Tripathy Offers Insights on Future of Breast Cancer From SABCS, ASCO

Debu Tripathy, MD

Clinically Noteworthy Research From 2016: Top Abstracts From ASCO and SABCS

Extended Adjuvant Aromatase Inhibitor Therapy

The 34th Annual Miami Breast Cancer Conference^® featured a recap of significant research from the 2016 ASCO Annual Meeting and the 2016 San Antonio Breast Cancer Symposium (SABCS). Debu Tripathy, MD, of The University of Texas MD Anderson Cancer Center, provided highlights of those meetings (Table). Tripathy served as co-chair of the conference, which Physicians’ Education Resource^® (PER^®) sponsored March 9 to 12 in Miami Beach, Florida.Tripathy highlighted 4 trials that looked at extending aromatase inhibitor (AI) therapy beyond 5 years. The first was the phase III MA.17R trial, which compared letrozole with placebo. It found that women who extended their adjuvant therapy with an AI to 10 years after treatment for their early-stage hormone receptor (HR)—positive breast cancer reduced their risk of recurrence by more than a third and experienced no new toxicities or worsening of quality of life. However, the impact on distant metastases was minimal.¹

Whereas the MA.17R trial showed promising disease-free survival (DFS) results, 3 other trials found that extended hormonal therapy with an AI did not improve DFS rates in patients with HR-positive breast cancer. The multicenter phase III DATA study compared 3 versus 6 years of anastrozole after 2 to 3 years of tamoxifen in postmenopausal women with HR-positive early breast cancer. The study found that the 5-year adapted DFS, the primary endpoint of the study, was 79% in the 3-year anastrozole treatment group and 83% in the 6-year treatment arm.²

The IDEAL study compared 7.5 and 10 years of hormonal therapy. Patients were randomized to letrozole for 2.5 or 5 years of extended therapy. The 5-year DFS rate was 88.4% in patients receiving an additional 2.5 years of treatment and 87.9% for those receiving 5 more years of treatment with letrozole (HR, 0.96; P = .70). Overall survival (OS) rates were 93.5% and 92.6%, respectively (HR, 1.08; P = .59).³

Then, in the NSABP B-42 trial, the DFS at approximately 7 years was 84.7% with extended letrozole versus 81.3% with placebo (HR, 0.85; P = .048, which did not achieve statistical significance based on the analysis plan). OS was 91.8% with letrozole compared with 92.3% for patients on placebo (HR, 1.15; P = .22).⁴

“We have typically used 5 years [of hormonal therapy], but many patients recur after 5 years, even 10, 20 years out,” said Tripathy. “Perhaps we should be selective about whom we give 10 years of aromatase inhibitor versus just 5 years, because you do have more side effects when you keep them on for longer. This should probably be con ned to patients who have high-risk breast cancer, such as stage III or high-risk stage II.” Adjuvant Anthracycline Therapy Does the use of adjuvant anthracycline therapy contribute to better outcomes despite the associated toxicity profile? The Anthracyclines in Early Breast Cancer (ABC) trials examined this question in women with high-risk, HER2-negative breast cancer. A pooled analysis of 3 studies found that anthracyclines do appear to be slightly better for patients. The phase III trials (USOR 06-090, NSABP B-46I/USOR 07132, and NSABP B-49) compared docetaxel plus cyclophosphamide versus anthracycline/taxane- based chemotherapy regimens (TaxAC). With 397 invasive DFS events, the 3-year invasive DFS rate was 91.7% for cyclophosphamide versus 92.4% for TaxAC. For triple-negative breast cancer (TNBC), it was 86.6% versus 89.6%, and for HR-positive disease it was 94.1% versus 93.7%, respectively.⁵

“The large trial was designed to see if we do get noninferior results with nonanthracycline therapy, and the answer is no,” said Tripathy. “We cannot say that it is OK to omit an anthracycline; there is still a bene t. What we probably should be doing is offering nonanthracycline therapy only in lower-risk cancers. Higher-risk cancers should probably be getting anthracycline-based therapy even though there are more side effects.” Neoadjuvant HER2-Positive Therapy In a phase III study presented at ASCO, researchers looked at lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer.⁶

Researchers studied the effect on tumor response to neoadjuvant therapy with the substitution of lapatinib for trastuzumab (Herceptin) in combination with weekly paclitaxel after doxorubicin plus cyclophosphamide treatment, and through the addition of combination lapatinib and trastuzumab after doxorubicin plus cyclophosphamide treatment.

