Afatinib, an irreversible inhibitor of the ErbB family of tyrosine kinases, is under development with Boehringer Ingelheim for the once-daily, oral treatment of cancer. Afatinib downregulates ErbB signalling by covalently binding to epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER) 2 and HER4, irreversibly inhibiting tyrosine kinase autophosphorylation. It also inhibits transphosphorylation of HER3. Oral afatinib (Gilotrif™) has been approved in the US for the first-line treatment of patients with metastatic non-small-cell lung cancer (NSCLC) who have tumours with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test. Afatinib has also been approved in Taiwan for the first-line treatment of patients with EGFR mutation-positive NSCLC. In addition, the European Medicines Agency's Committee for Medicinal Products for Human Use has recommended the approval of afatinib (Giotrif®) for the treatment of patients with locally advanced or metastatic NSCLC with activating EGFR mutations who are EGFR tyrosine kinase inhibitor naive. Afatinib is also under regulatory review in Canada, Japan and other Asian countries. This article summarizes the milestones in the development of afatinib, leading to this first approval in patients with metastatic NSCLC.

Afatinib: First Global Approval

Background Locally advanced and metastatic breast cancer remains a challenge to treat. With emerging study results, it is important to interpret the available clinical data and apply the evidence offering the most effective treatment to the right patient. Poly(ADP Ribose) Polymerase (PARP) inhibitors are a new class of drug and their role in the treatment of locally advanced and metastatic breast cancer is being established. Objectives To determine the efficacy, safety profile, and potential harms of Poly(ADP-Ribose) Polymerase (PARP) inhibitors in the treatment of patients with locally advanced or metastatic breast cancer. The primary outcome of interest was overall survival; secondary outcomes included progression-free survival, tumour response rate, quality of life, and adverse events. Search methods On 8 June 2020, we searched the Cochrane Breast Cancer Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via OvidSP, Embase via OvidSP, World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) search portal and ClinicalTrials.gov. We also searched proceedings from the major oncology conferences as well as scanned reference lists from eligible publications and contacted corresponding authors of trials for further information, where needed. Selection criteria We included randomised controlled trials on participants with locally advanced or metastatic breast cancer comparing 1) chemotherapy in combination with PARP inhibitors, compared to the same chemotherapy without PARP inhibitors or 2) treatment with PARP inhibitors, compared to treatment with other chemotherapy. We included studies that reported on our primary outcome of overall survival and secondary outcomes including progression-free survival, tumour response rate, quality of life, and adverse events. Data collection and analysis We used standard methodological procedures defined by Cochrane. Summary statistics for the endpoints used hazard ratios (HR) with 95% confidence intervals (CI) for overall survival and progression-free survival, and odds ratios (OR) for response rate (RR) and toxicity. Main results We identified 49 articles for qualitative synthesis, describing five randomised controlled trials that were included in the quantitative synthesis (meta-analysis). A sixth trial was assessed as eligible but had ended prematurely and no data were available for inclusion in our meta-analysis. Risk of bias was predominately low to unclear across all studies except in regards to performance bias (3/5 high risk) and detection bias for the outcomes of quality of life (2/2 high risk) and reporting of adverse events (3/5 high risk). High-certainty evidence shows there may be a small advantage in overall survival (HR 0.87, 95% CI 0.76 to 1.00; 4 studies; 1435 patients). High-certainty evidence shows that PARP inhibitors offer an improvement in PFS in locally advanced/metastatic HER2-negative, BRCA germline mutated breast cancer patients (HR 0.63, 95% CI 0.56 to 0.71; 5 studies; 1474 patients). There was no statistical heterogeneity for these outcomes. Subgroup analyses for PFS outcomes based on trial level data were performed for triple-negative breast cancer, hormone-positive and/or HER2-positive breast cancer, BRCA1 and BRCA2 germline mutations, and patients who had received prior chemotherapy for advanced breast cancer or not. The subgroup analyses showed a persistent PFS benefit regardless of the subgroup chosen. Pooled analysis shows PARP inhibitors likely result in a moderate improvement in tumour response rate compared to other treatment arms (66.9% vs 48.9%; RR 1.39, 95% CI 1.24 to 1.54; 5 studies; 1185 participants; moderate-certainty evidence). The most common adverse events reported across all five studies included neutropenia, anaemia and fatigue. Grade 3 or higher adverse events probably occur no less frequently in patients receiving PARP inhibitors (59.4% for PARP arm versus 64.5% for non-PARP arm, RR 0.98, 95% CI 0.91 to 1.04; 5 studies; 1443 participants; moderate-certainty evidence). Only two studies reported quality of life outcomes so this was not amenable to meta-analysis. However, both studies that did assess quality of life showed PARP inhibitors were superior compared to physician's choice of chemotherapy in terms of participant-reported outcomes. Authors' conclusions In people with locally advanced or metastatic HER2-negative, BRCA germline mutated breast cancer, PARP inhibitors offer an improvement in progression-free survival, and likely improve overall survival and tumour response rates. This systematic review provides evidence supporting the use of PARP inhibitors as part of the therapeutic strategy for breast cancer patients in this subgroup. The toxicity profile for PARP inhibitors is probably no worse than chemotherapy but more information is required regarding quality of life outcomes, highlighting the importance of collecting such data in future studies. Future studies should also be powered to detect clinically important differences in overall survival and could focus on the role of PARP inhibitors in other relevant breast cancer populations, including HER2-positive, BRCA-negative/homologous recombination repair-deficient and Programmed Death-Ligand 1 (PDL1) positive.

