ONCAlert | Upfront Therapy for mRCC

Broader Applications for Targeted Agents in Breast Cancer Expand Patient Use

Krithika Subramanian, PhD
Published Online: Oct 07,2019
Joshua J. Gruber, MD
Joshua J. Gruber, MD
A greater understanding of the mechanisms underlying endocrine resistance, along with the development of targeted agents directed at key regulatory oncogenic pathways, continue to lead to new options in the treatment of hormone receptor (HR)–positive, HER2-negative breast cancer. These therapies offer the promise of better disease control rates and improved quality of life for patients with advanced disease.1

HR-positive, HER2-negative breast cancer is the most common subtype, accounting for more than 70% of breast cancer cases.2 Endocrine  therapy  is the mainstay of first-line treatment of this disease in patients without visceral crises, yielding improved outcomes in early and metastatic disease.3 However, de novo or acquired resistance to endocrine therapy remains a significant clinical challenge, leading to therapeutic failure and limiting survival, especially in patients with metastatic disease.3

Targeted agents approved or in clinical development for treatment of HR-positive, HER2-negative disease include CDK4/6 inhibitors, selective PI3K inhibitors, and PARP inhibitors. These advances have had practice-changing implications; for instance, CDK4/6 inhibitors have yielded significant improvements in progression-free survival (PFS) and  are  now the treatment of choice in patients with HR- positive, HER2-negative, treatment-naïve or endocrine therapy–pretreated metastatic breast cancer without visceral crisis.1 In addition, exciting overall survival (OS) data from pivotal trials for CDK4/6 inhibitors are helping to inform the magnitude of benefit in patients with advanced ormetastatic disease.4-6

“The value of having these different inhibitors on the market is  in  the ability to tailor [treatment] to a specific patient who may have certain comorbidities and be able to give them the appropriate therapy,” said Joshua J. Gruber, MD, an instructor of medicine in the division of medical oncology at Stanford University Medical Center in California.

Moreover, alpelisib (Piqray), the first FDA-approved PI3K  inhibitor  for  the  treatment  of postmenopausal women, as well as men, with PIK3CA-mutated tumors, also gained the first new drug application for a new molecular entity approved under the FDA’s Real-Time Oncology Review pilot program.7

In Recent Updates, CDK4/6 inhibitors Show Survival Advantages

Three CDK4/6 inhibitors are approved for breast cancer. The first, palbociclib (Ibrance), received accelerated approval in  2015 for the first-line treatment  of estrogen receptor (ER)–positive, HER2-negative advanced breast cancer for postmenopausal women, in combination with letrozole, based on the phase II PALOMA-1 study.8 Later, both ribociclib (Kisqali) and abemaciclib (Verzenio) gained  similar  indications  in this patient population based on study results in MONALEESA-29,10 and MONARCH 3,11,12 respectively. Additionally, abemaciclib is approved as monotherapy for adults who progressed following endocrine therapy and prior chemotherapy in the metastatic setting.

Results of a protocol-specified interim analysis of OS from ribociclib treatment in the MONALEESA-7 trial were recently published and showed an OS  rate  at  42 months of 70.2% (95% CI, 63.5%-76.0%) in the ribociclib  group  compared  with 46.0%  (95%  CI, 32.0%-
58.9%) in  the placebo group (hazard ratio,  0.71; 95% CI, 0.54-0.95; P = .00973 by log-rank test).4,5

“Improvement in overall survival is  the best endpoint one could hope for,” said Aditya Bardia, MD, MPH, one of the report’s authors, as well as an assistant professor of medicine at Harvard Medical School and an attending physician at Massachusetts General Hospital, both in Boston. “[This] highlights the impact of CDK4/6 inhibitors in changing the natural history of metastatic HR-positive breast cancer.” Results of the MONALEESA-3 trial presented at the European Society for Medical Oncology (ESMO) 2019 Congress showed that first and second-line treatment with the CDK4/6 inhibitor ribociclib plus fulvestrant significantly improved overall survival in postmenopausal patients with HR-positive, HER2-advanced breast cancer. These benefits were seen in women not previously treated with hormonal therapy as well as  in  those who had become resistant to endocrine therapy.13

“[CDK4/6 inhibitors] seem to improve survival by about  a  year  in  patients  with  ER-positive disease,” Gruber  said.  “It  has  been  one  of the  most  important  advancements in metastatic breast cancer within the past 5 or 10 years. It has had a dramatic impact.”

