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ASCO Annual Meeting Spotlight
Key news updates from the ASCO Annual Meeting
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Tuesday, July 30, 2013

BY MARK FUERST

 

CHICAGO -- New insights into the biology of human epidermal growth factor receptor-2 positive (HER2+) advanced breast cancer have begun to change clinical practice, with a combination of chemotherapy and anti-HER2 agents emerging as the most effective current therapy. That was the consensus here in discussions at the American Society of Clinical Oncology at an Educational Session titled “Beyond Trastuzumab and Lapatinib: New Options for HER2-Positive Breast Cancer” as well as in other presentations

 

Two agents, pertuzumab and trastuzumab emtansine (T-DM1), have been recently approved for advanced breast cancer, and new combinations, including trastuzumab, vinorelbine, and everolimus; pertuzumab, trastuzumab, and paclitaxel; and lapatinib plus vinorelbine are now being tested.

 

At the session, experts discussed potential therapeutic options in development for the treatment of patients with HER2+ breast cancer, particularly those resistant to HER2 blockade. Speakers outlined what is now understood about the efficacy of dual therapy, examined new clinical trial designs that may answer questions about efficacy of anti-HER2 agents, and highlighted the questions that remain about how to best select patients who could benefit from chemotherapy or other options.

Combining anti-HER2 agents for the treatment of patients with HER2+ breast cancer is currently more effective than giving one agent on its own, said the Chair of the session, David A. Cameron, MD, Professor of Oncology and Director of Cancer Services at the University of Edinburgh.

 

He noted that several studies have confirmed a higher number of pathologic complete responses with use of dual anti-HER2 therapy. In the EGF104900 trial, dual HER2 blockade with trastuzumab plus lapatinib resulted in significant prolongation of both median progression-free survival (PFS) and overall survival (OS), with an acceptable toxicity rate. Another monoclonal antibody, pertuzumab, has shown efficacy in combination with trastuzumab in the adjuvant and metastatic setting.

 

In the randomized Phase III CLEOPATRA trial, patients were treated with either docetaxel plus trastuzumab or the same regimen plus pertuzumab, and the dual HER2 blockade significantly prolonged median PFS (18.5 months) compared with use of standard therapy (12.4 months).

 

BOLERO-3

In her report an oral session on breast cancer, Ruth O’Regan, MD, Professor and Vice-Chair for Educational Affairs in the Department of Hematology and Medical Oncology at Emory University School of Medicine, explained that although trastuzumab has markedly improved outcomes for patients with all stages of HER2+ breast cancer, in the metastatic setting, the majority of patients do eventually develop resistance to the drug.

 

She presented data on BOLERO-3 (Breast cancer trials of OraL EveROlimus-3), a Phase III, randomized, double-blind study of trastuzumab and vinorelbine plus everolimus conducted at 159 clinical trial sites globally (Abstract 505). The addition of everolimus, an mTOR inhibitor, to trastuzumab and vinorelbine in heavily pretreated advanced breast cancer patients led to a 22 percent reduction in the risk of disease progression. This is the first Phase III study to show that inhibition of the HER2+ receptor and mTOR provides significant benefit in HER2+ advanced breast cancer, she said.

 

The trial included 569 women with HER2+ locally advanced or metastatic breast cancer who were previously treated with a taxane and were resistant to trastuzumab. Participants were randomized to receive either everolimus at 5 mg/day orally (284 patients) or placebo (285 patients), plus weekly vinorelbine at 25 mg/m2 intravenously and weekly trastuzumab at 2 mg/kg intravenously following a loading dose of 4 mg/kg. All patients had prior taxane therapy, and 27 percent of patients in each group had received prior lapatinib.

 

The study met its primary endpoint of improved PFS, with a median time to progression of 7.0 months in the everolimus combination arm and 5.8 months in the placebo combination arm. Overall survival data are not yet mature, and will be available next year, she said.

 

She noted that in subgroup analyses everolimus seemed to have a greater effect on PFS among patients younger than 65, those with hormone receptor-negative cancers, and those who had received prior adjuvant or neoadjuvant trastuzumab. The overall response rate (ORR) was not significantly different between the two groups.

