Maintenance Therapy for Recurrent Ovarian Cancer

Kristi A. Acker, DNP, PhD, FNP-BC, AOCNP, ACHPN
University of Alabama

Key Takeaways

  • Maintenance therapy for ovarian cancer has been shown to be effective in first-line and recurrent settings; its use is rapidly expanding and continues to evolve as new data emerge.
  • Bevacizumab can be given concurrently with platinum-based chemotherapy, then continued on its own as maintenance therapy; poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors can be used as maintenance therapy following completion of primary chemotherapy.
  • All patients with newly diagnosed epithelial high-grade serous carcinomas should undergo germline testing for BRCA1, BRCA2, and other ovarian cancer susceptibility genes as well as somatic tumor testing for BRCA1 and BRCA2 variants, including homologous recombination deficiency (HRD).
  • Further research is needed to discover biomarkers that can identify those patients who could benefit most from treatment with PARP inhibitors.
  • Patients’ goals and values must be part of the discussion, and financial implications of treatment must be reviewed along with benefits and risks.

Kristi A. Acker, DNP, PhD, FNP-BC, AOCNP, ACHPN, is a clinical assistant professor at Capstone College of Nursing of the University of Alabama, Tuscaloosa. She is also a family nurse practitioner, an oncology advanced practice nurse, and a hospice and palliative care advanced practice nurse. Dr Acker maintains her clinical practice with Oncology Associates of West Alabama, and she provides outpatient oncology services at the Lewis and Faye Manderson Cancer Center in Tuscaloosa. She serves on the Alabama State Advisory Council on Palliative Care and Quality of Life and advocates for advancing palliative care for patients with serious illness at both the state and national levels.

The US Food and Drug Administration (FDA) has approved 4 drugs — the antiangiogenic agent bevacizumab and the PARP inhibitors niraparib, olaparib, and rucaparib — for 6 different ovarian cancer maintenance indications based on the results of clinical trials demonstrating their efficacy and tolerability. What factors help clinicians to determine which agent(s) may be the most effective for an individual patient? Are these drugs administered primarily as monotherapy or in combination?

When I started practicing in oncology nearly 30 years ago, treatment options for ovarian cancer were limited, and performance status essentially dictated what regimens were recommended. Now, given the availability of targeted therapies with improved tolerability profiles (ie, antiangiogenics and PARP inhibitors), the landscape is changing. As far as factors to consider are concerned, there is still one key consideration: treatment should align with the patient’s values and goals. Shared decision-making must be central, especially as providers consider a myriad of emerging options. 

Platinum-based chemotherapy and optimal surgical interventions remain the cornerstone of primary treatment for ovarian cancer. However, novel drugs are proving to be instrumental for improving progression-free survival (PFS) in both the first-line maintenance phase and in maintenance therapy following recurrence.  Maintenance therapy for ovarian cancer is not new; bevacizumab has been routinely used in ovarian cancer maintenance therapy since being approved by the FDA in 2018 for use concurrently with chemotherapy in this setting.1

Bevacizumab is a monoclonal antibody that specifically targets the VEGF/VEGFR [vascular endothelial growth factor/vascular endothelial growth factor receptor] pathway. One word of caution with bevacizumab is that if surgery is planned, then this drug should be held for 6 weeks prior to surgery due to its negative impact on postoperative healing. 

As the landscape changes, greater attention should be paid to uncovering the molecular processes underlying tumor histology. Early germline and somatic testing for BRCA1/BRCA2 and HRD, along with testing for other molecular mutations, is indicated. Results of the groundbreaking SOLO-1 study (ClinicalTrials.gov Identifier: NCT01844986) show that patients with genomic profiles bearing these mutations benefit significantly from treatment with PARP inhibitors, although these agents have shown less efficacy against BRCA wild type or homologous recombination proficient [HRP] tumors.2 Genomic assays to identify potential genomic aberrations should be performed at the time of diagnosis and have been widely studied in patients with stage III-IV disease.

