Momentum for Change Builds in Recurrent Advanced Breast Cancer

OncologyLive, Vol. 20/No. 20, Volume 20, Issue 20

New treatment approaches for patients with relapsed or refractory advanced breast cancer are making their way into clinical practice or are on the horizon.

Debu Tripathy, MD

New treatment approaches for patients with relapsed or refractory advanced breast cancer (ABC) are making their way into clinical practice or are on the horizon, depending on the disease state, setting the stage for exciting advancements, according a panel of experts in breast cancer who participated in a recent OncLive Peer Exchange® program.

In hormone receptor (HR)—positive/HER2negative ABC, the combination of endocrine therapy plus a CDK4/6 inhibitor is increasingly regarded as the new standard, but optimal treatment for relapsed or refractory disease remains unsettled.1 The role of PI3K inhibition for patients in this setting with progressive disease has added another consideration, panel members said.

In May 2019, alpelisib (Piqray) became the first FDA-approved PI3K inhibitor for breast cancer. The FDA approved the drug in combination with fulvestrant (Faslodex) for postmenopausal women and men with HR-positive, HER2-negative ABC or metastatic breast cancer (MBC) harboring a PIK3CA mutation whose disease has progressed on or after an endocrine-based regimen.2

The new option was part of a wide-ranging discussion in which panelists reviewed key data presented at the 2019 American Society of Clinical Oncology Annual Meeting (2019 ASCO).

Additionally, the roundtable talk centered on investigational agents for relapsed or refractory HER2-positive ABC, another unmet need.3

The group reviewed data for margetuximab, an engineered anti-HER2 antibody with immunomodulating and antineoplastic effects4; trastuzumab deruxtecan (DS-8201), an antibodydrug conjugate that may be submitted to the FDA later this year for a biologics license application5; and pyrotinib, an irreversible pan-HER receptor tyrosine kinase inhibitor being evaluated in conjunction with capecitabine.6

Early study results for these novel agents were presented at 2019 ASCO. Debu Tripathy, MD, said the conference showed that in the field of breast cancer, “the momentum has picked up, and the rate of discovery is picking up.”

PI3K Inhibition

At least 70% of newly diagnosed breast cancers are HR positive/HER2 negative.7 Despite the approval in the past few years of several CDK4/6 inhibitors, which panelists agreed should be used with endocrine therapy as first-line therapy for patients in this setting with ABC, progression is inevitable.8

The optimal treatment after progression on a CDK4/6 inhibitor is unclear, but approximately 40% of patients in this cohort have an activating PIK3CA mutation.7 “In terms of what we do after progression on CDK4/6, we have the FDA approval of alpelisib,” said Joyce A. O’Shaughnessy, MD. Alpelisib is an oral PI3K inhibitor highly selective for the p110α isoform, an important regulator of insulin response.7,9

SOLAR-1 Findings

The pivotal data for alpelisib came from SOLAR-1, a phase III randomized trial in which previously treated patients with confirmed HR-positive/HER2-negative ABC received hormonal therapy with fulvestrant plus alpelisib or placebo.7

For the cohort of 341 patients with PIK3CA mutations, Tripathy said, median progression-free survival (PFS) was more than 5 months longer in the alpelisib arm than in the placebo arm (11 vs 5.7 months, respectively), with a hazard ratio for progression or death of 0.65 (95% CI, 0.500.85; P <.001). The benefit was demonstrated across subgroups (Table).7 “SOLAR-1 had a separate cohort that was PI3K wild-type, and they did not benefit,” he said.

Tripathy said SOLAR-1 did not include enough patients previously treated with a CDK inhibitor to fully assess the efficacy of alpelisib in this population. He said interim data from the BYLieve study presented at ASCO 2019 suggested alpelisib has activity in this group.10 The open-label study is evaluating alpelisib with fulvestrant or letrozole and reported an overall response rate (ORR) of 13.7% (n = 51) with fulvestrant and 27.6% (n = 29) with letrozole.10

Toxicity was a concern in initial trials of pan-PI3K inhibitors for ABC, prompting investigators to shift their focus to more selective PI3K inhibitors such as alpelisib.11,12 In SOLAR-1, Tripathy said, “the toxicities were still there but [were] less than [what] we saw with the nonspecific inhibitors.”