 

Adverse events were consistent with the known safety profile of everolimus, she said, and were “quite manageable.” The most common all-grade adverse reactions were neutropenia, stomatitis, anemia, leukopenia, fatigue, pyrexia, diarrhea, nausea, decreased appetite, and constipation. The most common Grade 3-4 adverse reactions were neutropenia, leukopenia, anemia, stomatitis, fatigue, febrile neutropenia, diarrhea, pyrexia, nausea, hyperglycemia and thrombocytopenia.

 

The Global Health Status was not significantly different in the two arms: “The toxicity of everolimus did not affect quality of life,” she said.

 

O’Regan said she believes that this everolimus combination could be used as third-line therapy after trastuzumab and pertuzumab in the metastatic setting. “Ultimately, based on known mechanisms of resistance, and with more mature survival data, I hope it will become another treatment option for advanced breast cancer,” she said.

 

Joyce O’Shaughnessy, MD, Co-Director of Breast Cancer Research at the Baylor Charles A. Sammons Cancer Center, said the BOLERO-3 study could be practice changing: “It gives us another option in HER2+ metastatic breast cancer. Everolimus is already available, and we will see it used immediately.”

 

In her remarks as Discussant for the study, Kimberly Blackwell, MD, Professor of Medicine at Duke University School of Medicine, said, “Everolimus should lessen the effect of upstream signaling and acquired resistance to trastuzumab. The unique aspect of the trial is that it allowed prior lapatinib, which suggests that patients were more treatment refractory.”

 

The BOLERO-3 results have landed in a crowded space of trastuzumab-resistant trials, she added. “At the end of the day, there is a role for mTOR inhibition. This is an active combination and leads to significant improvement in PFS.”  

 

Overcoming Resistance

Resistance to therapeutic agents is a continuing problem in advanced breast cancer, but only a limited number of resistance mechanisms have been validated,

 Ian Krop, MD, PhD, Instructor in Medicine, Adult Oncology, at Dana-Farber Cancer Institute. Speaking at the Education Session, he said that the goals of research in HER2+ breast cancer should be to reduce the relapses in the adjuvant setting, improve efficacy in metastatic breast cancer, reduce toxicity in both settings, and better tailor specific therapy to patients. Researchers need to identify ways to overcome mechanisms of resistance that could provide new therapeutic targets as well as predictive markers, he added.

 

A study by Spanish researchers called Long-HER, reported by Enrique Espinosa, MD, a medical oncologist at Hospital de la Pas in Madrid, used whole genome analysis to find predictors of early progression to trastuzumab, particularly in the phosphatidylinositol-3-kinase (PI3K) pathway (Abstract 608). The researchers used clinical and molecular analysis of advanced HER2+ breast cancer patients treated with trastuzumab.  

 

This observational, multicenter study compared 103 long-term survivors of breast cancer who had an objective response or stable disease for at least three years after trastuzumab therapy, and compared them with a control group of18 patients who had disease progression in the first year of similar first-line therapy.

 

A microarray platform was used to assess whole genome expression in 53 samples, including 35 from the long-term survivors and all of the controls. The PI3K pathway was most strongly associated with response to trastuzumab, Espinosa said, and to elucidate the mechanisms responsible for trastuzumab resistance, 97 genes related to the PI3K-mTOR pathway were evaluated. Five of these genes act upstream of mTOR complexes, and could modulate mTOR signaling, he said. Most patients in the control group had low expression of three of the genes, and high expression of the other two.

 

“It appears that you need several hits of the mTOR pathway for the tumor to become resistant to trastuzumab,”  he said. “A patient who has one or two alterations in the pathway is more likely to do well. For a patient with four or five alterations at the same time, the tumor is more likely to be resistant.”

 

He said he believes that combining new drugs, such as pertuzumab plus everolimus, makes sense after it is possible to define which patients are more likely to benefit from therapy, because they are more likely to be resistant to trastuzumab.

 

“In the near future, we will have a way to select patients for new anti-HER therapies,” he said. “When a patient needs an anti-HER2 drug, we will be able to test the tumor to see if it responds to trastuzumab. If the tumor is resistant, then we should combine trastuzumab with something else, such as an mTOR inhibitor.”