The goal of first-line maintenance therapy is to keep cancer controlled for an extended period of time following a complete or partial response to primary therapy, but data on use of PARP inhibitors in stage II populations are limited. Current guidelines recommend olaparib with or without bevacizumab for first-line maintenance in patients with BRCA1/BRCA2 germline or somatic HRD mutations, and studies in this area are ongoing. The PAOLA-1 trial (ClinicalTrials.gov Identifier: NCT02477644) evaluated combined maintenance therapy with bevacizumab up to 15 months plus olaparib until toxicity or disease progression or up to 24 months. This combination is increasingly used in first-line maintenance therapy.3 When bevacizumab is given in conjunction with a PARP inhibitor, the need for dose reductions and/or treatment discontinuation is notably increased.

Results of PRIMA (ClinicalTrials.gov Identifier: NCT02655016) found that niraparib yielded an increase in PFS in both the HRD and HRP populations, thus providing an option for first-line maintenance therapy regardless of biomarker status. 4 Niraparib and olaparib may both be administered as monotherapy in first-line maintenance following primary treatment for up to 36 months (niraparib) or 24 months (olaparib) or until disease progression.

To summarize, all patients with newly diagnosed epithelial high-grade serous carcinomas (HGSC), including fallopian tube cancer and peritoneal cancer, regardless of family history, should undergo germline testing for BRCA1/BRCA2 and other ovarian cancer susceptibility genes. Additionally, somatic tumor testing for BRCA1/BRCA2 variants, including HRD, should be performed upfront in patients with high-risk disease; such testing arms oncology providers with as much information as possible to make informed treatment plans alongside the patient, while bearing in mind the patient’s goals and values. 

Recurrent ovarian cancer is considered incurable, but is efficacy of the current treatment options similar in terms of extending survival? Can you discuss treatment tolerability and adverse events associated with use of these agents in recurrent ovarian cancer?

Unfortunately, patients with advanced ovarian cancer may continue to exhibit persistent disease or experience disease recurrence, thus making their disease incurable. With ovarian cancer, there is no tumor marker screening in place — so when a woman begins to exhibit symptoms, these are usually attributed to advanced disease at the time of diagnosis. However, recurrent disease is often responsive to therapy.  In certain subgroups of patients with germline BRCA1/BRCA2 or somatic HRD mutations, therapy with PARP inhibitors has significantly improved the PFS endpoints, revolutionizing treatment outcomes in advanced ovarian cancer. Further, modest PFS is achieved regardless of the biomarkers; therefore, PARP inhibitors should be an option for all patients interested in treatment.

There is promise for transitioning to a more chronic management approach, rather than a fatalistic one, to recurrent ovarian cancer, especially for those tumors with biological mutations. For patients facing recurrent disease, ensure that shared decision-making remains at the forefront of care; this includes informing patients about the availability of clinical trials. In patients with recurrent platinum-sensitive ovarian cancer, returning to platinum-based combination chemotherapy is optimal and has a favorable response rate.  Patients with HGSC have a remarkable rate of response with initial platinum-based treatment (approximately 80%).9 Oncology providers should closely monitor patients for hypersensitivity reactions and for higher-grade myelosuppression with repeated courses of platinum-based regimens. If combination chemotherapy is not an option, then single-agent chemotherapy regimens should be considered. In platinum-resistant recurrent disease, nonplatinum-based chemotherapy, either as monotherapy or combination therapy, should be considered.

Bevacizumab should be considered as single-agent therapy or in combination with chemotherapy, especially if marked ascites or symptom burden is a concern. In the setting of recurrent ovarian cancer, there are limited data supporting overall survival in patients treated with chemotherapy plus bevacizumab. Bevacizumab has a class effect risk for increased bleeding, blood clots, bowel complications, proteinuria, and hypertension, which may require pharmacologic management.

PARP inhibitors are postrecurrence maintenance options that can be considered in selected patients, especially those with BRCA1/BRCA2 mutations and platinum-sensitive disease. Agents with FDA approval for postrecurrence maintenance therapy include olaparib,5 niraparib,6 and rucaparib7 in patients with platinum-sensitive disease who have achieved a complete or partial response following platinum-based chemotherapy. PARP inhibitors are given orally, and common side effects include nausea, vomiting, anemia, thrombocytopenia, neutropenia, asthenia, fatigue, diarrhea, and/or constipation. Nonhematologic adverse effects can often decrease over time but must be closely monitored.  Renal and hepatic functioning should also be monitored. 


In certain subgroups of patients with germline BRCA1/BRCA2 or somatic HRD mutations, therapy with PARP inhibitors has significantly improved the PFS endpoints, revolutionizing treatment outcomes in advanced ovarian cancer. Further, modest PFS is achieved regardless of the biomarkers; therefore, PARP inhibitors should be an option for all patients interested in treatment.