The most common grade 3/4 treatment- related adverse event (TRAE) associated with alpelisib was hyperglycemia (37%). As O’Shaughnessy noted, the high rate of hyperglycemia occurred despite exclusion of patients with hemoglobin (Hb) A1c ≥6.5%. She predicted that clinicians would be less restrictive about HbA1c levels than the trial was and warned of the need to proceed with care.7

“We have to make sure that our patients with prediabetes are well controlled before we start,” O’Shaughnessy said. She recommended a low-carbohydrate diet, which she described as no more than 100 g/day of carbohydrates. Evidence suggests that inhibiting p110α blocks insulin signaling; this causes the liver to break down glycogen and release it into circulation, whereas the lack of insulin prevents glucose uptake.9 In an effort to restore glucose homeostasis, the pancreas releases more insulin, which may remain in circulation in patients with baseline insulin resistance and stimulate PI3K signaling in tumors.9

O’Shaughnessy expressed concern that administering insulin to treat hyperglycemia might also counteract PI3K inhibition, comparing it with “stepping on the accelerator at the same time you’re stepping on the brakes.” She said if metformin were to prove ineffective, she would consider a sodium-glucose cotransporter 2 inhibitor.

“The toxicity is going to be a learning curve for clinicians again—learning how to follow fasting plasma glucose, [checking] HbA1c every 3 months, and using drugs like metformin,” said Sara A. Hurvitz, MD.

The package insert recommends monitoring blood glucose or fasting plasma glucose at least once per week for the first 2 weeks and then once every 4 weeks or as needed.13 It also provides recommendations for medical management of hyperglycemia.13

Table. Subgroup Findings for PIK3CA-Mutant Patients in SOLAR-17

Other common grade 3/4 TRAEs more frequent in the alpelisib arm included rash (10%) and diarrhea (7%), both grade 3.7 “We’re going to have to learn how to proactively manage diarrhea and skin rash with antihistamines,” Tripathy said. The FDA also advised clinicians to monitor patients taking alpelisib for pneumonitis or interstitial lung disease, which would require treatment interruption or discontinuation.2,13

Molecular Profiling

Because alpelisib is indicated only for patients with a PIK3CA mutation, clinicians will need to decide when and how to profile patients. “It’s really going to be a paradigm shift,” said Erika P. Hamilton, MD. “We’re going to have to either biopsy these patients or at least do blood testing that helps us determine which pathway to go down after the first-line setting,” she explained. She suggested testing for mutations in PIK3CA and also for ESR1, which she said predicts response to exemestane and everolimus (Afinitor).

The FDA approved the Therascreen PIK3CA RGQ PCR Kit as a companion diagnostic test for alpelisib.2 The assay uses single-gene liquid biopsy, which measures circulating tumor DNA (ctDNA).14 Some liquid biopsy techniques use next-generation sequencing to scan for multiple genomic alterations.

Tripathy said results of earlier trials that investigated pan-PIK3 inhibitors showed a concordance level of almost 80% between PIK3CA status in tumor tissue and ctDNA.11 Hurvitz added that SOLAR-1 results also showed strong concordance between the liquid and tissue biopsies, which was “very encouraging and reassuring that you can pretty much reasonably rely on it.”

O’Shaughnessy noted that although PIK3CA mutations are mostly truncal and present at diagnosis, they can also be acquired. Because of the potential for the mutation profile to evolve during first-line treatment, the panelists agreed it would be best to perform the liquid biopsy at progression.

