SABCS Report: Tackling the Optimal Use of Established Therapies

Debu Tripathy, MD

William Gradishar, MD

The search for the appropriate duration of therapy for long-term treatment of patients with breast cancer and the continuing challenges of identifying which patients would benefit from novel treatments were among the most-discussed topics at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium in Texas.

More than 1000 abstracts were featured during the symposium, which drew approximately 7500 oncologists, researchers, and other oncology specialists from around the world to the Henry B. Gonzalez Convention Center.

Much of the discussion revolved around whether more treatment translates into a greater clinical benefit. In the case of tamoxifen and fulvestrant (Faslodex), women with hormone-responsive breast cancer may benefit from longer durations or higher doses of these therapies in the long-term, research indicated. However, that was not the case with trastuzumab (Herceptin), where one year of therapy appeared to have just as much benefit as two years of the drug for HER2-positive breast cancer.

Finding the right therapies has also proved challenging. Multiple studies failed to show that bevacizumab (Avastin) improved survival across all breast cancer patients, though some subgroups may experience modest benefits. After gaining approval more than a year ago in later lines of therapy, eribulin mesylate (Halaven) for earlier-line therapy has failed to show superiority over capecitabine (Xeloda), a drug that has been widely available for a longer period of time.

Some emerging therapies appear to have promise, such as a novel drug that significantly improved progression- free survival in women with estrogen receptor (ER)-positive breast cancer.

10-Year Tamoxifen Regimen Superior

In interviews with OncologyLive, Debu Tripathy, MD, co-leader of the Women’s Cancer Program and professor of Medicine at the University of Southern California/ Norris Comprehensive Cancer Center in Los Angeles, California, and William Gradishar, MD, Betsy Bramsen Professorship of Breast Oncology and a professor of Medicine-Hematology/Oncology at Northwestern University Feinberg School of Medicine in Chicago, Illinois, discussed their views of the most important abstracts presented during the symposium.A large study involving women with ER-positive breast cancer found that patients who received 10 years of treatment with tamoxifen had fewer recurrence events and fewer deaths than patients who received five years of treatment with the drug.¹

“Ongoing hormonal therapy is something that has been investigated, but we have very little data beyond five years of treatment,” Tripathy said. “We know in the case of tamoxifen that five years is certainly better than one or two years, but we also know that after five years of therapy, patients are still at risk for recurrence.”

The ATLAS trial enrolled 6846 women with ER-positive breast cancer between 1996 and 2005. All of the women used tamoxifen for at least four years, after which patients were randomized to either continue treatment with tamoxifen for another five years or stop treatment with tamoxifen immediately.

Gradishar said that the most striking aspect was that researchers observed little difference in recurrence rates and death rates between the two groups in years five through nine. However, during the second decade after diagnosis, patients who continued on tamoxifen for 10 years had a 25% lower recurrence rate and a 29% lower breast cancer mortality rate compared with women who received tamoxifen for five years.

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Dr. William Gradishar Discusses 10 Years of Adjuvant Tamoxifen

Overall, the risk for death from breast cancer between five and 14 years after diagnosis was 12.2% in patients who received 10 years of tamoxifen compared with 15% in patients who stopped taking tamoxifen after five years, with the greatest benefit being observed between years 10 and 14. Patients who continue on tamoxifen are at risk for developing endometrial cancer, though the disease is generally curable and the reduced risk of death from breast cancer heavily outweighs the risk of death from endometrial cancer.

“It begs the question of whether or not we should revisit longer durations of tamoxifen,” Gradishar said.

Gradishar and Tripathy both noted that aromatase inhibitors have since become the preferred treatment in postmenopausal women with hormonal disease; tamoxifen is a nonsteroidal antiestrogen agent. However, these findings could have the greatest impact in premenopausal women who are not candidates for aromatase inhibitors.

Higher Fulvestrant Dose Supported

“I think that if a patient has been tolerating tamoxifen well, especially if they have higher-risk disease, positive lymph nodes, or a larger tumor, that they should be offered five more years of tamoxifen,” Tripathy said. “For these patients, this is truly practice-changing.”A 500-mg dose of fulvestrant appears to have a greater survival benefit in postmenopausal women with advanced ER-positive breast cancer compared with the 250 mg dose, according to a final analysis of the phase III CONFIRM trial.²

“There’s always been some question as to what the appropriate dose of fulvestrant is,” Tripathy said. “It is a drug that has to be given at the right dose to fully downregulate the estrogen receptor.”

In this trial, 736 women with locally advanced or metastatic ER-positive disease were randomized 1:1 to receive either 500 mg of fulvestrant (intramuscularly; days 0, 14, and 28, and every 28 days thereafter; n = 362) or 250 mg of fulvestrant (intramuscularly; every 28 days; n = 374). In order to maintain a placebocontrolled trial, patients in the 250-mg arm of the study also received one placebo injection on days 0 and 28 and two placebo injections on day 14 (Figure).