Most patients with ovarian cancer will experience disease recurrence.  What are the options at this point? Is this largely an unmet need?

As I mentioned earlier, recurrent ovarian cancer is considered incurable. Despite the observed marked response to treatment in platinum-sensitive disease, recurrence of disease is expected. In patients with platinum-sensitive tumors who experience relapse more than 6 months after treatment, further cytoreductive surgery may be indicated, followed by enrollment in a clinical trial and/or additional platinum-based therapy. PARP inhibitors are considered in relapsed disease for patients who are PARP-naive and have demonstrated increased disease activity compared with that seen with nonplatinum chemotherapy in platinum-sensitive disease. Many patients with relapsed disease will have received at least 2 prior lines of cytotoxic treatment, so persistent and worsening myelosuppression is a consideration. Risks for myeloproliferative disorders have been shown to be greater in patients with platinum-sensitive recurrent disease who have completed 2 regimens of platinum-based cytotoxic therapy. In the setting of relapsed and/or persistent disease, best supportive care and aggressive palliative care may be preferable and should be based on open communication with the patient. 

With that said, oncology providers are learning to reframe discussions around recurrence, particularly given the strides in benefit seen with postrecurrence maintenance therapy in certain subset populations. For patients who demonstrate platinum-sensitivity and have germline or somatic mutations, progression-free endpoints are impressive. With the advent of novel therapies, the importance of clinical trials is even more vital. The available treatment options may have burdensome adverse effects, and managing these requires close monitoring and effective communication. Risks for developing myelodysplastic syndromes must be fully communicated as well. With each recurrence comes the increased likelihood of worsening and more complicated adverse events. Discussing with the patient the financial implications of treatment along with benefits and risks is imperative.

What is the future direction of PARP inhibitor therapy, other emerging agents, and/or new drug classes under investigation in ovarian cancer? 

The benefit of using a PARP inhibitor as monotherapy over combination therapy with bevacizumab has not yet been determined. Questions include whether there will be a beneficial impact regardless of biomarker status; the utility of PARP inhibitor options upstream; and the benefits of PARP inhibitors in other cancers that have BRCA mutations, such as breast, pancreatic, and prostate cancers. Additionally, oncology care providers need to have access to predictive models that can help streamline decision-making in clinical settings.

There is optimism about data on the PARP inhibitor veliparib as primary therapy for high-risk ovarian cancer.8 Also being explored are olaparib in combination with bevacizumab as primary therapy and niraparib plus bevacizumab in patients with recurrent disease.

Immunotherapy for ovarian cancer has become an area of intensive ongoing research, with some agents now being evaluated in recurrent ovarian cancer. Are any of the data promising?

Pembrolizumab, an immune checkpoint inhibitor targeting PD-1/PD-L1 [programmed death 1/programmed death ligand-1] pathways, has been approved for subsets of patients with advanced ovarian cancer that has DNA mismatch repair deficiency (dMMR), high microsatellite instability (MSI-H), or high tumor mutational burden (TMB-H). The immune checkpoint inhibitor durvalumab is showing efficacy and tolerability in combination with chemotherapy. Obviously, with response rates showing promise, additional monoclonal antibodies are in the pipeline for investigation in ovarian cancer, including atezolizumab and tisotumab.

This Q&A was edited for clarity and length.

References

  1. US Food and Drug Administration.  FDA approves bevacizumab in combination with chemotherapy for ovarian cancer. Content current as of: 06/13/2018. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-bevacizumab-combination-chemotherapy-ovarian-cancer
  2. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379:2495-2505. doi:10.1056/NEJMoa1810858
  3. Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381(25):2416-2428. doi:10.1056/NEJMoa1911361
  4. González-Martín A, Pothuri B, Vergote I, et al, for the PRIMA/ENGOT-OV26/GOG-3012 investigators. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391-2402. doi:10.1056/NEJMoa1910962
  5. Poveda A, Floquet A, Ledermann JA, et al. Final overall survival (OS) results from SOLO2/ENGOT-ov21: A phase III trial assessing maintenance olaparib in patients (pts) with platinum-sensitive, relapsed ovarian cancer and a BRCA mutation. J Clin Oncol. 2020;38(15suppl):6002.
  6. Mirza MR, Monk BJ, Herrstedt J, et al, for the ENGOT-OV16/NOVA investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375:2154-2164. doi:10.1056/NEJMoa1611310
  7. Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10106):P1949-P1961. doi:10.1016/S0140-6736(17)32440-6
  8. Coleman RL, Fleming GF, Brady MF, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. 2019;381:2403-2415. doi:10.1056/NEJMoa1909707
  9. Lheureux, S, Braunstein, M, Oza, AM. Epithelial ovarian cancer: Evolution of management in the era of precision medicine. CA Cancer J Clin. 2019; 69: 280-304. doi:10.3322/caac.21559

