio Santillana, Kathleen I. Pritchard, Antonio C. Wolff, Christian Jackisch, Istvan Lang, Michael Untch, Ian E. Smith, Frances Boyle, Binghe Xu, Henry Leonidas Gomez, Richard D. Gelber, Edith A. Perez; Jules Bordet Institute, Breast International Group, Brussels, Belgium; Frontier Science Scotland Ltd, Kincraig, United Kingdom; Memorial Sloan-Kettering Cancer Center, New York, NY; Institut Jules Bordet, Brussels, Université Libre de Bruxelles, Brussels, Belgium; Mayo Clinic, Scottsdale, AZ; Division of Pathology, European Institute of Oncology, Milan, Italy; National Cancer Institute, Bethesda, MD; Division of Medical Oncology, European Institute of Oncology, Milan, Italy; GlaxoSmithKline, Malvern, PA; Sunnybrook Odette Cancer Centre and the University of Toronto, Toronto, ON; The Johns Hopkins Hospital and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Sana Kliniken Offenbach, Offenbach, Germany; Országos Onkológiai Intézet, Budapest, Hungary; Helios Klinikum Berlin-Buch, Berlin, Germany; The Royal Marsden NHS Foundation Trust, London, United Kingdom; Patricia Ritchie Centre for Cancer Care and Research, The University of Sydney, Mater Hospital, Sydney, Australia; Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China; Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA; Mayo Clinic, Jacksonville, FL

Background: Lapatinib (L) is a HER1-HER2 tyrosine kinase inhibitor. The Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) Trial is a randomised, phase III trial comparing 3 oral L-containing regimens with T, each given for 1 year. Methods: From June 2007 to July 2011, 8381 patients (pts) were randomised from 946 sites in 44 countries to receive either L+T, T→L, L, or T. Anti-HER2 therapy was initiated after completing all chemotherapy (N=4613), concurrently with a taxane following anthracycline (N=3337), or concurrently with a non-anthracycline, platinum-containing regimen (N=431). The L arm was closed in Aug 2011 for futility and is not presented. The primary endpoint is invasive disease-free survival (DFS). L+T vs. T is tested for superiority and T→L vs. T is tested for non-inferiority at 1.11 margin. P≤0.025 is required for statistical significance. 850 DFS events in the L+T vs. T comparison would provide 80% power to detect a true hazard ratio (HR) of 0.80 with experiment-wide alpha=0.05. The current analysis was planned to occur either after observing these 850 events or at 4.5 yrs median follow up (MFU). Results: Pt and disease characteristics were well balanced. 40% were node-negative and 57% were hormone receptor positive. Only 555 DFS events for the L+T vs. T comparison were observed at 4.5 years MFU. HR for DFS was 0.84 (97.5% CI, 0.70-1.02; P=0.048; 4-yr DFS%=88% vs. 86%) for L+T vs. T and 0.93 (97.5% CI, 0.76-1.13; non-inferiority P=0.044; 4-yr DFS%=87% vs. 86%) for T→L vs. T. Diarrhoea (75% vs. 20%), rash (55% vs. 20%) and hepatobiliary (23% vs. 16%) adverse events were more frequent in L+T vs. T. Primary cardiac endpoints were infrequent (<1%) in all arms. Conclusions: L+T has lower risk of a DFS event compared with T, and T→L appeared non-inferior to T, but neither finding was statistically significant. The first DFS results of dual HER2 blockade in the adjuvant ALTTO at 4.5 years MFU are unexpected considering the effect shown by doubling the pCR rate with L+T vs. T in the NeoALLTO trial. Follow up continues.

Disclosures: Martine J. Piccart-Gebhart, Consultant or Advisory Role with PharmaMar, Honoraria from MSD, Symphogen, Synthon, Verastem, Novartis, Amgen, Bayer, Sanofi, Pfizer, Roche/Genentech, AstraZeneca, Lilly, Astellas Pharma, and Invivis; Evandro De Azambuja, Consultant or Advisory Role with GlaxoSmithKline, Honoraria from Roche, Research Funding from GlaxoSmithKline, Other Remuneration from GlaxoSmithKline and Roche; Giuseppe Viale, Consultant or Advisory Role with DAKO and Roche, Honoraria from DAKO, GlaxoSmithKline, and Roche; Sergio Santillana, Employment/Leadership Position with GlaxoSmithKline, Stock Ownership with GlaxoSmithKline; Kathleen I. Pritchard, Consultant or Advisory Role with Roche, Honoraria from Roche, Research Funding from Roche, Expert Testimony for Roche; Christian Jackisch, Honoraria from GlaxoSmithKline and Roche; Frances Boyle, Honoraria from GlaxoSmithKline, Research Funding from GlaxoSmithKline

Research Funding Source: GSK and US NCI


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