Figure. CONFIRM Trial Details²

Key Eligibility

Postmenopausal

Advanced ER+ disease

736

patients

Randomized

1:1

Treatment Arms

Fulvestrant 250 mg + placebo

Days 0, 14, 28, and every 28

days thereafter

(374 patients)

Fulvestrant 500 mg

Days 0, 14, 28, and every 28

days thereafter

(362 patients)

Findings

Median PFS | 5.5 mo

Median OS | 22.3 mo

Median PFS | 6.5 mo

Median OS | 26.4 mo

ER indicates estrogen receptor; OS, overall survival; PFS, progression-free survival.

In the final analysis, the median overall survival (OS) in the 500-mg fulvestrant arm was 26.4 months compared with 22.3 months in the 250-mg fulvestrant arm (HR = 0.81; 95% CI, 0.69-0.96; nominal P = .016). Though statistically significant, the authors of the study noted that it is a nominal P value because this study was an exploratory analysis that was not powered to detect true statistical significance between the two arms. However, the authors also said that the study shows a clear trend toward improved survival.

“I think what it tells us for clinical practice is, in fact, that the higher dose of fulvestrant is the one to go with,” Gradishar said. “It translates into an improved outcome for patients.”

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Dr. Debu Tripathy Reviews the Phase III CONFIRM Trial

Tripathy said the study raises the question of whether fulvestrant may now be the second-line hormonal therapy of choice for postmenopausal patients, since it has been shown to be equivalent in efficacy to exemestane (Aromasin). Additionally, he said there is still considerable interest in combining fulvestrant with aromatase inhibitors. Two large clinical trials have yielded conflicting results, so the future of fulvestrant hormonal combinations in breast cancer as a whole is still being determined.

PD 0332991 Results Promising

“I don’t think it’s the standard to use combination hormonal therapy, but certainly it deserves to be looked at for updates to be examined that may impact on practice later,” Tripathy said.Results of a phase II study demonstrated that patients with advanced ER-positive breast cancer who received the investigational agent PD 0332991 in combination with letrozole (Femara) as first-line therapy experienced a median progression-free survival (PFS) of 26.1 months compared with 7.5 months for letrozole alone (P = .006).³

PD 0332991 is an oral, selective cell-cycle inhibitor of cyclin-dependent kinase (CDK) 4/6 that prevents cellular DNA synthesis by blocking tumor cell-cycle progression.

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Dr. Debu Tripathy on the CDK4/6 Inhibitor PD 0332991

“The cell cycle is what drives cells into division in response to growth factors and a variety of other stimuli, but directly targeting the cell cycle has been of interest for quite some time,” Tripathy said.

In this particular phase II trial, two groups of postmenopausal women with ER-positive/HER2-negative advanced breast cancer were randomized 1:1 to receive letrozole plus PD 0332991 or letrozole alone. The first group included 66 patients, while the second group included 99 patients who were also screened for amplification of the cyclin D1 (CCND1) gene and/or loss of the natural CDK inhibitor p16 by fluorescence in situ hybridization (FISH) analysis. The primary endpoint of the study was PFS.

Pooled results from both parts 1 and 2 of the trial, based on a total of 165 patients, indicated that median PFS was 26.1 months (95% CI, 12.7—26.1) with the combination versus 7.5 months (95% CI, 5.6–12.6) with letrozole alone, representing a 63% improvement in risk of progression (HR= 0.37; 95% CI, 0.21–0.63, P < .001).

In patients with measurable disease, response rates were 45% for the combination versus 31% for letrozole alone. Clinical benefit rate (complete and partial response rates plus stable disease) was 70% versus 44%, respectively.

The most commonly observed treatment-related adverse events in the combination arm were neutropenia, leukopenia, anemia, and fatigue. There was no evidence of febrile neutropenia, according to the authors.

A phase III study of PD 0332991 will begin enrolling patients in 2013. Gradishar said that difference in survival is striking enough to warrant keeping a close eye on further data regarding this drug.

Bevacizumab Combination Falters

“Of course, this is nothing that’s going to be applicable tomorrow or next week or next year, but it holds the hope that some of these new drugs will really be a hit and will ultimately find their way through FDA approval,” Gradishar said.A phase III trial showed that combining bevacizumab with either letrozole or fulvestrant as first-line therapy in advanced breast cancer did not demonstrate a statistically significant improvement in PFS when compared with patients who received either letrozole or fulvestrant alone.⁴

The LEA trial, the first phase III trial to explore the use of an antiangiogenic agent in combination with endocrine therapy, enrolled 380 patients who were postmenopausal and had HER2-negative, hormone receptor-positive disease and randomized them 1:1 to receive endocrine therapy alone (n = 189) or endocrine therapy plus bevacizumab (n = 191).

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Dr. William Gradishar Reviews Findings From the LEA Trial

An improvement in PFS was observed in the combination arm compared with the endocrine therapy-alone arm, although the improvement did not achieve statistical significance (18.4 vs 13.8 months; HR = 0.83; 95% CI, 0.65—1.06; P = .14). During the four-year study period, there were 117 PFS events in the group that received the combination compared with 131 in the monotherapy group.

