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Targeted Therapy Updates in Hormone Receptor–Positive Advanced Breast Cancer

June 7, 2018 – Presentations at the 2018 Annual Meeting of the American Society of Clinical Oncology (ASCO 2018) highlighted the ongoing development of targeted therapy for advanced, hormone receptor (HR)-positive breast cancer. In recent years, the introduction of cyclin-dependent kinase (CDK) 4 and 6 inhibitors has transformed the standard of care, both for newly diagnosed and recurrent disease.1 In addition, inhibitors of molecules in the PI3K/Akt/mTOR pathway have emerged as potential treatment options for patients with HR-positive disease.2

Ribociclib shows encouraging efficacy along with fulvestrant in first-line HR+ advanced breast cancer

The ongoing development of CDK4/6 inhibitors was the focus of several oral presentations at ASCO 2018. First, findings from MONALEESA-3 were presented by Dennis Slamon, MD (University of California, Los Angeles).3 This phase III study randomized 726 postmenopausal women with HR-positive, HER2-negative, metastatic breast cancer and ≤1 prior line of endocrine therapy to receive either ribociclib-fulvestrant or placebo-fulvestrant. Key findings from this study included:

  • Ribociclib improved both progression-free survival (PFS) and overall response rate (ORR) compared with placebo
    • Median PFS, ribociclib vs placebo: 20.5 months vs 12.8 months (HR 0.593, P<.001)
    • PFS benefit was consistent in patients with either 0 or 1 prior line of endocrine therapy
    • ORR in all patients, ribociclib vs placebo: 32.4% vs 21.5%, P = .000912
  • Ribociclib increased the risk of grade 3/4 neutropenia and liver enzyme elevation compared with placebo
    • Neutropenia (grade 3/grade 4): ribociclib (46.6%/6.8%) vs placebo (0%/0%)
    • ALT increase (grade 3/grade 4): ribociclib (6.6%/1.9%) vs placebo (<1%/0%)
  • Ribociclib increased the rate of post-baseline QT prolongation (>480 ms) compared with placebo (5.6% and 2.5%, respectively)

These findings demonstrate for the first time that the addition of ribociclib to fulvestrant can improve outcomes, including as first-line therapy for patients with endocrine-naïve, HR-positive advanced breast cancer.

Preplanned mutation analysis identifies potential drivers of CDK4/6 inhibitor resistance

The identification of mechanisms of resistance to CDK4/6 inhibitors has been a key area of focus in recent years, with the goal of optimizing selection of salvage therapy. Nicholas Turner, MD, PhD (Royal Marsden Hospital, London, United Kingdom), presented findings from an analysis of PALOMA3 that used circulating tumor DNA (ctDNA) to identify potential drivers of resistance to palbociclib and fulvestrant.4 Important findings included:

  • At the end of treatment, mutations in RB1 were more frequently detected in the palbociclib arm than in the placebo arm (4.8% vs 0%)
  • Mutations in PIK3CA and ESR1 appeared with similar frequency between the two groups

These findings suggest that PIK3CA and ESR1 mutations are likely drivers of resistance to fulvestrant, and palbociclib treatment does not increase the risk of acquiring these mutations. Furthermore, RB1 mutations may drive resistance to palbociclib in a small minority of patients, which was not observed in the placebo group. However, with such a low incidence, the development of RB1 mutations is clearly not the predominant resistance mechanism underpinning progression on palbociclib, and other drivers of resistance need to be identified.

Continuous CDK4/6 inhibition demonstrates improved outcomes for pre-/perimenopausal women

Recent findings from MONALEESA-7 have led to increased interest in the role of CDK4/6 inhibition in pre- or perimenopausal women with HR-positive breast cancer.5 At ASCO 2018, Patrick Neven, MD, PhD (University of Leuven, Belgium), presented data from the MONARCH 2 study’s pre- and perimenopausal patient cohort. A total of 114 patients were randomized to receive a GnRH agonist and either abemaciclib-fulvestrant or placebo-fulvestrant.6 Important results included:

  • Addition of abemaciclib to fulvestrant improved response rates and PFS
    • Median PFS, abemaciclib vs placebo: Not reached vs 10.5 months (HR 0.446, P = .002)
    • ORR, abemaciclib vs placebo: 60.8% vs 28.6%, P = .006
  • Addition of abemaciclib to fulvestrant increased the risk of any-grade diarrhea (87.3% vs 23.8%), neutropenia (59.2% vs 7.1%), and leukopenia (43.7% vs 4.8%)

These findings provide further support for the use of CDK4/6 inhibitors in combination with endocrine therapy and a GnRH agonist for pre-/perimenopausal women with HR-positive advanced breast cancer.

Targeted/endocrine therapy combinations have efficacy, but toxicity concerns remain

The mammalian target of rapamycin (mTOR) inhibitor everolimus is approved in the United States in combination with exemestane for patients who progress on first-line anastrozole or letrozole, based on the findings from BOLERO-2.7 At ASCO 2018, Guy Jerusalem, MD, PhD (University of Liège, Belgium), presented findings from BOLERO-6, an open-label, phase II study evaluating everolimus-exemestane, everolimus monotherapy, and capecitabine in patients with HR-positive advanced breast cancer that progressed on a prior nonsteroidal aromatase inhibitor.8 Key findings from the study included:

