Cynthia X. Ma, MD, PhD

Question

What are your key takeaways from the TAILORx trial results presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting?

Answer

The primary takeaway from the TAILORx trial is that postmenopausal women (ie, older than 50 years of age) with hormone receptor (HR)-positive, HER2-negative, axillary lymph node¬-negative breast cancer with an Oncotype recurrence score (RS) in the intermediate range (between 11-25) may safely forgo chemotherapy after surgery.1 For patients who are premenopausal or age 50 or younger, there was a small benefit from chemotherapy in preventing breast cancer recurrence when the RS was between 16 and 25. Therefore, for this younger patient population, a lower Oncotype RS (< 16) cutpoint should be considered when deciding whether to recommend chemotherapy. Overall, results of TAILORx provide level 1 evidence for the use of Oncotype RS in women with HR-positive, HER2-negative, lymph node-negative disease to determine the need for chemotherapy after surgery. It is important to point out that all patients in the trial received adjuvant hormonal therapy, which is the most important treatment in this patient population.

Question

Which data from the MONARCH trials (MONARCH 1 and MONARCH 2) do you find to be most relevant and/or compelling for clinicians who treat patients with breast cancer?

Answer

MONARCH 1 is a phase 2 study that investigated the CDK4 and CDK6 inhibitor abemaciclib as monotherapy for women with metastatic HR-positive, HER2-negative breast cancer refractory to hormonal therapy; eligible patients had to have received 1 or 2 chemotherapy regimens in the metastatic setting.² The study demonstrated a confirmed objective response rate of approximately 20%, clinical benefit rate (no progression for at least 6 months) of 42%, and a median progression-free survival (PFS) of 6 months in patients with a median of three prior lines of therapy in the metastatic setting. This trial lead to the U.S. Food and Drug Administration (FDA) approval of abemaciclib as a single agent for patients with metastatic breast cancer (MBC).

MONARCH 2 is a randomized, double blind, placebo controlled phase 3 trial that compared fulvestrant in combination with either abemaciclib or placebo in women with HR-positive, HER2-negative breast cancer whose disease progressed while they were receiving neo(adjuvant) endocrine therapy, either within 12 months from the end of adjuvant endocrine therapy or while receiving first-line endocrine therapy for metastatic disease.³ Results demonstrated a significant improvement in PFS with the addition of abemaciclib (16.4 vs 9.3 months) and in overall response rate (ORR; 48% vs 21%). This study led to the FDA approval of abemaciclib in combination with fulvestrant for this patient population.

Both trials are important, but MONARCH 1 is unique in that it provided the basis for monotherapy with abemaciclib, the only CDK4/6 inhibitor approved as a single agent in the later line setting. The combination of palbociclib plus fulvestrant was already available for clinical use prior to publication of the MONARCH 2 results.

Question

What is your perspective on the SANDPIPER results presented at the 2018 ASCO Annual Meeting?

Answer

SANDPIPER is a randomized, double blind, placebo controlled phase 3 trial that compared fulvestrant in combination with either the PI3K inhibitor taselisib or placebo in women with HR- positive, HER2-negative breast cancer who progressed during or after aromatase inhibitor therapy, with the primary objective to assess PFS in patients with PIK3CA-mutant tumors.4 The study demonstrated an improvement in median PFS from 5.4 to 7.4 months with the addition of taselisib (P = .0037), and in ORR from 11.9% to 27.3% in those with PIK3CA-mutant tumors. However, approximately 50% of patients in the taselisib arm experienced grade 3 and higher adverse events (AEs). Discontinuation (16.8%), dose interruption (40.6%), and dose reductions (36.5%) were frequent with taselisib. Common AEs were diarrhea, hyperglycemia, rash, and stomatitis; colitis and pneumonitis were also observed.

Although the study met its primary endpoint, the significant toxicity profile and modest improvement in PFS present challenges for its clinical application. SANDPIPER data reminded us of the BELLE2 data with the PI3K inhibitor buparlisib.⁵ Although PFS was significantly improved in that trial, the safety profile led to the discontinuation of further clinical development of buparlisib in breast cancer. Other PI3K inhibitors are being evaluated in clinical trials. The SOLAR-1 trial (phase 3 study of alpelisib, an alpha isoform selective PI3K inhibitor in combination with fulvestrant) is in progress.⁶

Question

Were there any other breast cancer studies reported at the 2018 ASCO Annual Meeting that you found to be of particular interest/importance? Are there any ongoing studies that you think will yield important results for practitioners?

Answer

Two interesting phase 2 studies, the PAKT trial⁷ and LOTUS trial,⁸ were presented. Both trials randomly assigned patients with metastatic triple-negative breast cancer (mTNBC) to receive paclitaxel/placebo or paclitaxel with an AKT inhibitor in the first-line setting. Both demonstrated a significant improvement in PFS and manageable toxicities, with activity more pronounced in patients with PI3K/AKT/PTEN mutations. These studies highlight AKT as a potential therapeutic target in TNBC, especially for those patients with PI3K/AKT/PTEN mutations, with results warranting phase 3 investigations.

Results from a phase 1/2 study of sacituzumab govitecan in patients with HR-positive, HER2- negative MBC were reported, which demonstrated a response rate of 31% in a patient population that had received at least 2 prior therapies, with a median of 3 prior hormonal agents and 2 prior chemotherapy regimens.⁹ The data were encouraging and support further evaluation of the antibody-drug conjugate in this patient population. Sacituzumab govitecan is already undergoing phase 3 evaluation in patients with mTNBC on the basis of promising activity demonstrated in phase 2 trials.

Finally, a presentation on circulating tumor DNA data derived from the PALOMA-3 trial demonstrated that treatment with palbociclib and fulvestrant was associated with acquired mutations in RB1, ESR1, and PIK3CA at disease progression, which may suggest strategies for managing resistance.¹⁰