 

Anthony Goncalves, MD, of Marseille University commented: “The PI3K-mTOR pathway is frequently activated in HER2+ breast cancer and may play a major role in resistance to trastuzumab. Trastuzumab has transformed the natural history of HER2+ metastatic breast cancer, but primary or secondary resistances are ineluctable.

 

“Thirty to 50 percent of patients with HER2+ metastatic breast cancer do not respond to trastuzumab-based treatments, and virtually all will relapse ultimately.”  

 

O’Shaughnessy added that it is necessary to have a good reason to order genomic tests, and that includes clinical utility to justify the costs.

 

Speaking at the Education Session, Martine J. Piccart-Gebhart, MD, PhD, Director of the Medicine Department at Institut Jules Bordet in Belgium, said, “Optimization of treatment in this setting is our obligation.”

 

Methods must be devised that can identify patients who do not need intensified regimens and those with disease-resistant HER2 blockade. “Much larger collaboration networks are needed to make progress in anti-HER2 agent ‘tailoring,’ and to discover and validate predictive biomarkers of response.”

 

Several other studies presented at the meeting examined various combinations of agents in advanced breast cancer. For example, researchers at Memorial Sloan-Kettering Cancer Center combined pertuzumab, trastuzumab, and weekly paclitaxel in a phase II study of 53 patients with HER2-overexpressing metastatic breast cancer. The preliminary six-month progression-free survival rate was 81 percent in the 36 evaluable patients, with few grade 3/4 toxicities and no sign of increased cardiac toxicity to date.

 

In addition, a multicenter Phase II study examined a combination of lapatinib with vinorelbine as first- or second-line therapy in 44 women with HER2-overexpressing metastatic breast cancer. The combination of lapatinib and vinorelbine resulted in a 44 percent overall response rate, where half of the patients were receiving second-line therapy, and it was well tolerated.


Monday, July 29, 2013

BY PETER GOODWIN

 

CHICAGO -- Patients with metastatic KRAS wild-type colorectal cancer lived longer if cetuximab was added to their chemotherapy rather than bevacizumab, according to the results of a Phase III study from Germany reported here at the American Society of Clinical Oncology Annual Meeting (Abstract LBA3506).

 Volker Heinemann, MD, Professor of Medical Oncology and Director of the Comprehensive Cancer Center at  Klinikum der Universität in Munich, presented the data from the study, KRK-0306 (FIRE-3), showing that patients receiving cetuximab lived 3.7 months longer.

 

He emphasized that recruitment was restricted to patients with the non-mutated form of the KRAS gene (60 percent of all colorectal cancer cases), based on the discovery in 2008 that mutant KRAS disables cetuximab in colorectal cancer.  Bevacizumab, on the other hand, is unaffected by KRAS status and is an effective and licensed treatment for all patients.

 

“It became clear that cetuximab -- as an anti-EGFR [epidermal growth factor receptor] agent -- is active only in patients with KRAS wild-type tumors. For this reason we could include only such patients in the trial, he said in an interview. “Cetuximab targets the EGF receptor, which is involved in cell growth, while bevacizumab targets vascular endothelial growth factor – i.e., it targets blood supply to the tumor.”

 

The FIRE-3 study investigated whether cetuximab could be superior to its sister targeted agent in the subgroup of patients who are sensitive to it; the updated results from FIRE-3 provide the first Phase III evidence that it is.

 

A total of 592 patients with KRAS wild-type metastatic colorectal cancer (median age of 64) were randomized to receive either cetuximab or bevacizumab to supplement their first-line FOLFIRI chemotherapy (leucovorin, fluorouracil, and irinotecan). Median overall survival times were 25 months in patients receiving FOLFIRI plus bevacizumab vs. 28.7 months in patients receiving FOLFIRI plus cetuximab, with a hazard ratio of 0.77, which is  equivalent to a 23 percent reduction in the risk of death and 3.7 months extension of life.

 

In the intention-to-treat (ITT) analysis, progression-free survival was similar between the two arms: 10.3 months with bevacizumab versus 10.0 months among patients receiving cetuximab. Objective response rates and complete remission rates were also similar: 62 and 4.4 percent, respectively, with cetuximab vs. 58 and 1.4 percent with bevacizumab.