PARP (Poly ADP‐Ribose Polymerase) inhibitors for locally advanced or metastatic breast cancer

Despite advances in detection and treatment, metastatic breast cancer (MBC) remains the second highest cause of cancer-related death for women in the United States. Human epidermal growth factor receptor-2 (HER2) is amplified in 25-30% of breast cancers and is associated with aggressive disease and, historically, with poorer outcomes. The advent of trastuzumab, a monoclonal antibody to HER2, revolutionized the management of HER2-positive breast cancer (BC) in the metastatic and adjuvant settings. However, relapse despite adjuvant trastuzumab and resistance to trastuzumab in the metastatic setting remain substantial clinical problems for many patients with HER2-positive BC. As such, analyzing the mechanisms of trastuzumab resistance and developing new therapy to overcome trastuzumab resistance are research priorities. There has been progress, with the approval of three additional HER2-targeted agents in the last six years: lapatinib, pertuzumab, and ado-trastuzumab emtansine (T-DM1). Other HER2-targeted therapies, including neratinib and afatinib, are in clinical development, and trials of novel agents such as heat shock protein-90 (HSP90) inhibitors, phosphatidylinositol-3-kinase (PI3K) inhibitors, and HER2-targeted vaccines are ongoing. In addition to developing new therapy, research is addressing several unique challenges in the management of HER2-positive MBC. In this article, we discuss advances in the treatment of HER2-positive MBC, with a focus on novel HER2-targeted therapy and HER2-targeted agents recently approved by the United States Food and Drug Administration (FDA). Additionally, we also address the management of brain metastases (BM) and hormone receptor (HR) - positive, HER2-positive MBC.

/pdf/therapeutic-considerations-when-treating-her2-positive-49raxflw3q.pdf

Therapeutic Considerations When Treating HER2-positive Metastatic Breast Cancer

SUMMARY Metastatic breast cancer is still incurable and, thus, the goals of treatment focus on optimal palliation and extending the quality of survival through effective anticancer therapies that have acceptable toxicities. Cancer progression and development of drug resistance are dynamic processes of clonal adaptation both to evolving microenvironments with acquired tumor mutations and to continuous drug exposure. Preclinical research is constantly improving our understanding of breast cancer biology at a molecular level and, as such, current clinical research is focusing on designing trials with new targeted drugs and their appropriate combinations with endocrine and chemotherapy agents. In this review, we provide an overview of the most recent advances in the metastatic breast cancer setting by clinical subtype, giving emphasis to recently concluded or ongoing trials that have the potential to challenge and change current clinical practice.