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Oncology Nurse Advisor had no role in this content’s preparation.

Reviewed October 2021

Managing Multiple Myeloma With Anti-CD38 Combination Therapy

Srinivas S. Devarakonda, MD
The Ohio State University, Columbus, Ohio

Key Takeaways

  • Therapies targeting CD38, a protein highly expressed on the surface of plasma cells, have been incorporated into 3 drug regimens for patients with relapsed or refractory multiple myeloma (MM).
  • Isatuximab is similar to daratumumab but binds to a different and unique epitope amino-acid sequence, and is the only CD38 antibody that can initiate apoptosis directly.
  • Daratumumab has received US Food and Drug Administration (FDA) approval for use in the frontline setting for patients with MM who are either eligible or ineligible for autologous stem-cell transplantation.
  • Isatuximab and daratumumab have demonstrated efficacy in clinical trials in all subgroups of patients with poor-prognosis MM.
  • Several novel strategies directed at CD38 in MM are in earlier stages of development, including ones that employ bispecific antibodies and chimeric antigen-receptor T cells.

Srinivas S. Devarakonda, MD, is assistant professor in the division of hematology at the James Cancer Hospital and Solove Research Institute of The Ohio State University Wexner Medical Center, Columbus, Ohio. He specializes in the treatment of plasma-cell dyscrasias, including multiple myeloma, amyloidosis, and Waldenstrom macroglobulinemia.

CD38 is a cell-surface protein that has receptor and enzyme functions and that is highly and uniformly expressed on multiple myeloma (MM) cells.1 CD38 is also expressed, at a relatively low level, on normal lymphoid and myeloid cells, as well as on some tissues of nonhematopoietic origin, such as prostatic epithelial cells, pancreatic islet cells, and striated airway muscle. During the past 5 years, therapies targeting CD38 have been helping fuel rapid growth in treatment options for patients with MM.

What is the recommended first-line standard of care for patients with relapsed or refractory MM (RRMM)?

For patients with RRMM, 3-drug regimens that incorporate a CD38 antibody (daratumumab or isatuximab) or proteasome inhibitor (carfilzomib or ixazomib), or both, as backbones are recommended as initial treatment, depending on the treatment history and whether the patient is resistant to these agents. These drugs are usually combined with steroids and an immunomodulator, such as lenalidomide and pomalidomide. Several combination regimens have been approved, including:

●       Daratumumab plus pomalidomide plus dexamethasone;
●       Daratumumab plus lenalidomide plus dexamethasone;
●       Carfilzomib plus pomalidomide plus dexamethasone; and
●       Ixazomib plus carfilzomib plus dexamethasone.

Daratumumab was the first monoclonal antibody directed at CD38 to gain FDA approval for patients with MM. Now, daratumumab has been joined by isatuximab-irfc, an anti-CD38 monoclonal antibody with a novel mechanism of action.

Where do these 2 drugs fit in treatment regimens? When is one used ahead of the other? Are there patient characteristics that favor the use of one anti-CD38 agent over the other when used in combination regimens?

The 2 drugs are similar, but there are differences in their mechanisms of action and  approved indications. The FDA recently expanded the indication for daratumumab to include patients who are newly diagnosed with MM, in addition to those in the RRMM setting. Regulatory approval was granted for daratumumab to be used in combination with bortezomib, thalidomide, and dexamethasone for patients who are eligible for autologous stem-cell transplantation on the basis of results from the CASSIOPEIA trial (ClinicalTrials.gov Identifier: NCT02541383).2,3 Patients for whom daratumumab was added to their regimen experienced a 53% reduction in the risk of progression or death, compared with the control group.