 

But when patients who did not actually receive their allocated treatment were excluded, a statistically significant superiority in response rate emerged in favor of cetuximab: 72.2 vs. 63.1 per cent, p = 0.17, which Heinemann said could be driving the observed extension of overall survival in patients on cetuximab in the ITT analysis: “The finding was that with regard to the primary endpoint of the objective response rate, there was no difference in the ITT population, while in patients assessable for efficacy there was a significant difference between the cetuximab and bevacizumab arms.”

 

To qualify as “assessable,” patients needed to have received enough of the allocated treatment and have been assessed by computed tomography. “If you look at the efficacy of a treatment with regard to response rate you want to make sure that patients also actually received your agent and didn’t drop out before,” Heinemann explained. “For that reason we decided to look at patients who had received at least three cycles of treatment and also had one CT imaging, which could demonstrate for us the efficacy of that agent.”

 

Toxicities for either of the targeted agents was “as expected, and manageable,” he said, with both arms equivalent overall. The two agents gave different toxicities, but this was not considered to change the overall iatrogenic morbidity rates.

 

Clinical Implications

Heinemann noted that the FIRE-3 findings are consistent with earlier smaller Phase II studies such as the PEAK trial, which provided preliminary indications of a survival benefit among patients with KRAS wild-type cancers who had an anti-EGFR agent added to their regimen in comparison with those having bevacizumab added. “Now, with the data from a large randomized Phase III trial, this points to a clear way of clarifying your choice of targeted therapy,” he said.

 

No ‘Home Run’

Another expert in this area, Richard M. Goldberg, MD, Physician-in-Chief at Ohio State University Comprehensive Cancer Center, stressed in an interview that the results should not be viewed as a “home run” – “The huge progress in extending life recently for patients with metastatic colorectal cancer has been achieved by a number of different important developments in treatment, not just one ‘inning.’”

 

He was also cautious because the primary goal of the FIRE-3 study (in the ITT analysis) -- objective response rate -- had not been met. “There also was no difference in progression-free survival between the two regimens.”

 

Nevertheless, Goldberg said he believed the data, and speculated about the extent that subsequent – i.e., second, third, and fourth -- lines of treatments after the initial five months of therapy with the target agents might have influenced the outcome: “Perhaps starting with FOLFIRI plus cetuximab allows a different sequencing later?,” he suggested.

 

He said that although he would not change his own standard practice on the basis of the FIRE-3 evidence alone, but the results are definitely something to pay attention to: “There’s something there about the 3.7 month advantage in median overall survival -- we need to understand why these patients lived longer.”

 

Key CALGB Trial Results Expected Soon

Goldberg also said that since US practice is to use FOLFOX rather than FOLFIRI as first-line chemotherapy rather than FOLFIRI, and that he considers the regimens to be generally equivalent in efficacy, it is worth waiting for more data comparing cetuximab with bevacizumab as an addition to chemotherapy in patients expressing wild-type KRAS. Results are soon to be released from the Cancer and Leukemia Group B 80405 study, he said, which, like FIRE 3, also puts cetuximab head to head with bevacizumab but with the option of using either FOLFOX or FOLFIRI chemotherapy.

 

“That study has completed accrual of over 1,700 patients: 70 percent of the patients were treated with FOLFOX, and 30 percent with FOLFIRI, and that will give us additional information about the cetuximab-versus- bevacizumab comparison.,” he said.

 

Heinemann agreed: “Our Phase III trial supports these data, and we are presently waiting for the larger CALGB trial to confirm these data: and then we’re going to make a final decision.” But he was adamant that these were important data advancing the state of knowledge significantly.


Monday, July 29, 2013

BY MARK FUERST

 

CHICAGO -- Extending adjuvant treatment with tamoxifen from five to 10 years affords women with estrogen receptor-positive (ER+) breast cancer greater protection against late recurrence and breast cancer death, according to data reported at the American Society of Clinical Oncology Annual Meeting (Abstract 5).