Emerging treatments for metastatic breast cancer: update from 2012

Development of therapeutic resistance limits the efficacy of current cancer treatment. Understanding the molecular basis for therapeutic resistance should facilitate the identification of actionable targets and development of new combination therapies for cancer patients. Although extensive studies have been applied to elucidate the underlying mechanisms, evidence is far from enough to establish a well-defined picture to correct resistance. The unveiling point mutations within the kinase domain, gene amplification or overexpression, or modification of signaling pathway have been implicated in drug resistance. In the review, we will describe different currently developed strategies that have the potential to overcome drug resistance in different types of cancer therapies and facilitate prolonged anticancer effects of the first-line therapies. The knowledge obtained from these studies will allow to design better strategies to offer significant challenges on the path towards superior cancer treatment.

Resistance to Tyrosine Kinase Inhibitors in Different Types of Solid Cancer

Background: Afatinib is a ErbB Family Blocker that irreversibly blocks signaling from all relevant ErbB Family dimers. Afatinib is being developed in EGFR (ErbB1)-driven (non-small cell lung cancer [NSCLC]/head and neck squamous cell carcinoma) and HER2 (ErbB2)-driven (breast) malignancies, and has shown clinical efficacy in NSCLC patients with EGFR activating mutations.1,2 In trastuzumab-resistant, HER2-positive (SUM190) xenografts, afatinib showed antitumor activity which was superior to lapatinib. Afatinib monotherapy activity in this SUM190 model was increased by the addition of intravenous (i.v.) vinorelbine. Clinically, afatinib monotherapy demonstrated activity in an open-label, single-arm, Phase II trial in patients with HER2-positive MBC after progression on trastuzumab, with a progression-free survival (PFS) of 15.1 weeks, an overall survival (OS) of 61.0 weeks and 10% objective response (OR).3 HER-reprogramming appears to play an important role in resistance4 and recent clinical trial results have indicated that targeting more than one ErbB Family member increases efficacy.5 Thus afatinib, as an ErbB Family Blocker, should add to the portfolio of drugs available to treat trastuzumab resistance in HER2-positive BC patients. This is currently being tested in the LUX-Breast 1 trial. Methods: LUX-Breast 1 (NCT01125566) is a Phase III, open-label, multicenter trial evaluating the efficacy and safety of afatinib + vinorelbine vs. trastuzumab + vinorelbine in patients with HER2-overexpressing MBC who progressed on, or after one prior trastuzumab-based treatment regimen. Patients are randomized 2:1 to afatinib (40 mg/day oral) + vinorelbine (i.v. 25 mg/m2/week) or trastuzumab (i.v. 2 mg/kg/week after 4 mg/kg loading dose) + vinorelbine (i.v. 25 mg/m2/week). Patients receive continuous treatment in the absence of disease progression or unacceptable toxicity. Key eligibility criteria include histologically-confirmed HER2-positive MBC; no prior treatment with vinorelbine or HER2-targeted treatment other than trastuzumab; progression on one prior trastuzumab based regimen in either the adjuvant (or 240 sites with a recruitment target of 780 patients. 1. Yang JCH. Lancet Oncol 2012;13:539–48. 2. Yang JCH. J Clin Oncol 2012;30(suppl; abstr LBA7500). 3. Lin NU, et al. Breast Cancer Res Treat 2012. DOI: 10.1007/s10549-012-2003-y. 4. Metro G, et al. Expert Opin Pharmacother 2008;9:2583–601. 5. Bischoff J and Ignatov A. Breast Care 2010;5:134–41. *Updated abstract from ASCO 2012. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-16.