The primary objective was to determine pathological complete response (pCR) rates. In the trastuzumab group, pCR in the breast was noted in 93 (52.5%; 95% CI, 44.9-59.5) of 177 patients compared with 91 (53.2%; 95% CI, 45.4-60.3) of 171 patients in the lapatinib group (P = .99). In the combination group, 106 (62.0%; 95% CI, 54.3- 68.8) of 171 patients had a pCR.

Grade 3/4 toxicities were experienced in the trastuzumab, lapatinib, and combination groups including neutropenia and diarrhea. Symptomatic congestive heart failure occurred in 7 patients (4%) in the trastuzumab group, 7 (4%) in the lapatinib group, and 1 (<1%) in the combination group.

The Role of Capecitabine

While several studies have shown improvement in pCR with the addition of lapatinib to standard trastuzumab-based therapy, the ALTTO trial, which was powered to assess long-term outcome, did not show a DFS advantage.The Finland Capecitabine (FinXX) trial studied capecitabine in the adjuvant setting among 1500 patients. Patients were randomly assigned to receive either 3 cycles of docetaxcel and capecitabine, followed by 3 cycles of cyclophosphamide, epirubicin, and capecitabine (CEX; n = 753), or 3 cycles of docetaxel followed by 3 cycles of cyclophosphamide, epirubicin, and uorouracil (CEF; n = 747). The primary endpoint was recurrence-free survival (RFS).⁷

During a median follow-up time of 10.3 months, 301 RFS events occurred (local or distant recurrences or deaths), including 142 events in the docetaxel/capecitabine/CEX combination arm and 161 events in the docetaxel/CEF group (HR, 0.85; 95% CI, 0.68-1.07; P = .168).

Hormonal Therapy in HR-Positive Breast Cancer

However, the trial found that in a certain subset of patients with TNBC there was a better outcome in terms of RFS (HR, 0.43; 95% CI, 0.24-0.79; P = .007) and OS (HR, 0.55; 95% CI, 0.31-0.96; P = .037) for treatment with docetaxel/capecitabine/CEX combination over docetaxel/CEF. “Capecitabine is a drug that seems to improve outcome in very high-risk patients who get neoadjuvant therapy,” said Tripathy. “We need to re-look at how we use this drug.”The FALCON trial, initially presented at the European Society for Medical Oncology 2016 Congress, was a large study that compared treat- ment with fulvestrant (Faslodex) versus anastrozole in patients with HR-positive advanced breast cancer who had not previously received hormonal therapy.

Confirming results of an earlier phase II study, the FALCON trial yielded a median progression-free survival (PFS) of 16.6 months in patients treated with first-line fulvestrant versus 13.8 months with anastrozole. Moreover, a consistent advantage favoring fulvestrant emerged from a subgroup analysis. The overall advantage appeared to be driven by a substantial difference in PFS among patients without visceral metastases treated with fulvestrant.⁸

Cyclin-Dependent Kinase Inhibitors

“Typically, we treat these patients with hormonal therapy and we usually use aromatase inhibitors and fulvestrant, which is another drug that is usually used in second-line,” said Tripathy. “The question is, which should we use first in select patients?”The phase III PALOMA-2 trial compared the use of the CDK4/6 inhibitor palbociclib (Ibrance) with letrozole to letrozole alone. It reduced the risk of disease progression by 42% compared with letrozole alone in patients with estrogen receptor (ER)—positive, HER2-negative advanced or metastatic breast cancer. The median PFS was improved by greater than 10 months with the addition of palbociclib.⁹

Abemaciclib as a single agent induced a response rate of nearly 20% in heavily pretreated patients with refractory, HR-positive, HER2-negative advanced breast cancer, according to findings from the phase II MONARCH 1 trial. In the single-arm phase II study, the median PFS was 6 months (95% CI, 4.2-7.5) and the median OS was 17.7 months (95% CI, 16 to not reached).¹⁰