 

“Five years of adjuvant tamoxifen is already an excellent treatment, but we thought that longer treatment might be even better because women with ER+ breast cancer can have recurrences long after treatment is completed,” said lead author Richard G. Gray, MA, MSc, Professor of Medical Statistics at the University of Oxford. Until now, though, there have been doubts about whether continuing tamoxifen beyond five years is worthwhile. This study and its international counterpart, ATLAS (OT, 2/10/13), confirm that there is definitely a survival benefit from longer tamoxifen treatment, and many doctors will likely recommend continuing tamoxifen for an extra five years.”

 

Prior studies have shown that five years of tamoxifen reduces breast cancer death rates by about a third over a 15-year period following diagnosis. In the randomized, Phase III aTTom study, the benefits of longer treatment emerged later on, with reductions in recurrence seen after year 7 and reductions in mortality becoming evident after year 9, Gray said. The continued use of tamoxifen resulted in an additional 24 percent reduction in mortality after year 10.

“What is really impressive is the effect on breast cancer mortality: 10 years of tamoxifen compared with no tamoxifen reduces breast cancer mortality by a third in the first decade and a half in the second decade.”

 

Trial Data

For the study, between 1991 and 2005, a total of 6,953 women in the United Kingdom who had been taking tamoxifen for five years were randomly assigned to continue treatment with tamoxifen for another five years or to stop immediately. The women were contacted yearly to assess treatment compliance, recurrence, hospital admissions, and death rates. Compliance was good, with about 75 percent of women in the 10-year group continuing to take tamoxifen.

 

With 5,000 women followed for more than 10 years after randomization, and some as long as 20 years, there were 580 recurrences among women who had taken tamoxifen for 10 years, compared with 672 recurrences among those who took the drug for five years. There were 392 breast cancer deaths after disease recurrence in the 10-year arm compared with 443 deaths among those in the five-year arm.

 

A pooled analysis of the 17,477 patients enrolled in both the aTTom and ATLAS trials showed a nine percent reduction in the risk of death after patients received 10 years versus five years of tamoxifen for the entire follow-up period. The relative risk reduction increased to 16 percent starting at year 10.

 

There was an increased risk of endometrial cancer with the use of extended tamoxifen: 102 cases and 37 (1.1%) deaths attributed to endometrial cancer in the 10-year tamoxifen arm, compared with 45 cases and 20 (0.6%) deaths in the five-year group. The researchers estimated, though, that for every endometrial cancer death that occurs as a side effect of long-term tamoxifen, 30 deaths from breast cancer are prevented.

 

“The benefits of continuing tamoxifen to 10 years greatly outweigh the risks,” Gray said.

 

In conclusion, he said, “the aTTom and ATLAS trials together provide proof beyond reasonable doubt that continuing tamoxifen beyond five years reduces recurrence over the following years.”

 

He said that he and his colleagues are now planning to follow women in both of the studies for at least five more years to see if there is additional long-term benefit. A retrospective analysis of combined data from aTTom, ATLAS, and three smaller trials will be conducted to determine if there are subgroups of women who benefit the most from longer tamoxifen treatment.

 

In addition, he noted, ongoing clinical trials are comparing five and 10 years of use of aromatase inhibitors (AIs) to see if longer use of those agents also leads to additional benefits.

 

Late Recurrences

The Discussant for the study, Ann Partridge, MD, MPH, Director of the Program for Young Women with Breast Cancer at Dana-Farber Cancer Institute, noted that late recurrences in HR+ breast cancer are a major problem and remain a challenge as early treatment increases. “Even with recent advances, including AIs and trastuzumab, there appears to be a persistent risk of late recurrences.

 

“Five years of tamoxifen continues to improve the risks beyond five years. There is a carry-over effect. As time goes on, we are more likely to see a difference in breast cancer mortality out to 15 years,” she said.

 

Several studies have addressed the issue of whether extending tamoxifen would be helpful, she continued. There are suggestions that tamoxifen continuation may be better, but also that continued tamoxifen may worsen breast cancer outcomes.