Abstract OT1-1-16: LUX-Breast 1: Randomized, Phase III trial of afatinib (BIBW 2992) and vinorelbine vs. trastuzumab and vinorelbine in patients with HER2-overexpressing metastatic breast cancer (MBC) failing one prior trastuzumab treatment*

Background: We have recently reported that starting bevacizumab (BE) 1 day before chemotherapy could further induce tumor vascular normalization, thereby significantly enhanced the activity of etoposide (E) and cisplatin (P) in breast cancer patients (pts) with progressing brain metastases after whole brain radiotherapy (WBRT) (ESMO 2013). Lapatinib plus capecitabine is the only proven active regimen for the treatment of brain metastases of HER2 positive breast cancer, with a central nerve system (CNS) objective response rate (ORR) of 18-38% and median time to progression (TTP) of 3.6-5.1 months (mo) in those who had had prior WBRT.

Material and methods: Twenty-three HER2 positive breast cancer pts with progressing brain metastases after WBRT were enrolled from Jan 2011 to Jan 2013. Protocol treatment was given in 21 day cycles: BE 15 mg/kg on day 1, E 70 mg/m2/day from day 2 to day 4, and P 70 mg/m2 on day 2 (BEEP regimen), for a maximum of 6 cycles. The primary endpoint was a centrally assessed CNS ORR. A CNS objective response was defined as a ≥50% reduction in the volumetric sum of all measurable CNS lesions in the absence of increasing steroid use, development of new CNS lesion, or progressive neurologic symptoms. This trial is registered with ClinicalTrials.gov ([NCT01281696][1]).

Results: Median age was 55.1 (range 33-75); 9 pts were ER+, 14 pts were ER-; 15 pts were ECOG 0-2 (65.2%), and 8 pts were ECOG 3 (34.8%). All of them had previous exposure to trastuzumab, and 20 (87.0%) of them had received trastuzumab containing regimen for the treatment of metastatic disease. Eleven pts (47.8%) received lapatinib treatment before enrollment into this trial. The median lines of chemotherapy for the treatment of metastatic disease were 3 (range 1-8). The median BEEP treatment cycles were 6 (range 1-6). Sixteen of 23 pts (69.6%; 95%CI 47.1-86.8) achieved CNS objective response, including 6 pts (26.1%) with ≥80% and 10 pts (43.5%) with 50-80% CNS volumetric reduction, respectively. Five pts (21.7%) had 20-50% CNS volumetric reduction. Seven of 11 (63.6%) who were refractory to lapatinib treatment had CNS tumor response, and 9 of 12 (75.0%) who were lapatinib naive had CNS ORR. With median follow-up of 12.1 months (mo), the median time to progression was 7.7 mo (95% CI 6.6-8.8), and overall survival was 11.8 mo (95% CI 7.0-16.6) among the 23 pts. Only 3 pts (13.0%) had disease progression during protocol treatment. Grade 3/4 toxicities (≥1%) included neutropenia, leukopenia, thrombocytopenia, infection, anemia, and in 32.7%, 14.0%, 8.4%, 8.4%, and 5.6% per cycles, respectively. Ten pts (43.5%) needed dose reduction of E to 60 mg/m2 and P to 60 mg/m2, and 2 pts discontinued from treatment due to toxicity.

Conclusions: BEEP regimen has a significant anti-tumor effect for HER2 positive breast cancer with brain metastasis which progresses after WBRT.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-02.

 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01281696&atom=%2Fcanres%2F73%2F24_Supplement%2FP2-16-02.atom

Abstract P2-16-02: Bevacizumab, etoposide, and cisplatin (BEEP) is highly effective in brain metastases of HER2 positive breast cancer progressing from whole brain radiotherapy - Subgroup analysis of a multi-center phase II study