  • Everolimus had activity as a single agent, but the hazard ratio for PFS suggested benefit for everolimus-exemestane vs everolimus (HR 0.74), and Dr Jerusalem concluded that the combination remains an important treatment option and there is no reason to exclude exemestane in routine clinical practice.
  • There were some imbalances in patient characteristics between the everolimus-exemestane and capecitabine cohorts, and the HR of 1.26 apparently in favor of capecitabine is difficult to interpret.
    • Median PFS, everolimus-exemestane vs everolimus vs capecitabine: 8.4 months vs 6.8 months vs 9.6 months
    • Median OS for everolimus-exemestane, everolimus, and capecitabine was 23.1 months, 29.3 months, and 25.6 months, respectively
  • Serious adverse events were more common in the everolimus-exemestane arm (36%) than in the everolimus (29%) and capecitabine (29%) arms, but the risk of treatment discontinuation due to adverse events was comparable between the three arms

Dysregulated PI3K signaling is a frequent aberration in HR-positive breast cancer, particularly through mutation in the PIK3CA gene. The PI3K-alpha inhibitor taselisib was designed to target mutant forms of PI3K-alpha, and early clinical study demonstrated encouraging response rates from the combination of this agent and fulvestrant.9 At ASCO 2018, José Baselga, MD, PhD (Memorial Sloan Kettering Cancer Center, New York City, New York), presented the primary analysis of SANDPIPER, a placebo-controlled, phase III study investigating the addition of taselisib to fulvestrant in postmenopausal women with HR-positive, PIK3CA-mutant advanced breast cancer.10 Key findings included:

  • Taselisib improved investigator-assessed PFS and ORR in PIK3CA-mutant advanced breast cancer
    • Median PFS, taselisib vs placebo: 7.4 months vs 5.4 months (HR 0.70, P = .0037)
    • ORR, taselisib vs placebo: 28.0% vs 11.9%, P = .0002
  • Taselisib did not significantly improve PFS in an exploratory cohort of patients without PIK3CA-mutant disease
    • Median PFS, taselisib vs placebo: 5.6 months vs 4.0 months (HR 0.69, P = .1062)
  • Taselisib treatment increased the risk of grade ≥3 adverse events (49.5% vs 16.4% with placebo), in particular the risk of grade ≥3 diarrhea (11.5% vs 0.9%) and hyperglycemia (10.8% vs 0.5%)
  • Adverse events leading to discontinuation were more frequent in the taselisib arm (16.8%) than in the placebo arm (2.3%)

Taken together, these findings indicate that the tolerability profile of taselisib-fulvestrant may lead to limited clinical benefit for patients, in spite of the improvement in PFS.

 

Conclusions

The trial data delivered at ASCO 2018 provide further clarity on the role of targeted therapy in combination with endocrine therapy in a variety of treatment contexts. These findings further support the use of CDK4/6 inhibitors in first-line combination therapy for pre-/perimenopausal women. However, the benefit of combining PI3K/Akt/mTOR pathway inhibitors with endocrine therapy is unclear, given the significant risk of toxicity associated with the combinations tested to date; we await the results with truly alpha-specific compounds currently being evaluated in phase III clinical trials.

References:

  1. Abraham J, Coleman R, Elias A, et al. Use of cyclin-dependent kinase (CDK) 4/6 inhibitors for hormone receptor-positive, human epidermal growth factor receptor 2-negative, metastatic breast cancer: A roundtable discussion by The Breast Cancer Therapy Expert Group (BCTEG). Breast Cancer Res Treat. 2018. [Epub ahead of print]
  2. Brufsky AM, Dickler MN. Estrogen receptor-positive breast cancer: Exploiting signaling pathways implicated in endocrine resistance. Oncologist. 2018;23(5):528-539.
  3. Slamon DJ, Neven P, Chia SK, et al. Ribociclib (RIB) + fulvestrant (FUL) in postmenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC): Results from MONALEESA-3. J Clin Oncol. 2018;36(suppl): Abstract 1000.
  4. Turner NC, O’Leary B, Cutts R, et al. Genetic landscape of resistance to CDK4/6 inhibition in circulating tumor DNA (ctDNA) analysis of the PALOMA3 trial of palbociclib and fulvestrant versus placebo and fulvestrant. J Clin Oncol. 2018;36(suppl): Abstract 1001.
  5. Tripathy D, Sohn J, Im SA, et al. First-line ribociclib vs placebo with goserelin and tamoxifen or a non-steroidal aromatase inhibitor in premenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: Results from the randomized phase III MONALEESA-7 trial. Cancer Res. 2018;78(4 Suppl): Abstract GS2-05.
  6. Neven P, Rugo HS, Tolaney SM, et al. Abemaciclib for pre/perimenopausal women with HR+, HER2- advanced breast cancer. J Clin Oncol. 2018;36(suppl): Abstract 1002.
  7. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520-529.
  8. Jerusalem GH, Kovalenko E, Yardley DA, et al. Everolimus (EVE) + exemestane (EXE) vs EVE alone or capecitabine (CAP) for estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC): BOLERO-6, an open-label phase 2 study. J Clin Oncol. 2018;36(suppl): Abstract 1005.
  9. Dickler MN, Saura C, Richards DA, et al. A phase II study of the PI3K inhibitor taselisib (GDC-0032) combined with fulvestrant (F) in patients (pts) with HER2-negative (HER2-), hormone receptor-positive (HR+) advanced breast cancer (BC). J Clin Oncol. 2016;34(suppl): Abstract 520.
  10. Baselga J, Dent SF, Cortés J, et al. Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA-mutant (MUT), locally advanced or metastatic breast cancer (MBC): Primary analysis from SANDPIPER. J Clin Oncol. 2018;36(suppl): Abstract LBA1006.