 

In the aTTom trial, the absolute reduction of recurrence was four percent out to 15 years, and the absolute reduction of breast cancer mortality was two percent , which is of borderline significance, she said. “But this is impressive given that majority of these patients were ER-unknown. Undoubtedly some of them were ER-negative and would not be expected to respond to tamoxifen. Also, women followed the longest do appear to have a mortality benefit.”

 

Making Decisions

How should clinicians use this data to make decisions with early breast cancer survivors?, Partridge asked. “When assessing the anti-cancer benefit in an individual patient, stage clearly matters for early and late recurrence, and tumor biology matters tremendously. Can gene expression profiling help us here? How can we better understand tumor dormancy and endocrine resistance mechanisms? For the individual patient, we also need to consider comorbidity and age.”

 

She also encouraged clinicians to assess the risks of therapy, such as endometrial cancer: “Especially five years out, symptoms and quality of life become important. A patient’s preferences and values also need to be considered.”

 

Extended endocrine therapy options are largely driven by menopausal status as well as prior treatment experience. Partridge recommended that most postmenopausal women should consider receiving an AI in the first five years of therapy. “Consider tamoxifen if a patient has a contraindication or intolerance to AIs. Beginning tamoxifen after completing five years of AI might be reasonable,” she said, adding that the data do not support continuing AIs beyond five years.

 

For women who remain premenopausal, “extended tamoxifen is a great option where there has been no prior standard,” she said. These women have higher risk disease and therefore potentially the greatest risk reduction. “But the personal cost may be great, with a greater effect on long-term quality of life and future plans for fertility. Continued tamoxifen is a new option, but it also is reasonable to stop therapy, take a break, and have a woman think about the options.

 

“For some women, these are very difficult decisions. We need ways to better support our patients to make these decisions not only at diagnosis but also in long-term survivorship. Ultimately, decisions must be tailored to the individual patient based on her own risk/benefit profile.”

 

Future Research

Future research priorities should include improved understanding of the biology of late recurrence, identification of markers of late recurrence, and improved strategies to reduce late recurrence, she said.

 

The Chair of the Scientific Program for the meeting, Douglas Yee, MD, Professor of Medicine and Pharmacology and Director of the Masonic Cancer Center at the University of Minnesota, said the aTTom trial was “well-designed and provides additional data from a large number of patients to really settle the question of efficacy and safety of 10 years of tamoxifen.”

 

He noted that until now, extended tamoxifen regimens have been used infrequently in the U.S. because a smaller National Surgical Adjuvant Breast and Bowel Project (NSABP) study had suggested that 10 years of therapy was not beneficial. “However, it was recognized that this study was very underpowered to demonstrate benefit, so the NSABP was supportive of this larger trial,” he said.

 

Many places in the world are not using AIs routinely in adjuvant therapy, partially due to cost, Yee continued. “The aTTom trial provides validation of an alternative for extended endocrine therapy. In addition, it identifies an option for certain subgroups of women, particularly premenopausal women, for whom AIs would not be effective. It also shows that some women with ER+ breast cancer have an extended risk over time and provides an additional way to manage that risk.”


Sunday, July 28, 2013

BY PETER GOODWIN

 

CHICAGO -- In women with early breast cancer who were clinically node negative but with a positive sentinel node, complete axillary clearance was not found to be superior to use of radiotherapy, which also had the benefit of being less toxic. The final analysis of the European Phase III EORTC AMAROS (After Mapping of the Axilla: Radiotherapy Or Surgery?) trial, were reported here at the American Society of Clinical Oncology

Annual Meeting (Abstract LBA1001) by Emiel J.T. Rutgers MD, PhD, head of the department of surgery at the Netherlands Cancer Institute.

 

 

 

 

The results also showed that patients treated with radiotherapy were only half as likely to develop lymphedema as compared with those having surgery.

 

The aim of the study, he explained in an interview, was to see if there was a way to lessen the toxicity of surgical clearance of lymph nodes when metastases are found in the sentinel node but were not detectable clinically: “When we designed the study 12 years ago axillary clearance was dogma for these patients,” he said, noting, though, that there was also recent interest in looking at other approaches to treating sentinel node positivity.

 

The researchers were concerned about the high level of side effects from lymph node surgery -- particularly obstruction of the lymphatics of the arm, which usually necessitates lifelong treatment to manage lymphedema necessary.