Previously reported data from MONALEESA-3 showed that ribociclib induced a median PFS of  20.5 months (95%  CI, 18.5-23.5) versus placebo at 12.8 months  (95% CI, 10.9-16.3), resulting in a statistically significant improvement in the primary endpoint (hazard ratio, 0.593;95% CL, 0.480-0.732, P <.001).14

In a recent reversal of an earlier decision to reject ribociclib, the National Institute of Health and Care Excellence in the United Kingdom recommended ribociclib in combination with fulvestrant for use on the  British  National  Health  Service—where exemestane plus everolimus is the most appropriate alternative—based on the second-line subpopulation of the MONALEESA-3 trial. In this subgroup of patients who had received up to 1 line of prior endocrine therapy for advanced disease, the ribociclib combination demonstrated a  median PFS of  14.6 months compared with 9.1 months for the placebo arm.14,15

Another CDK4/6 inhibitor, abemaciclib is highly selective, reversible, and currently the most potent  of the approved agents, with reported concentration of inhibitor required for achieving  50%  inhibition, or IC50, of 2 nM and 10 nM for CDK4 and CDK6, respectively. The brain-blood-barrier crossing potential of abemaciclib has also generated interest in clinical evaluation in patients with ER-positive breast cancer and brain metastases.16

Assessment of abemaciclib levels from clinical samples obtained in the JPBO study—a phase II, Simon 2-stage design trial evaluating 6 patient cohorts with brain  metastases secondary to HR-positive metastatic breast  cancer,  non–small  cell  lung  cancer,  or melanoma—showed comparable abemaciclib levels in brain metastases tissues, cerebrospinal fluid, and time-matched plasma samples from patients with brain metastases secondary to HR-positive metastatic breast cancer.17

In data presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, analyses of outcomes in part 2 of the study showed that abemaciclib monotherapy yielded a confirmed objective intracranial response rate (OIRR) of 6% in 52  evaluable  patients.  The intracranial clinical benefit rate, which included all responses of stable disease lasting 6 months or better, was  25%  and  the  median PFS was 4.4 months (95% CI, 2.6-5.5). Although the study did not meet the primary endpoint of 11% OIRR, the intracranial benefit in this heavily pretreated population of patients with poor prognoses prompted the authors to conclude that further studies of abemaciclib monotherapy and combinations for controlling brain metastases in cancers, including in advanced breast cancer, are warranted.18

Also at 2019 ESMO Congress, MONARCH-2 showed statistically and clinically  meaningful improvement in overall survival with the CDK4/6 inhibitor abemaciclib plus fulvestrant in pre-, and peri-as well as in postmenopausal women patients with HR-positive, HER2- advanced breast cancer resistant to hormonal therapy.19 The abemaciclib-plus-fulvestrant combination was  approved  based  on  PFS  data from MONARCH 2, in which the combination significantly extended PFS compared with fulvestrant alone (median, 16.4 vs 9.3 months; hazard ratio, 0.553;95% Cl, 0.449-0.681; P <.001).20

“It would be important to see the published data,” Bardia said, when asked how this relates to the OS findings observed with ribociclib therapy. “[Although] the CDK4/6 inhibitors are broadly similar, there are subtle differences in potency; ability to impact CDK 4, CDK 6, and  other CDKs; and safety profile. The latter in particular tends to [affect] clinical decision making in the setting of similar efficacy (TABLE).9,11

Findings were presented in a Presidential Symposium at the ESMO 2019 Congress.6

PI3K Inhibitors for PIK3CA-Mutated Disease

Activating mutations or amplifications of the PIK3CA gene that encodes p110α dysregulate PI3Kα expression and are common in many cancers, including breast cancer.21 Clinical development of PI3K inhibitors is  predicated  on the importance of PI3K/AKT signaling in tumor growth and proliferation promotion, high frequency of PIK3CA mutations in HR-positive breast cancer, and their association with the luminal B breast cancer subtype, as well as unfavorable OS outcomes in node-positive disease.22-24

Agents Under Investigation

The pan-PI3K inhibitor buparlisib and the PI3K-selective inhibitors taselisib and alpelisib have been tested in clinical  trials,  and  the  FDA recently granted an approval to alpelisib combined with fulvestrant for the treatment of postmenopausal women, as well as men, with PIK3CA-mutated tumors.7 This marks the entry of the first PI3K inhibitor into the breast cancer therapeutic landscape.