Approval was also granted to daratumumab, in combination with lenalidomide and dexamethasone, for patients with newly diagnosed MM who are ineligible for autologous stem-cell transplantation.4 The basis for that indication was findings from the MAIA trial (ClinicalTrials.gov Identifier: NCT02252172) that adding daratumumab in combination with lenalidomide and low-dose dexamethasone improved progression-free survival, compared with treatment with the standard regimen.5 The percentage of patients with a complete response or better was 47.6% in the daratumumab group compared with 24.9% in the control group (P <.001).

Isatuximab-irfc targets CD38 but binds to a different, and unique, epitope amino-acid sequence than daratumumab. It is the only CD38 antibody that can initiate apoptosis directly by targeting an enzyme uniformly expressed on myeloma cells through the CD38 mechanism of action. 6 Isatuximab-irfc has been approved for the treatment of RRMM only, to be used in combination with pomalidomide plus dexamethasone and carfilzomib plus dexamethasone. Because daratumumab is approved for subcutaneous use in some regimens, it might be preferred — by patients and providers — for its ease of administration and convenience.7 However, when given intravenously, the recommended duration of infusion for isatuximab-irfc is slightly shorter than that of daratumumab, and isatuximab-irfc does not require post-infusion prophylaxis with a corticosteroid or bronchodilator. A subcutaneous formulation of isatuximab-irfc is being tested and developed in a phase 1b study (ClinicalTrials.gov Identifier: NCT04045795).

Daratumumab adverse effects
Flip
Adverse effects commonly reported were upper respiratory-tract infection, neutropenia, infusion-related reaction, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia.

Are there subgroups of patients who seem to derive the most benefit when these agents are added to their regimen? Does cytogenetic risk status have an impact on outcomes?

Both daratumumab and isatuximab-irfc demonstrated efficacy in clinical trials in all poor-prognosis patient subgroups. These include patients with advanced-stage disease (that is, International Staging System stage III), high-risk cytogenetics, renal impairment, and resistance to protease inhibitors and immunomodulators, as well as older patients. However, when used in combination, isatuximab-irfc appears to be synergistic with pomalidomide in terms of inducing antibody-dependent cellular toxicity; the same synergism is seen with bortezomib and lenalidomide for daratumumab. 8 The activity of isatuximab-irfc with other drugs is being investigated in clinical trials.

Both CD38 antibodies have efficacy in patients with high-risk cytogenetics, which is defined by the presence of a del(17p) or a t(4;14) or t(14;16) translocation by fluorescence in situ hybridization.

Will isatuximab-irfc offer better outcomes in patients previously exposed to daratumumab, instead of retreatment with daratumumab — a scenario that will become common, given the incorporation of daratumumab in the upfront setting?

We don’t have data yet to tell us if treatment with isatuximab-irfc offers better outcomes than daratumumab retreatment in patients with RRMM who had prior exposure to daratumumab. In the ICARIA-MM study (ClinicalTrials.gov Identifier: NCT02990338), adding isatuximab-irfc to pomalidomide plus dexamethasone almost doubled median progression-free survival: 11.5 months in the isatuximab-irfc plus pomalidomide plus dexamethasone group, compared with 6.5 months in the pomalidomide plus dexamethasone group.9 However, approximately half of patients in the pomalidomide plus dexamethasone group, compared with 10% in the isatuximab-irfc plus pomalidomide plus dexamethasone group, received daratumumab, and the overall survival analysis didn’t seem to be affected by prior exposure to daratumumab. The efficacy of an CD38 antibody after a previous one in a different line of treatment still should be investigated in randomized trials.

Both daratumumab and isatuximab-irfc demonstrated efficacy in clinical trials in all poor-prognosis patient subgroups. These include patients with advanced-stage disease, high-risk cytogenetics, renal impairment, and resistance to protease inhibitors and immunomodulators, as well as older patients.

Several novel strategies directed at CD38 in MM are in earlier stages of development, including employing bispecific antibodies and chimeric antigen-receptor (CAR) T cells. Are any new agents nearing approval, or in phase 3 trials? Where might they fit into treatment regimens — that is, where is the greatest need?