 

The study included 4,806 patients with clinically node-negative early breast cancer, 3,382 of whom had no or only minimal metastasis and were allocated to follow-up. A total of 744 of the remaining 1,425 patients were allocated to surgery and 681 patients to radiotherapy. No significant differences in five-year overall survival (92.5 and 93.3 percent) emerged between the two treatment groups. Disease-free survival rates were also similar (82.6 and 86.9 percent).

 

The rate of cancer recurrence in the axilla was very low in both groups: 0.54 percent (4/744 patients) for surgery and 1.03 percent (7/681) for radiotherapy.

 

Arm edema (measured as any incidence of any symptom and/or treatment) was double -- at 28 percent -- in the group allocated to complete axillary dissection as compared with 14 percent in those treated with radiotherapy.

 

In terms of quality of life and shoulder movement impairment there were no significant differences between the study arms. “Radiotherapy to the axilla is a good alternative to surgical removal of the lymph nodes,” Rutgers said. “If treatment is deemed necessary [in T1/T2 N0 breast cancer] radiotherapy, is better than surgery.”

           

Long-Term Toxicity

With a median follow-up of only 6.1 years, however, the long-term toxicity comparison remains to be determined,  but Rutgers said he was fairly confident that those results will still favor radiotherapy. “In the long run the downside of using radiotherapy could be a small risk of damage to the nerves to the arm – plexopathy -- and radiation-induced sarcomas,” he said. But there has been no sign of such nerve damage yet, he noted, estimating that even if there was, the incidence of serious damage was not likely to exceed one percent of serious damage at 10 years. 

 

Lymphedema, on the other hand, was a different situation: “Lymphedema in the long run is associated with serious side effects and very rare but serious sarcoma of the arm, and if you prevent lymphedema, you may prevent that serious side effect in the long run.”

 

Clinical Recommendations

For cancer doctors the recommendation is quite clear, he said: “First, do sentinel node. Second, think what you do with the outcome -- if it’s negative, do nothing; if positive – if there is a small primary tumor -- you can refrain from any axillary treatment. If there’s more involved tumor, then radiotherapy is now the standard of care instead of a axillary clearance.

 

In early breast cancer, axillary clearance -- complete axillary dissection -- is obsolete.”

 

The moderator of a news conference that included the study, Andrew D. Seidman MD, of Memorial Sloan-Kettering Cancer Center, and a member of ASCO’s Cancer Communications Committee, noted that big steps have been made recently in the treatment of early breast cancer: “In the last few years we’re re-thinking the local-regional management of breast cancer, with less surgery and perhaps now an increased consideration for the role of radiotherapy for local control.”

 

Only for Defined Population

Asked for her opinion for this article, Pat Price, MD, Visiting Professor of Oncology at Imperial College in London and Chairperson of the UK’s Action Radiotherapy charity, said that for this defined population of women (T1/T2 breast cancer, clinically node-negative with positive sentinel node biopsy) the AMAROS findings are grounds for change: “For this small group of patients surgery would not necessarily be the right option,” she said.

 

“Axillary surgery will still be required for other groups of patients and there’s a lot of work to be done about selecting those who need axillary node clearance, or perhaps those who don’t need any surgery or radiotherapy at all.”

 

Price said she was impressed by the size of the AMAROS study but had some reservations about the current definitions of lymphedema, which she said has been poorly studied and still needs to be researched: “We’ve got some very crude measurements of it and definitions of it. We don’t even understand the mechanism.”

 

Still, she called the reduction of lymphedema “startling” – “That’s really important, because lymphedema is a huge problem -- long term -- for patients, and takes up a lot of health care costs -- and there is also the worry that patients have about lymphedema. Since we’ve been doing more clearances, lymphedema has become a bigger problem. So if we can reduce this, this will be fantastic for women,” she said.


Sunday, July 21, 2013

BY PETER GOODWIN

 

CHICAGO – For patients with advanced adenocarcinoma of the lung not responding to first-line therapy, median overall survival improved from 7.4 to 9.8 months after use of the inhibitor of heat shock protein (Hsp)90 ganetespib, according to a report here at the American Society of Clinical Oncology’s Annual Meeting (Abstract CRA8007).