The potent and selective PI3K  inhibitor taselisib (GDC-0032) has demonstrated  greater sensitivity for mutant PI3Kα isoforms than wild-type PI3Kα, and preclinical studies have demonstrated the agent’s potent proliferation inhibition activity on p110α-mutant breast cancer cell lines (IC50, 70 nM), as well as tumor growth inhibition in human breast cancer xenograft models harboring PIK3CA mutations.25

In June 2018, the company responsible for developing the drug decided not to pursue an FDA submission based on data from the phase III SANDPIPER trial, which showed that taselisib and fulvestrant improved PFS by a modest 2 months in patients with HR-positive, HER2-negative breast cancer but resulted in more toxicity. 26,27

“[These] findings are proof that targeting this pathway in breast cancer is effective; however, the benefits to patients are more modest than we had hoped for,” said José Baselga, MD, PhD, the study’s lead author, who presented the SANDPIP- ER data at the 2018 ASCO Annual Meeting.27 Still optimistic about the potential role of this class of agents, Bardia said that results of trials testing taselisib in this patient population “[highlight] the therapeutic role of PI3K inhibition for PIK3CA-mutant tumors, but also the need to carefully weigh toxicity considerations.”

An orally bioavailable PI3Kα-selective inhibitor, alpelisib has demonstrated higher efficacy (IC50,  about  4  nM)  and  wider  safety  profile than the pan-class I PI3K inhibitor buparlisib in patients with PIK3CA mutations.28

The alpelisib approval was based on data from the phase III SOLAR-1 trial, which evaluated fulvestrant with either alpelisib or placebo in patients with HR-positive, HER2-negative breast cancer who received prior treatment with endocrine therapy.7 In the cohort of patients with PIK3CA-mutated cancer (n = 341), PFS was 11.0 months (95% CI, 7.5-14.5) in the alpelisib group compared with 5.7 months (95% CI, 3.7-7.4) in the placebo group (hazard ratio, 0.65; 95% CI, 0.50-0.85; P <.001).29

The overall response rate among all the patients in the cohort with PIK3CA-mutated breast cancer was greater with alpelisib at 26.6% versus placebo at 12.8%.

Concomitant  with  the  approval  of  alpelisib, the FDA approved the companion  diagnostic test therascreen PIK3CA RGQ PCR Kit (Qiagen) to select patients who have PIK3CA mutations.7 In their review of recent advancements  in the treatment of metastatic breast cancer, the authors led by Marie-France Savard, MD, said, “The results of SOLAR-1 represented a notable milestone in precision medicine and for the use of PI3K inhibitors in metastatic breast cancer.”30

PARP Inhibitors

The synthetic lethality invoked by PARP inhibition in the background of BRCA1/2 mutations, present in 5% to 10% of patients who have received a diagnosis of breast cancer,31 forms the basis for clinical use of PARP inhibitors in treatment of breast and other cancers characterized by mutations/defects in the DNA-repair  pathway. In 2018, 2 PARP inhibitors, olaparib (Lynparza) and talazoparib (Talzenna), were approved for deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer.32,33

The FDA’s first approval of a treatment for patients with gBRCAm HER2-negative metastatic breast cancer was based on data from the OlympiAD trial, which demonstrated that PARP inhibitor monotherapy provided a significant benefit over standard therapy among patients with HER2-negative gBRCAm metastatic breast cancer.31

Subsequent analyses indicated no statistically significant improvement in OS with olaparib; however, potential for meaningful OS benefit among patients who had not received chemotherapy for metastatic disease was noted, with no evidence of cumulative toxicity during extended exposure.34

At this year’s ASCO meeting, data from the phase II GeparOLA trial of olaparib plus paclitaxel followed by epirubicin/cyclophosphamide as neoadjuvant treatment of HER2-negative early breast cancer with homologous recombination deficiency (HRD) indicated that olaparib may have expanded clinical utility in certain patient subgroups (FIGURE).35 Stratified sub-group analysis showed higher pathologic complete response rates with the olaparib regimen in the cohorts of patients <40 years and in HR-positive patients.35

“In the subgroup analysis, which are hypothesis generating, we could see a pronounced effect in favor of olaparib in HR-positive tumors, in patients who were younger than 40 years, and in patients who had an HRD score [that] was high with a mutation in the BRCA1 or BRCA2 gene,” said Peter A Fasching, MD, lead author. “The results are good enough to pursue this treatment option further in the neoadjuvant setting.”