Idecabtagene vicleucel, a B-cell maturation antigen (BCMA)–directed CAR T-cell therapy, was recently approved by the FDA for the treatment of patients with RRMM after 4 or more prior therapies, including an immunomodulatory drug, a proteasome inhibitor, and a CD38 antibody. It is the first CAR T-cell product approved for this disease, and several other anti-B-cell maturation antigen–directed CAR T-cell products are being investigated in phase 3 trials. Various bispecific antibodies are also being investigated in early-phase trials — mostly, phase 1/2 — and early data are demonstrating efficacy.10

These newer agents are going to play a major role in the treatment of patients with RRMM whose disease has progressed on multiple prior therapies, including anti-CD38 agents. More so, with CD38 antibodies making a foray into the frontline treatment of newly diagnosed MM, agents with novel mechanisms of action, such as CAR T-cell therapy and bispecific antibodies, are crucial to overcoming drug resistance and improving survival in relapsed disease.

The Q&A was edited for clarity and length.

References

  1. van de Donk NWCJ, Janmaat ML, Mutis T, et al. Monoclonal antibodies targeting CD38 in hematological malignancies and beyond. Immunol Rev. 2016;270(1):95-112. doi:10.1111/imr.12389
  2. FDA approves daratumumab for transplant-eligible multiple myeloma. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-transplant-eligible-multiple-myeloma. Published September 26, 2019. Accessed April 25, 2021.
  3. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394(10192):29-38. doi:10.1016/S0140-6736(19)31240-1
  4. US Food & Drug Administration. FDA approves daratumumab for multiple myeloma ineligible for autologous stem cell transplant. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-multiple-myeloma-ineligible-autologous-stem-cell-transplant. Published June 28, 2019. Accessed May 4, 2021.
  5. Facon T, Kumar S, Plesner T, et al; MAIA Trial Investigators. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104-2115. doi:10.1056/NEJMoa1817249
  6. Martin TG, Corzo K, Chiron M, et al. Therapeutic opportunities with pharmacological inhibition of CD38 with isatuximab. Cells. 2019;8:1522. doi:10.3390/cells8121522
  7. Mateos M-V, Nahi H, Legiec W, et al. Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial. Lancet Haematol. 2020;7(5):e370-e380. doi:10.1016/S2352-3026(20)30070-3. Erratum in: Lancet Haematol. 2020;7(10):e710. doi:10.1016/S2352-3026(20)30296-9
  8. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945. doi:10.1182/blood.2020005288
  9. Attal M, Richardson PG, Rajkumar SV et al; ICARIA-MM study group. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019;394(10214):2096-2107. doi:10.1016/S0140-6736(19)32556-5. Erratum in: Lancet. 2019;394(10214):2072. doi:10.1016/S0140-6736(19)32944-7
  10. Li C, Mei H, Hu Y, et al. A bispecific CAR-T cell therapy targeting Bcma and CD38 for relapsed/refractory multiple myeloma: updated results from a phase 1 dose-climbing trial. Blood. 2019;134(Suppl 1):930. doi:10.1182/blood-2019-130340

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Oncology Nurse Advisor had no role in this content’s preparation.

Reviewed May 2021

Therapeutic Options for Patients With High-Risk, HER2-Positive Early Breast Cancer

Charles Shapiro, MD
Icahn School of Medicine at Mount Sinai and Mount Sinai Health System, New York

Key Takeaways

  • The standard of care for patients with HER2-positive early breast cancer experiencing residual disease following neoadjuvant therapy is ado-trastuzumab emtansine (T-DM1) in the adjuvant setting, which is superior to trastuzumab in reducing the risk of recurrence.
  • Non-anthracycline regimens are noninferior to those containing an anthracycline and are a feasible option, especially for patients with a pre-existing cardiac condition or borderline ejection fraction at baseline.
  • Patients who achieve pathologic complete response after neoadjuvant therapy should continue with adjuvant trastuzumab, with or without pertuzumab, for a full year, because data supporting a shorter duration of treatment have been mixed.
  • There is an unmet need for new therapies to treat the approximately 25% of patients with HER2-positive early breast cancer who eventually experience relapse and develop brain metastasis.
  • Neoadjuvant therapy should be given to patients with stage II or III disease, whereas surgery is appropriate as an initial treatment for patients with smaller, node-negative tumors.