Capivasertib: FAKTION Trial

Capivasertib is an oral PIK3 inhibitor that targets AKT.15 Hamilton said that at ASCO 2019, investigators for the phase II FAKTION trial reported that median PFS was 6 months longer in the capivasertib plus fulvestrant arm versus the fulvestrant-only arm (10.3 vs 4.8 months, respectively), for a hazard ratio of 0.58 (95% CI, 0.39-0.84; 2-sided P = .004).15

Hamilton said the P value for overall survival with capivasertib therapy was not statistically significant. She nothed that she found it interesting that “about 40% of participants had a PI3K, PTEN, or AKT activation, but there was no difference seen between those who had activations in that pathway and those who did not.” O’Shaughnessy said capivasertib was also associated with a lower rate of hyperglycemia than alpelisib. Other adverse events included gastrointestinal issues, fatigue, and rash.

Emerging Agents for HER2-Positive ABC

Anti-HER2 therapy is generally recommended for patients with HER2-positive ABC that has progressed after prior therapy.1,3 Several novel agents with different mechanisms for targeting HER2 expression are under study, along with neratinib (Nerlynx), which binds to HER2 and HER4 and is already approved as adjuvant treatment for early-stage, HER2-positive breast cancer following trastuzumab (Herceptin).16


Margetuximab is an immunoglobulin G (IgG) monoclonal antibody that targets HER2 but is engineered to have greater affinity for the Fc receptor III than trastuzumab.3,4 Natural killer cells mediate antibody-dependent, cell-mediated cytotoxicity via the IgG Fc receptor CD16A.4

The phase III SOPHIA trial compared chemotherapy plus margetuximab or trastuzumab in patients with heavily pretreated HER2-positive MBC.3 Margetuximab was associated with greater activity than trastuzumab in patients with CD16A genotypes who had a 158F allele.3 Tripathy pointed out, however, that median PFS was only 1 month longer in the margetuximab arm. He said, “That biology is elegant and it does seem to work, but I think the big question is: How big is that clinical benefit?” The toxicity profile was similar between the 2 monoclonal antibodies.3

Trastuzumab Deruxtecan

Trastuzumab deruxtecan is an antibody—drug conjugate that also targets HER2. “It’s not totally like trastuzumab, but it is the same idea. It’s [a monoclonal antibody] linked to DXd, which is along the lines of a topoisomerase I inhibitor,” Hurvitz said. Investigators evaluated the compound in a phase I trial in patients with HER2-positive ABC that progressed during or after trastuzumab emtansine (T-DM1; Kadcyla).17

Hurvitz expressed amazement at the level of activity, which she said she had never seen before in such a heavily treated population. “The median prior number of therapies in the phase I study was around 6 or 7, and their objective response rate was north of 50%,” she said.

In the cohort with HER2-positive MBC (n = 111), the median duration of response was 20.7 months, and median PFS was 22.1 months; median overall survival had not been reached.17 Common TRAEs included nausea, anorexia, vomiting, alopecia, fatigue, anemia, diarrhea, and constipation. In a press release, AstraZeneca said the phase II DESTINYBreast01 trial confirmed those findings, supporting the company’s decision to seek FDA approval later this year.5

Hurvitz, who was involved in the phase II study, said investigators have some concerns about the risk of interstitial lung disease (ILD). “They’ve had a handful of fatal cases…in Japan,” she said.

Hamilton said some fatalities might have occurred because no one knew to watch for ILD, resulting in delayed treatment. “We haven’t seen as many pneumonitis cases in recent patients,” she said.


Chinese investigators for a phase III study of the pan-HER2 tyrosine kinase inhibitor pyrotinib in patients with previously treated HER2-positive MBC presented results at 2019 ASCO.6 Participants were randomly assigned to capecitabine with either oral pyrotinib or placebo.6

Hamilton described the results as “pretty impressive.” Median PFS was 11.1 months in the pyrotinib/capecitabine arm versus 4.1 months in the placebo/capecitabine arm, translating into a hazard ratio of 0.18 (95% CI, 0.13-0.26; P <.001).6 In patients who received pyrotinib monotherapy after placebo/capecitabine, median PFS was 5.5 months (95% CI, 4.1-6.9). The most common ≥grade 3 TRAEs associated with pyrotinib therapy were diarrhea (31%) and hand-foot syndrome (16%).

