Day Two – Focus on HER2+ and updated EBC guidelines

Day Two – Focus on HER2+ and updated EBC guidelines

By Heather Mason

Mini Oral Session Clinical Trial Updates

Patrick Neven presented an exploratory analysis from the phase III MONALEESA-3 trial at a median follow-up of 70.8 months⁷. Treatment-naive (first-line) or endocrine therapy (ET)-resistant (second-line) post-menopausal patients with HR+/HER2− advanced breast cancer (ABC) were treated with ribociclib and fulvestrant or placebo and fulvestrant. The addition of ribociclib led to an increase in median overall survival (OS) of 67.6 months in the treatment-naive population, 15.8 months longer than the placebo population. Consistent with prior analyses, ribociclib also continued to demonstrate an OS benefit in the second-line population. At five years, the survival rate of patients receiving ribociclib was 56.5%. These impressive results, and the fact that there were no new safety signals observed, support the continued use of ribociclib in HR+/HER2− ABC.

Other presentations from this Mini Oral Session from early phase trials explored antibody–drug conjugates in harder-to-treat patient populations. The first showed an objective response rate (ORR) of 73.3% in the 15 intention-to-treat breast cancer patients with active brain metastases receiving trastuzumab deruxtecan⁸. The second demonstrated a 74% ORR in patients with locally advanced or metastatic triple-negative breast cancer receiving datopotamab deruxtecan⁹. Neither study found new safety signals beyond previous trials or trials in drugs with similar mechanisms of action.

Focus on HER2+ early breast cancer (EBC)

John Crown discussed approaches for reducing the risk of recurrence in patients with HER2+ EBC¹⁰. Trastuzumab reduces HER2+ EBC recurrence and mortality, but an unmet need remains as one in six patients dies within two years, and there is a 20% recurrence rate. The risk of recurrence increases proportionally with the level of nodal involvement. The pattern of recurrence differs according to oestrogen receptor (ER) status. A slightly improved invasive disease-free survival (iDFS) was seen in the APHINITY study, where pertuzumab was added to adjuvant trastuzumab in high-risk subgroups. However, no statistically significant OS benefit was observed. The KATHERINE study provided less ambiguous results, where trastuzumab emtansine (T-DM1) improved iDFS in patients with residual disease after neoadjuvant therapy. Reducing the risk of central nervous system (CNS) metastases remains a challenge in HER2+ EBC. Without further treatment, 2–6% of patients can expect the CNS to be one of the first sites of disease recurrence. Achieving a pathological complete response (pCR) improves iDFS but cannot overcome the prognostic impact of baseline tumour size and nodal status.

Tyrosine kinase inhibitors bring a unique mechanism of action with the potential to improve upon the established benefit of antibodies that target HER2 receptors

The unique mechanism of action of neratinib, targeting EGFR, HER2 and HER4, lends it an important role in HER2+ EBC. ExteNET, a pivotal phase III study of extended adjuvant neratinib in HER2+ EBC patients, resulted in a 5% improvement in iDFS at five years. However, the OS improvement at eight years was only around 2%. Risk assessment is integral to the treatment algorithm for HER2+ EBC.

Nadia Harbeck discussed which therapies can be offered to patients with high-risk HER2+ EBC¹¹. The clinical benefit of neoadjuvant systemic chemotherapy improves prognosis by individualising neoadjuvant and post-neoadjuvant therapy. The KATHERINE study showed that the iDFS benefit with T-DM1 was independent of HR status, but that HR+ tumours do better. This benefit will be more apparent at the subsequent follow-up. Half of the patients who relapsed in this study had CNS metastases. Subgroup analysis of the ExteNET study showed that patients with higher risk gained more benefit from neratinib. Therefore, patients armed with this information can make informed treatment choices. Exploratory analysis of ExteNET data from patients with residual disease after neoadjuvant therapy shows an iDFS of 7.4% at five years and a 9.1% OS at eight years, with a 53% relative risk reduction in the risk of recurrence. Numerically, there were fewer CNS metastases in neratinib-treated patients, although patient numbers were small.

Diana Lüftner presented strategies for treatment adherence in HER2+ EBC¹². The adverse event profile of many cancer medications results in low compliance. Data presented from the ExteNET study showed a high rate of diarrhoea in patients, emphasising the need for diarrhoea management. However, patients who completed the one-year duration of extended adjuvant therapy with neratinib may have improved outcomes. Strategies for maintaining patients on treatment include: involving the patient in treatment planning; explaining the impact of non-adherence, including the data on recurrence rates in the discussion; integrating family members; and preventing and managing adverse effects. Updates to the Early Breast Cancer Guidelines Lisa Carey presented the rationale and summary of changes that will soon be made to the current ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up in early breast cancer¹³. A lot has happened since the previous 2019 guidelines¹⁴.