The Phase II GALAXY-1 study, reported by Suresh S. Ramalingam, MD, Chief of Thoracic Oncology at Winship Cancer Institute of Emory University, randomized 252 patients to treatment with docetaxel with or without ganetespib.

 

In an interview afterwards, he described Hsp90 as a molecular “chaperone” because it oversees several different molecular processes leading to cancer, such as those involving epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), which individually have therapeutic applications in cancer treatment. “Hsp90 is a unique target – by inhibiting it, you can actually get to a number of key oncoproteins that are critical for the cancer cell,” he said.

 

In the study, patients with stage IIIB/IV lung adenocarcinoma experienced “mild to moderate” gastrointestinal and other toxicities — described as manageable’ — with median progression-free survival (PFS) of 4.5 months in the docetaxel-plus-ganetespib arm compared with 3.2 months in the docetaxel arm. The unadjusted hazard ratio was 0.84 (p = 0.038), and the hazard ratio for overall survival was 0.82 (p = 0.082).

 

Patients who received the combination had an improved progression-free and overall survival,” Ramalingam said “Even more important and interesting, was the fact that patients who came in more than six months from the time of diagnosis had a hazard ratio of 0.6, for both PFS and overall survival with very significant p values [HR = 0.61, p = 0.0041 and HR = 0.61, p = 0.0093], and these were 70 percent of all patients enrolled to the trial -- suggesting that this group derived the maximal benefit from the combination therapy.”

 

He quoted improvements of 32 percent in median overall survival with the combination for the group as a whole and 67 percent gain for those diagnosed more than six months previously -- equivalent to a 39 percent reduced risk of death (p < 0.01) in this group.

 

“This is a large randomized Phase II trial, and these exciting observations have now prompted a Phase III trial, which will test the regimen against the same control arm,” he said. “We will enroll only patients who are more than six months from diagnosis.”

 

Andrew D. Seidman, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center and member of ASCO’s Cancer Communications Committee, was moderator of a news briefing covering the study. “It’s exciting to see a totally new class of agent that disrupts a novel pathway and has great implications for many different tumors,” he said.

 

Robert Pirker, MD, Professor of Medical Oncology and Program Director for Bronchial Carcinoma at the University of Vienna, was also impressed by the findings: “The data here are certainly promising. There’s no doubt about it,” he said in an interview. But he was cautious -- having reservations about reading too much into the findings among patients diagnosed more than six months before the treatment began.

 

Better Prognosis Selection

The time interval between diagnosis and treatment correlates with better outlook overall because it selects for patients who have a good prognosis, he explained. “And it might be easier to get a certain improvement in patients with a good prognosis compared with those who are rapidly progressing.”

 

Pirker said he agreed that the enhanced efficacy of Hsp90 inhibition in these patients would need to be established by further research, and said he thought the main value of the GALAXY 1 results was that they provide justification for conducting the Phase III research. “The take-home message is that you have a clear signal of efficacy at an acceptable toxicity in a randomized Phase II trial,” he said.

 

Still the heterogeneity of lung cancer is a hurdle to be overcome: “We need a randomized Phase III trial. This trial is ongoing, the trial is warranted, and this would then answer the question of whether the mechanism of inhibition of heat shock protein will result in improvement in outcomes.”

 

Changed Landscape

Ramalingam was adamant about the positive scene his group’s study had set: “If you look at the landscapes for lung cancer in the salvage therapy setting, for nearly 10 years there has not been a single drug approved. And we’ve reached a plateau for those patients. Having a combination or a drug that extends survival will be a breakthrough for these patients,” he said.

 

“We now have lung adenocarcinoma being viewed as distinct molecular subsets. You have EGF mutations that account for 15 percent, ALK translocations that account for five percent, and a slew of other abnormalities that are seen in one or less percent of patients. So for specific subgroups, if you can have a targeted agent, we treat them. But that’s only about 15 to 20 per cent of lung adenocarcinomas right now. So if we have a drug that broadly affects patients, it’s going to be very impactful for lung cancer.”