Background In the Phase III OlympiAD trial (NCT02000622, D0819C00003), olaparib (Lynparza™) showed a significant progression-free survival (PFS) improvement compared with chemotherapy treatment of physician9s choice (TPC) in patients (pts) with metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm) (Robson et al.NEJM 2017). Here, we present data from a subgroup analysis of Asian pts. It is not yet known whether Asian pts, in comparison with the global patient population, may experience instances of differential toxicity with olaparib therapy. Methods OlympiAD, an open-label, multicenter, Phase III trial, randomized (2:1) pts with HER2-negative mBC and a gBRCAm to olaparib tablets (300 mg twice daily) or single-agent TPC (21-day cycles of capecitabine, eribulin or vinorelbine). Pts must have received ≤2 lines of chemotherapy for mBC and prior anthracycline and taxane in the adjuvant, neo-adjuvant or metastatic setting. Primary endpoint was PFS by blinded independent central review (BICR). Region (Asia, Europe, North America, South America) was a pre-defined subgroup for PFS. Results The Asian subgroup analysis included pts randomized at centers in China, Japan, Korea and Taiwan. Of 87 Asian pts randomized (median age 46 years), 86 received study treatment (n=59, olaparib; n=27, TPC). In the olaparib group, 29/59 (49%) had estrogen receptor positive (ER+) and/or progesterone receptor positive (PR+) tumors, and 30/59 (51%) had triple negative breast cancer (TNBC). In the TPC group, 13/28 (46%) had ER+/PR+ tumors and 15/28 (54%) had TNBC. The primary endpoint, PFS by BICR, favored olaparib with a hazard ratio (HR) of 0.53 (95% confidence interval [CI] 0.29–0.97; median 5.7 vs 4.2 months; 77% maturity), and was supported by investigator-assessed PFS (HR 0.29, 95% CI 0.16–0.55). In the overall OlympiAD study population (N=302), the PFS by BICR favored olaparib with a HR of 0.58 (95% CI 0.43–0.80; P=0.0009). Within the Asian subgroup, objective response rate (ORR) (RECIST) was 64% for olaparib versus 38% for the TPC group. Time to second progression, PFS2, was longer for pts receiving olaparib versus TPC (HR 0.43, 95% CI 0.22–0.84; 57% maturity). Grade ≥3 adverse events (AEs) occurred in 46% and 59% of pts receiving olaparib and TPC, respectively. The most common grade ≥3 AE was anemia (olaparib, 20%; TPC, 15%). In both treatment groups, 7% of pts discontinued study treatment due to AEs (n=4, olaparib; n=2, TPC). The tolerability profile of olaparib between the subgroup of Asian pts and the overall OlympiAD population will be examined in our data presentation. Conclusion Olaparib demonstrated an efficacy benefit compared with TPC in pts with HER2-negative mBC and a gBRCAm in this subgroup analysis of Asian pts from the Phase III OlympiAD trial. Discontinuation rates due to toxicity were low, highlighting that olaparib was generally well-tolerated. The efficacy of olaparib within the subgroup of Asian pts was consistent with that shown for the full OlympiAD dataset; consistent hazard ratios were shown in favor of olaparib using the primary endpoint of PFS by BICR, and for the key secondary endpoints of PFS by investigator assessment, PFS2, and ORR. Citation Format: Im S-A, Xu B, Li W, Robson M, Ouyang Q, Yeh D-C, Iwata H, Park Y-H, Sohn JH, Tseng L-M, Goessl C, Wu W, Runswick S, Masuda N. Olaparib monotherapy versus chemotherapy for patients with HER2-negative metastatic breast cancer and a germline BRCA mutation: Asian subgroup analysis from the phase III OlympiAD trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-13.

Abstract P5-21-13: Olaparib monotherapy versus chemotherapy for patients with HER2-negative metastatic breast cancer and a germline BRCA mutation: Asian subgroup analysis from the phase III OlympiAD trial

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Abstract OT1-1-16: LUX-Breast 1: Randomized, Phase III trial of afatinib (BIBW 2992) and vinorelbine vs. trastuzumab and vinorelbine in patients with HER2-overexpressing metastatic breast cancer (MBC) failing one prior trastuzumab treatment*

Abstract P2-16-02: Bevacizumab, etoposide, and cisplatin (BEEP) is highly effective in brain metastases of HER2 positive breast cancer progressing from whole brain radiotherapy - Subgroup analysis of a multi-center phase II study

Abstract P5-21-13: Olaparib monotherapy versus chemotherapy for patients with HER2-negative metastatic breast cancer and a germline BRCA mutation: Asian subgroup analysis from the phase III OlympiAD trial