ESMO’s Clinical Practice Guidelines for early breast cancer will soon see a major update

The major updates:

• Neoadjuvant systemic therapy is separated from adjuvant systemic therapy and residual disease treatment for triple negative breast cancer (TNBC) and HER2+ tumours
• Incorporation of immune checkpoint inhibition (ICI) in TNBC
• Incorporation of PARP inhibition in germline BRCA 1/2 mutation carriers
• Incorporation of CDK4/6 inhibitors in HR+/HER2- EBC

The benefits of neoadjuvant systemic therapy are highlighted, and the forthcoming guidelines update will clarify the issue of treatment timing. A higher pCR is prognostic irrelevant to the subtype of breast cancer, which has implications for surgical management. Residual disease has a poor prognosis in TNBC and HER2+ chemo-dependent subtypes. Data from several recent studies, namely KEYNOTE-522, OlympiA and MonarchE, have contributed to the updated advice included in the new guidelines.

There were no major changes to the screening and diagnostic workup, other than these few exceptions:

• Germline testing for pathogenic variants in BRCA 1/2 (recommendations to be covered in a different guideline)
• Updates in HER2 clinical testing algorithm
• Tumour-infiltrating lymphocytes are increasingly standard and prognostic

No major changes to the guidelines concerning locoregional therapy other than redefining accelerated partial breast irradiation approaches. More extensive changes to the guidelines included treatment strategies for breast cancer subtypes.

• Luminal breast cancer (HR+/HER2−):
  • Advice on ET interventions, and aromatase inhibitors in later stages, in certain populations
  • Multiple genomic assays to reduce the need for chemotherapy, the timing and the regimens
  • Advice on the addition of abemaciclib
• HER2+ patients:
  • Neoadjuvant phase guidelines
  • Molecular assays to enable omission or tailoring treatments are undergoing validation
  • Neoadjuvant anti-HER2+ chemotherapy in all >T1N0 patients
  • In small tumours (T1N0), the adjuvant/paclitaxel/trastuzumab regimen, either neo- or adjuvant, has transformed pCR outcomes
  • Tailoring therapy by response.
• TNBC:
  • Chemotherapy is the mainstay, neoadjuvant timing for all but T1N0 tumours
  • ICI is added to chemotherapy for >T1N0, as long as there are no contraindications
  • Updated advice on adjuvant systemic therapy Guidelines on breast cancer treatment during pregnancy are also expected in the next three months.

References

1. Spira AI, Riely GJ, Gadgeel SM, Heist RS, Ou S-HI, Pacheco JM, et al. KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in patients with advanced/metastatic non–small cell lung cancer (NSCLC) harboring a KRASG12C mutation. Presented at the ASCO Annual Meeting 2022, 3 June. Chicago, IL, USA. 9002. Available at: https://meetings.asco.org/abstracts-presentations/208088. Accessed 7 June 2022.
2. Akinboro O. Outcomes of anti–PD-(L)1 therapy with or without chemotherapy (chemo) for first-line (1L) treatment of advanced non–small cell lung cancer (NSCLC) with PD-L1 score ≥ 50%: FDA pooled analysis. Presented at the ASCO Annual Meeting 2022, 3 June. Chicago, IL, USA. 9000. Available at: https://meetings.asco.org/abstracts-presentations/208075. Accessed 7 June 2022.
3. Lin NU. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). Presented at the ASCO Annual Meeting 2022, 4 June 2022. Chicago, IL, USA. 1005. Available at: https://meetings.asco.org/abstracts-presentations/185141. Accessed 7 June 2022.
4. Rugo HS, Bardia A, Marmé F, Cortes J, Schmid P, Loirat D, et al. Primary results from TROPiCS-02: A randomized phase 3 study of sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) in patients (Pts) with hormone receptor–positive/HER2-negative (HR+/HER2-) advanced breast cancer. Presented at the ASCO Annual Meeting 2022, 4 June. Chicago, IL USA. LBA1001. Available at: https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.17_suppl.LBA1001. Accessed 10 June 2022.
5. Tie J, Cohen J, Lahouel K, Lo SN, Wang Y, Wong R, et al. Adjuvant chemotherapy guided by circulating tumor DNA analysis in stage II colon cancer: The randomized DYNAMIC trial. Presented at the ASCO Annual Meeting 2022, 4 June. LBA100. Available at: https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.17_suppl.LBA100. Accessed 10 June 2022.
6. Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, et al. Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): Results of DESTINY-Breast04, a randomized, phase 3 study. Presented at the ASCO Annual Meeting 2022, 5 June. LBA3. Available at: https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.17_suppl.LBA3. Accessed 10 June 2022.
7. Yoshino T, Watanabe J, Shitara K, Yasui H, Ohori H, Shiozawa M, et al. Panitumumab (PAN) plus mFOLFOX6 versus bevacizumab (BEV) plus mFOLFOX6 as first-line treatment in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC): Results from the phase 3 PARADIGM trial. Presented at the Journal of Clinical Oncology 2022, 5 June. LBA1. Available at: https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.17_suppl.LBA1. Accessed 10 June 2022.
8. McCabe M, Kirton L, Khan M, Fenwick N, Strauss SJ, Valverde C, et al. Phase III assessment of topotecan and cyclophosphamide and high-dose ifosfamide in rEECur: An international randomized controlled trial of chemotherapy for the treatment of recurrent and primary refractory Ewing sarcoma (RR-ES). Presented at the ASCO Annual Meeting 2022, 5 June. LBA2. Available at: https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.17_suppl.LBA2. Accessed 10 June 2022.