A subsequently published phase II study compared capecitabine plus either pyrotinib or lapatinib (Tykerb) in Chinese women with HER2-positive MBC.18 The patients in the pyrotinib group (n = 65) had an ORR of 79% and a median PFS of 18 months compared with 57% and 7 months, respectively, in the lapatinib group (n = 63).18


In the phase III NALA trial, women with previously treated HER2-positive MBC were randomly assigned to capecitabine with either neratinib or lapatinib.19 “The bottom line is that overall, the trial was positive,” said Aditya Bardia, MD, MPH. “There was an improvement in PFS in the neratinib arm compared with the lapatinib arm,” he said. The neratinib/capecitabine combination was associated with a 24% reduction in disease progression or death compared with lapatinib/capecitabine, with a hazard ratio of 0.76 (95% CI, 0.63-0.93; P = .006).19 Bardia said that in the metastatic setting, “even a few months of improvement in PFS could be important for an individual patient.”

“In terms of the [adverse] effects, diarrhea was seen with a higher degree in the neratinib arm as compared with the lapatinib arm,” Bardia said. The discussants noted that diarrhea has also been a concern with adjuvant neratinib. Tripathy and Hurvitz are investigators for the phase II CONTROL trial, which is exploring prophylaxis regimens for neratinib-associated diarrhea in patients with breast cancer who are receiving adjuvant therapy.20

Tripathy said that although colestipol appears to be the most effective drug for reducing the severity and duration of neratinib-induced diarrhea, “what really helps us is slowly escalating the dose of neratinib until you get to the full dose and are just using loperamide as needed.” He said prophylaxis is needed primarily only for the first 2 months of neratinib therapy.

In September 2019, the FDA accepted a supplemental new drug application for neratinib in combination with capecitabine as a third-line regimen for HER2-positive MBC.21 “I think the data are compelling, and it is possible that neratinib will get approved in the metastatic setting,” Bardia said. He added that with the many new agents emerging for HER2-positive therapy, clinicians may be unsure of which ones to use when but that he guessed “that’s a good problem to have.