Targeting Specific Mutations

Tripathy noted that the CDK4/6 inhibitor class of drugs is expanding; ribociclib (Kisqali) was approved March 13. “We need to learn what groups of patients we should be using these in and why patients become resistant,” Tripathy said.In the PALOMA-3 study, the combination of palbociclib and fulvestrant was associated with significant improvements in PFS compared with fulvestrant plus placebo in patients with metastatic breast cancer. An analysis of the trial was carried out on the basis of estrogen receptor-alpha (ESR1) mutations’ known evolution after exposure and resistance to hormonal therapy.¹¹

Overall, median PFS was 5.7 months (95% CI, 3.7-9.4) for patients with an ESR1 mutation versus 9.2 months (95% CI, 7.5-10.9) for patients without an ESR1 mutation (HR, 1.33; 95% CI, 0.99-1.80; 2-sided P = .0572). Median PFS was significantly longer in the palbociclib plus fulvestrant group compared with the fulvestrant plus placebo group both in patients without a detectable ESR1 mutation and in patients with one.

Biosimilars

“The new era of targeting mutations is now here,” said Tripathy. “There’s some data on HER2 mutations and how they respond to a drug named neratinib, and ESR1 mutations we know predict the worst outcome, but we don’t yet have a drug to address this.”A biosimilar version of trastuzumab (Herceptin) demonstrated equivalent efficacy and safety to the FDA-approved branded drug in a randomized phase III study among patients with HER2-positive metastatic breast cancer.

In the Heritage trial, the antibody MYL-1401O demonstrated an overall response rate (ORR) after 24 weeks of 69.6% among women who received the biosimilar in combination with a taxane compared with a 64% ORR for patients who took trastuzumab plus a taxane. The ratio of ORR for MYL-1401O to trastuzumab was 1.09; both 90% CI (0.974-1.211) and 95% CI (0.954-1.237) were within the predefined equivalence margin.¹²

Immunotherapy

“We’re all concerned about the price of drugs rising, especially if the biological drugs really get to the point where they are barely affordable for many patients and sort of bankrupting the entire system,” Tripathy said. “Biosimilars have to go through testing by the FDA, but not the same degree of testing as the original drugs went through. So, are people going to have enough faith in them—both patients and physicians—that they will enter the marketplace, increase competition and lower the price?”The multicenter, nonrandomized phase Ib KEYNOTE-012 trial showed long-term responses with the anti—PD-1 antibody pembrolizumab (Keytruda) in women with metastatic TNBC. Median OS was 10.2 months (95% CI, 5.3-17.5) and 12-month OS rate was 41.1%; 25 patients (78.1%) died. Median PFS was 1.9 months (95% CI, 1.3-4.3) and 12-month PFS rate was 15%. One patient had a complete response, while 4 had partial responses. Of the 5 responders, 3 experienced long-lasting benefit from pembrolizumab.¹³

PARP Inhibitors for BRCA-Related Advanced Breast Cancer

“We have some longer follow-up that suggests that not all breast cancer patients respond to immunotherapies,” said Tripathy. “Patients with TNBC are the ones that seem to have responses, but still, even in this group only about 20% of them respond. However, some of the responders among these 20% seem to have very durable responses, some of them lasting a year or more. So, I think the challenge ahead is trying to understand how we can better identify the patients who are likely to respond to these therapies, and then maybe use combination therapies to make the tumors more immunogenic, so that we can get better responses from immunotherapy.”In a randomized, phase II study, researchers examined the efficacy and tolerability of the PARP inhibitor veliparib in combination with carboplatin and paclitaxel versus placebo in patients with BRCA1 or BRCA2 mutations and metastatic breast cancer. There was no significant difference in OS or PFS. However, the ORR for veliparib was 77.8% versus 61.3% for placebo (P = .027).¹⁴

“Unfortunately, and surprisingly, it didn’t show a benefit,” said Tripathy. “There was a trend there, but it wasn’t statistically significant. This is an important one to study because it’s really the first randomized trial to be presented.” A larger phase III trial of the same design is ongoing.