Charles Shapiro, MD, is a professor of medicine (hematology and medical oncology) at the Icahn School of Medicine at Mount Sinai in New York. He is director of Translational Breast Cancer Research for the Mount Sinai Health System and director of Survivorship Programs at The Tisch Cancer Institute. His clinical research interests include the impact of adjuvant chemotherapy on bone loss in premenopausal women, development of new treatments, and clinical trials that feature novel therapies.

HER2-positive breast cancer is a subtype that has seen a transformation of outcomes over the past 2 decades. What approaches are now used in this population that are considered the standard of care?

Development of HER2-directed therapies has led to advances in the treatment of HER2-positive disease, first in the adjuvant setting in the 2000s and then in the neoadjuvant setting in the 2010s. Adjuvant or neoadjuvant treatment, or both, with chemotherapy and trastuzumab is usually warranted in this setting, although other HER2-directed agents can also be used. Patients with stage II or III disease should receive neoadjuvant therapy, whereas surgery as initial treatment is appropriate for those with smaller, node-negative tumors.

The regimen varies depending on tumor size and node status. Treatment generally consists of chemotherapy with an anthracycline-based regimen containing cyclophosphamide given in a dose-dense fashion. If the patient is node positive, chemotherapy is given in combination with trastuzumab or pertuzumab. Chemotherapy plus trastuzumab is standard for all HER2-positive, node-positive breast cancers as well as for patients with larger node-negative tumors (>5 mm).

Non-anthracycline-based therapy consisting of docetaxel plus carboplatin plus trastuzumab, with or without pertuzumab is also an option for patients with stage II and III disease. But we tend to avoid anthracyclines in HER2/neu-overexpressing patients because of the risk of cardiotoxicity. Although this risk is small, with cardiac effects occurring in 1% or fewer of patients, anthracyclines do increase the risk of cardiomyopathy in this population.

Non-anthracycline-based therapy consisting of docetaxel plus carboplatin plus trastuzumab, with or without pertuzumab is also an option for patients with stage II and III disease. But we tend to avoid anthracyclines in HER2/neu-overexpressing patients because of the risk of cardiotoxicity.

Anthracyclines have been a mainstay of breast cancer therapy for decades because there has been strong evidence demonstrating their impact on breast cancer survival. As mentioned, there is a small but important increase in the risk of cardiotoxicity. Are non-anthracycline regimens as effective in the setting of early HER2-positive disease?

The Breast Cancer International Research Group 006 (ClinicalTrials.gov Identifier: NCT00021255) trial showed that non-anthracycline regimens were noninferior to those containing an anthracycline. More than 3000 women with HER2-positive, early-stage breast cancer were randomly assigned to receive 1 of 3 regimens studied: doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T); the same regimen plus 52 weeks of trastuzumab (AC-T plus trastuzumab); or docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH).1

Estimated disease-free survival rates at 5 years were 75% in the AC-T group; 84% among patients receiving AC-T plus trastuzumab; and 81% among those receiving TCH. Estimated overall survival rates were 87%, 92%, and 91%, respectively.

The researchers found that adding 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival and that the risk:benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab. Efficacy was similar, and there were fewer acute toxic effects and lower risks of cardiotoxicity and leukemia.


HER2+ Treatment Strategies
Flip
Treatment for early-stage HER2-positive breast cancer can include some combination of surgery, targeted therapy, chemotherapy, and, possibly, other therapies.

What is the postsurgical treatment regimen for women who receive neoadjuvant therapy?

The choice of adjuvant treatment depends on their response to neoadjuvant treatment. Patients with residual disease will be switched to T-DM1 in the adjuvant setting, where it will be administered for 14 cycles. That is the new standard of care, which is superior to trastuzumab in lowering the risk of recurrence and prolonging disease-free survival.

Data for T-DM1 come from the KATHERINE trial (ClinicalTrials.gov Identifier: NCT01772472), which was an open-label, randomized study that included 1486 women with HER2-positive early breast cancer who had residual invasive disease after neoadjuvant taxane-containing chemotherapy (with or without anthracyclines) and trastuzumab. Patients were randomly assigned to receive adjuvant T-DM1 or trastuzumab for 14 cycles, and the primary endpoint was invasive disease-free survival.2 At 3 years, the rate of invasive disease-free survival was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group (hazard ratio [HR] for invasive disease or death, 0.50 [95% CI, 0.39-0.64; P <.001]); distant recurrence as the first invasive disease event occurred in 10.5% of patients in the T-DM1 group compared with 15.9% in the trastuzumab group.