Talazoparib has been shown to exhibit a high degree of potency and oral bioavailability, com- pared with other clinical  PARP  inhibitors.31  Its FDA approval was based on data from the pivotal EMBRACA study, in which 431 patients with gBRCAm HER2-negative locally advanced or metastatic breast cancer were randomized 2:1 to receive talazoparib or physician’s choice of chemotherapy. The median PFS was significantly longer in the talazoparib group than in the standard-therapy group, at 8.6 months and 5.6 months, respectively (hazard ratio, 0.54; 95% CI, 0.41-0.71; P <.001).33

Although the PARP inhibitor regulatory approval is currently restricted to patients with BRCA mutations, studies have indicated that other mutations may also render tumors sensitive to PARP inhibitors, pointing to their potential beyond the context of BRCA mutations.36

Data from a proof-of-concept phase II study, which evaluated talazoparib monotherapy in patients with advanced HER2-negative breast cancer or other solid tumors with a germline or somatic alteration in homologous recombination pathway genes not including BRCA1/2, were recently reported at the 2019 ASCO Annual Meeting. In this study, patients with measurable disease and at least 1 prior therapy for advanced HER2-negative tumors with a mutation in 1 of the DNA-repair genes were treated with talazoparib until disease progression.37

“We know based on  basic  science, as well as clinical trials in other  disease  settings, that there are a number of mutations outside canonical BRCA1/2 that could potentially lead to HRD and therefore, through similar mechanisms, sensitize [the tumor] to PARP inhibitor therapy,” Gruber said. “This trial was designed to survey for those  mutations,  identify  them in metastatic biopsies, and select patients for treatment based on this biomarker. The relevance is that you have a certain set of patients with mutations aside from BRCA1/2 who could be good candidates for PARP inhibitor therapy.” Of 13 patients with breast cancer, which included 1 patient with triple-negative disease, 4 had a partial response (PR) to therapy and 3 had stable disease (SD) ≥6 months, for a clinical benefit rate of 54%. Of those, 4 patients (3 PRs and 1 SD ≥6 months) had mutations in gPALB2, suggesting that this and other HRD alterations may be useful biomarkers for predicting talazoparib response.37

“There does seem to be a signal for gPALB2 mutations, [and] there is possibly also a signal for CHEK2 mutations,” Gruber said. “All of these signals need to be identified and studied more carefully in further trials.”

The antitumor effects of PARP inhibition on cancers with defects in other DNA-repair pathway genes, and even in those without deficits in DNA repair, suggest a possible broader role for PARP inhibitors.36 The problem of identifying and incorporating predictive biomarkers that may distinguish patients likely to respond to PARP inhibitors and other targeted monotherapies or combinations is currently being unraveled.

Utility of Genomic Biomarkers in ER-Positive Tumors

Given the significant challenge of primary or secondary resistance to endocrine therapy, biomarkers predictive of early progression on endocrine therapy and of response to new and emerging targeted therapies are of great interest.

A recent report described analysis of somatic mutations, assessed with a 17-gene panel, in baseline plasma samples from the phase III PALOMA-3 trial, which compared fulvestrant plus either palbociclib or placebo. Analysis of associations between mutations and copy number aberrations to clinical characteristics and PFS indicated TP53 mutation, FGFR1 amplification, and tumor purity in plasma as markers for early progression.38

Ben O’Leary,  MBBS, who presented the data  at ASCO’s 2019 meeting, said, “These results in the future could perhaps inform clinical trials in advanced ER-positive breast cancer to identify a high-risk group of patients that may require escalation of therapy.”
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  18. Anders CK, Le Rhun E, Bachelot TD, et al. A phase II study of abemaciclib in patients (pts) with brain metastases (BM) secondary to HR+, HER2- metastatic breast cancer (Mbreast cancer). J Clin Oncol. 2019;37(suppl 15; abstr 1017). doi: 10.1200/JCO.2019.37.15_suppl.1017.
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  29. André F, Ciruelos E, Rubovszky G, et al; 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.
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  32. FDA approves olaparib for germline BRCA-mutated metastatic breast cancer. FDA website. bit.ly/2kFaAAU. Published January 21, 2018. Accessed September 11, 2019.
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  34. Robson ME, Tung N, Conte P, et al. OlympiAD final overall survival and tolerability results: olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol. 2019;30(4):558-566. doi: 10.1093/annonc/mdz012.
  35. Fasching PA, Jackisch C, Rhiem K, et al. GeparOLA: a randomized phase II trial to assess the efficacy of paclitaxel and olaparib in comparison to paclitaxel/carboplatin followed by epirubicin/cyclophosphamide as neoadjuvant chemotherapy in patients (pts) with HER2-negative early breast cancer (breast cancer) and homologous recombination deficiency (HRD). J Clin Oncol. 37(suppl 15; abstr 506). doi: 10.1200/JCO.2019.37.15_suppl.506.
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  38. O’Leary B, Cutts R, Huang X, et al. Genomic markers of early progression on fulvestrant with or without palbociclib for ER+ advanced breast cancer in the PALOMA-3 trial. J Clin Oncol. 37(suppl 15; abstr 1010). doi: 10.1200/JCO.2019.37.15_suppl.1010.

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Broader Applications for Targeted Agents in Breast Cancer Expand Patient Use
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