  1. Cardoso F, Senkus E, Costa A, et al. 4th ESO—ESMO international consensus guidelines for advanced breast cancer (ABC 4). Ann Oncol. 2018;29(8):1634-1657. doi: 10.1093/annonc/mdy192.
  2. FDA approves first PI3K inhibitor for breast cancer [news release]. Silver Spring, MD: FDA; May 24, 2019. Accessed October 2, 2019.
  3. Rugo HS, Im SA, Wright GLS, et al. SOPHIA primary analysis: a phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx). J Clin Oncol. 2019;37(suppl 15; abstr 1000). doi: 10.1200/JCO.2019.37.15_suppl.1000.
  4. NCI drug dictionary: margetuximab. National Cancer Institute website. Accessed October 3, 2019.
  5. Trastuzumab deruxtecan demonstrated clinically-meaningful response in patients with refractory HER2-positive metastatic breast cancer, a population with high unmet need [news release]. Basking Ridge, NJ: AstraZeneca and Daiichi Sankyo Company Ltd; May 8, 2019. Accessed October 2, 2019.
  6. Jiang Z, Yan M, Hu X, et al. Pyrotinib combined with capecitabine in women with HER2+ metastatic breast cancer previously treated with trastuzumab and taxanes: a randomized phase III study. J Clin Oncol. 2019;37(suppl 15; abstr 1001). doi: 10.1200/JCO.2019.37.15_suppl.1001.
  7. André F, Ciruelos E, Rubovszky G, et al; the SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor—positive advanced breast cancer. N Engl J Med. 2019;380(20):1929-1940. doi: 10.1056/NEJMoa1813904.
  8. Shah M, Nunes MR, Stearns V. CDK4/6 inhibitors: game changers in the management of hormone receptor—positive advanced breast cancer? Oncology (Williston Park). 2018;32(5):216-222.
  9. Hopkins BD, Pauli C, Du X, et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors [erratum in Nature. 2018;563(7731):E24. doi: 10.1038/s41586-018-0506-3]. Nature. 2018;560(7719):499-503. doi: 10.1038/s41586-018-0343-4.
  10. Rugo HS, Borrego MR, Chia SKL, et al. Alpelisib (ALP) + endocrine therapy (ET) in patients (pts) with PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor-2-negative (HER2-) advanced breast cancer (ABC): first interim BYLieve study results. J Clin Oncol. 2019;37(suppl 15; abstr 1040). doi: 10.1200/JCO.2019.37.15_suppl.1040.
  11. Baselga J, Im SA, Iwata H, et al. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial [erratum in Lancet Oncol. 2019;20(2):e71-e72. doi: 10.1016/S1470-2045(19)30015-4]. Lancet Oncol. 2017;18(17):904-916. doi: 10.1016/S1470-2045(17)30376-5.
  12. Di Leo A, Johnston S, Lee KS, et al. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial [erratum in Lancet Oncol. 2018;19(3):e137. doi: 10.1016/S1470-2045(18)30138-4]. Lancet Oncol. 2018;19(1):87-100. doi: 10.1016/S1470-2045(17)30688-5.
  13. Piqray [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2019. Accessed October 3, 2019.
  14. Ou SI, Nagasaka M, Zhu VW. Liquid biopsy to identify actionable genomic alterations. Am Soc Clin Oncol Educ Book. 2018;38:978-997. doi: 10.1200/EDBK_199765.
  15. Jones RH, Carucci M, Casbard AC, et al. Capivasertib (AZD5363) plus fulvestrant versus placebo plus fulvestrant after relapse or progression on an aromatase inhibitor in metastatic ER-positive breast cancer (FAKTION): a randomized, double-blind, placebo-controlled, phase II trial. J Clin Oncol. 2019;37(suppl 15; abstr 1005). doi: 10.1200/JCO.2019.37.15_suppl.1005.
  16. Nerlynx [package insert]. Los Angeles, CA: Puma Biotechnology Inc; 2019. Accessed October 3, 2019.
  17. Tamura K, Tsurutani J, Takahashi S, et al. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study [erratum in Lancet Oncol. 2019;20(6):e293. doi: 10.1016/S1470-2045(19)30292-X]. Lancet Oncol. 2019;20(6):816-826. doi: 10.1016/S1470-2045(19)30097-X.
  18. Ma F, Ouyang Q, Li W, et al. Pyrotinib or lapatinib combined with capecitabine in HER2—positive metastatic breast cancer with prior taxanes, anthracyclines, and/or trastuzumab: a randomized, phase II study. J Clin Oncol. 2019;37(29):2610-2619. doi: 10.1200/JCO.19.00108.
  19. Saura C, Oliveira M, Feng YH, et al. Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: findings from the multinational, randomized, phase III NALA trial. J Clin Oncol. 2019;37(suppl 15; abstr 1002). doi: 10.1200/JCO.2019.37.15_suppl.1002.
  20. Barcenas CH, Hurvitz SA, Di Palma JA, et al. Effect of prophylaxis on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer: phase II CONTROL trial. J Clin Oncol. 2019;37(suppl 15; abstr 548). doi: 10.1200/JCO.2019.37.15_suppl.548.
  21. Puma Biotechnology announces U.S. FDA acceptance of supplemental new drug application for neratinib to treat HER2-positive metastatic breast cancer [news release]. Los Angeles, CA: Puma Biotechnoilogy Inc; September 11, 2019. Accessed October 6, 2019.