There was no improvement in OS for women in the study who received bevacizumab combination therapy. The median OS was 41 months in the combination arm compared with 42 months in the endocrine therapy- alone arm (HR = 1.18; 95% CI, 0.77—1.81; P = .469). Additionally, patients who received bevacizumab experienced more frequent hematologic and nonhematologic adverse events.

Gradishar said that there’s really no positive information to come out of this trial, and noted that studies of bevacizumab have failed to demonstrate a clear indication as to which patients with breast cancer, if any, may benefit from the drug.

“There is some data calling out subsets from the metastatic trial suggesting triple-negative disease, again, might be a subset that it works in, but certainly, based on the LEA trial, the addition of bevacizumab to endocrine therapy did not result in an improvement in outcome,” Gradishar said.

Tripathy said other studies investigating the use of bevacizumab in combination with tamoxifen or aromatase inhibitors have been completed and will be reported soon. One of the key aspects of these trials, according to Tripathy, could be the toxicity profile, and while toxicities were more frequent with bevacizumab, he said they were lower than what has been observed with chemotherapy.

Mixed Picture in Eribulin Data

“There may be a different toxicity profile combining these drugs with endocrine therapy as opposed to chemotherapy,” Tripathy said. “So while this doesn’t change practice, it does deserve attention as time goes on.”A phase III study showed that women with previously treated metastatic breast cancer who received eribulin mesylate failed to achieve a statistically significant improvement in either PFS or OS when compared with capecitabine.⁵

The FDA approved eribulin, a nontaxane microtubule dynamics inhibitor, in 2010 for patients with metastatic breast cancer who had been previously treated with at least two chemotherapy regimens including an anthracycline and a taxane in either the adjuvant or metastatic setting. Early clinical trials showed a statistically significant improvement in OS when eribulin was compared with several different therapies currently used to treat the disease.

Study 301 evaluated eribulin versus capecitabine in earlier lines of treatment of metastatic breast cancer. In this study, 1102 patients were randomized 1:1 to receive either eribulin mesylate 1.4 mg/m² given on days 1 and 8 of a 21-day cycle or capecitabine 1250 mg/m² administered orally twice daily on days 1 to 14 of a 21-day cycle. In order to be eligible for the study, patients had to have locally advanced or metastatic breast cancer, ≤3 prior chemotherapy regimens (≤2 for advanced disease), and prior treatment with anthracycline and taxane chemotherapy.

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Dr. William Gradishar Reviews the Eribulin 301 Study

The median OS was 15.9 months for patients who received eribulin and 14.5 months patients who received capecitabine (HR = 0.879; 95% CI, 0.770- 1.003; P = .056). Median PFS was 4.1 months and 4.2 months, respectively (HR = 1.079; 95% CI, 0.932 — 1.250; P = .305). Objective response rates were 11% for eribulin and 12% for capecitabine (P = .849).

While the study was unable to demonstrate that eribulin was superior to capecitabine overall, subgroup data suggest that some patients fared better with eribulin. The median OS for HER2-negative patients was 15.9 months with eribulin compared with 13.5 months for capecitabine (HR = 0.838; 95% CI, 0.715 — 0.983; P = .030). In addition, patients with triple-negative breast cancer lived about five months longer when they received eribulin compared with capecitabine.

“Of course, we’re looking at subsets, smaller numbers than the total population, but clearly, in that group, there was a hint that eribulin might be particularly effective,” Gradishar said. “So although it could be spun as a negative trial, I would also interpret it as a trial that shows eribulin is equal to another drug that is used very commonly in early metastatic breast cancer treatment, not salvage therapy, and a signal that it might be effective in a particularly troublesome subset of breast cancer.”

References

1. Davies C, Pan H, Godwin J, et al. ATLAS. 10 v 5 years of adjuvant tamoxifen (TAM) in ER+ disease: efects on outcome in the first and in the second decade after diagnosis. Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4 — 8, 2012; San Antonio, Texas. Abstract S1-2.
2. Di Leo A, Jerusalem G, Petruzelka L, et al. Final analysis of overall survival for the phase III CONFIRM trial: fulvestrant 500 mg versus 250 mg. Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, Texas. Abstract S1-4.
3. Finn RS, Crown JP, Lang I, et al. Results of a randomized phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (TRIO-18). Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4 — 8, 2012; San Antonio, Texas. Abstract S1-6.
4. Martin M, Loibl S, von Minckwitz G, et al. Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer — first efficacy results from the LEA study. Presented at: 2012 CTRCAACR San Antonio Breast Cancer Symposium; December 4 – 8, 2012; San Antonio, Texas. Abstract S1-7.
5. Kaufman PA, Awada A, Twelves C, et al. A phase III, open-label, arndomized, multicenter study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes. Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, Texas. Abstract S6-6.