References

1. Goss PE, Ingle JN, Pritchard NJ, et al. A randomized trial (MA.17R) of extending adjuvant letrozole for 5 years after completing an initial 5 years of aromatase inhibitor therapy alone or preceded by tamoxifen in postmenopausal women with early-stage breast cancer. J Clin Oncol. 2016;34 (suppl; abstr LBA1).
2. Tjan-Heihnen VC, Van Hellemond IE, Peer PG, et al. First results from the multicenter phase III DATA study comparing 3 versus 6 years of anastrozole after 2-3 years of tamoxifen in postmenopausal women with hormone receptor-positive early breast cancer. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract S1-03.
3. Blok EJ, van de Velde CJH, Meershoek-Klein Kranenbarg EM, et al. Optimal duration of extended letrozole treatment after 5 years of adjuvant endocrine therapy; results of the randomized phase III IDEAL trial (BOOG 2006-05). Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract S1-04.
4. Mamounas EP, Bandos H, Lembersky BC, et al. A randomized, double-blinded, placebo-controlled clinical trial of extended adjuvant endocrine therapy (tx) with letrozole (L) in postmenopausal women with hormone-receptor (+) breast cancer (BC) who have completed previous adjuvant tx with an aromatase inhibitor (AI): Results from NRG Oncology/NSABP B-42. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract S1-05.
5. Blue JL, Flynn PJ, Yothers G, et al. Interim joint analysis of the ABC (anthracyclines in early breast cancer) phase III trials (USOR 06-090, NSABP B-46I/USOR 07132, NSABP B-49 [NRG Oncology]) comparing docetaxel + cyclophosphamide (TC) v anthracycline/taxane-based chemotherapy regimens (TaxAC) in women with high-risk, HER2-negative breast cancer. J Clin Oncol. 2016;34(suppl; abstr 1000).
6. Robidoux A, Tang G, Rastogi P, et al. Evaluation of lapatinib as a component of neoadjuvant therapy for HER2+ operable breast cancer: 5-year outcomes of NSABP protocol B-41. J Clin Oncol. 2016;34(suppl; abstr 501).
7. Joensuu H, Kellokumpu-Lehtinen P-L, Huovinen R, et al. Adjuvant capesitabine in combination with docetaxel (T), epirubicin (E), and cyclophospha- mide (C) in the treatment of early breast cancer (BC): 10-year survival results from the randomized FinXX trial. J Clin Oncol. 2016;34 (suppl; abstr 1001).
8. Robertson JFR, Noguchi S, Shao Z, et al. Progression-free survival results in patient subgroups from a Phase 3 randomized trial of fulvestrant 500 mg vs anastrozole for hormone receptor-positive advanced breast cancer (FALCON). Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract P2-08-02.
9. Finn RS, Martin M, Rugo HS, et al. PALOMA-2: Primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2— advanced breast cancer (ABC). J Clin Oncol. 2016;34(suppl; abstr 507).
10. Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH1: Results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for advanced disease. J Clin Oncol. 2016;34(suppl; abstr 510).
11. Turner NC, Jiang Y, O’Leary B, et al. Efficacy of palbociclib plus fulvestrant (P+F) in patients (pts) with metastatic breast cancer (MBC) and ESR1 mutations (mus) in circulating tumor DNA (ctDNA). J Clin Oncol. 2016;34(suppl; abstr 512).
12. Rugo HS, Barve A, Waller CF, et al. Heritage: A phase III safety and efficacy trial of the proposed trastuzumab biosimilar Myl-1401O versus Herceptin. J Clin Oncol. 2016;34(suppl; abstr LBA503).
13. Nanda R, Specht J, Dees C, et al. KEYNOTE-012: Long-lasting responses in a phase Ib study of pembrolizumab for metastatic triple-negative breast cancer (mTNBC). Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract P6-10-03.
14. Han HS, Diéras V, Robson ME, et al. Efficacy and tolerability of veliparib (V; ABT-888) in combination with carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer: A randomized, phase 2 study. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract S2-05.