If there is no residual disease and the patient has achieved pathologic complete response, adjuvant trastuzumab will be given, with or without pertuzumab, for 1 year. A newer therapy, neratinib, was approved in 2017 for extended adjuvant therapy for early-stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy. This approval was based on the phase 3 ExteNET trial (ClinicalTrials.gov Identifier: NCT00878709), which showed improvement, after 2 years of follow-up, in invasive disease-free survival (93.9% in the neratinib group compared with 91.6% in the placebo group).3 Neratinib is generally given to women at higher risk for recurrence. To date, there are no data showing a benefit in women who have received pertuzumab or T-DM1 as part of their neoadjuvant treatment.

Do all women receive trastuzumab for a year, regardless of their response to adjuvant treatment?

There has been some interest in de-escalating trastuzumab. A few trials have looked at decreasing follow-up treatment to 6 months, but results failed to reach a firm conclusion. The PHARE trial (ClinicalTrials.gov Identifier: NCT00381901) failed to show that 6 months of adjuvant trastuzumab therapy was noninferior to 12 months in patients after 7 months of follow-up. At 3 years, the rate of disease-free survival was 92.2% with 12 months of trastuzumab compared with 89.3% with 6 months of therapy. At 5 years, these rates were 86.2% and 84.2%, respectively, and at 7 years were 82.3% and 80.6%, respectively, favoring the longer course of treatment.4

However, the PERSEPHONE trial (ClinicalTrials.gov Identifier: NCT00712140) did show noninferiority of 12 months compared with 6 months of trastuzumab, albeit with shorter follow-up.5 The 4-year disease-free survival was 89.4% in the 6-month group and 89.8% in the 12-month group (HR for noninferiority of 6-month treatment, 1.07 [90% CI, 0.93-1.24; P =.011]).
 
Studies have also looked for any benefit to extending trastuzumab beyond 1 year. The HERA trial (ClinicalTrials.gov Identifier: NCT00045032), which randomly assigned more than 5000 women to observation or to the addition of trastuzumab for 1 or 2 years following completion of chemotherapy, found no difference in 10-year disease-free survival between 1 or 2 years of trastuzumab. The study reported survival to be 69% in both arms (HR, 1.02 [95% CI, 0.89-1.17]).6 Treatment with trastuzumab was superior to the 63% disease-free survival rate in the observation group, however.

Before the advent of HER2‐targeted therapy, this subtype was associated with aggressive disease, with a high recurrence rate and poorer survival outcomes. Newer therapies have changed the paradigm of HER2-positive breast cancer, but patients still experience relapse. What unmet needs do you see in this population?

Approximately 15% to 25% of patients treated with HER2-directed therapy experience disease relapse. Although relapse can occur in any part of the body, brain metastasis is really the unmet need. Approximately 25% of patients eventually develop brain metastases, which have been difficult to treat. Basically, the brain is a sanctuary, and current treatments are unsuccessful in that region. Trastuzumab, for example, can reach preclinical brain tumors, but it is not as effective at controlling intracranial disease in the clinical setting. This is reminiscent of, and parallels, what we saw early on in pediatric acute lymphoblastic leukemia, in that many recurrences were not in the body but in the brain. Patients with acute lymphoblastic leukemia now receive extensive CNS-directed chemotherapy — regimens that target systemic disease and these sanctuary sites.

In the HER2CLIMB study (ClinicalTrials.gov Identifier: NCT02614794), patients with either metastatic or nonoperable HER2-positive breast cancer who received the tyrosine kinase inhibitor tucatinib in combination with capecitabine and trastuzumab showed statistically significant improvement in progression-free survival.7 Secondary analysis of the HER2CLIMB trial data that focused on the 48% of patients with brain metastasis showed a 68% reduction in the risk of intracranial progression and death in this subset.8 Median CNS progression-free survival was 9.9 months in the tucatinib arm compared with 4.2 months for controls. Median overall survival was 18.1 months for tucatinib compared with 12.0 months for controls. Overall response rate was also higher in the tucatinib arm at 47.3% (95% CI, 33.7-61.2) compared with the control arm at 20.0% (95% CI, 5.7-43.7; P =.03). Based on these findings, tucatinib in combination with trastuzumab and capecitabine received regulatory approval for use in this setting.9

The variables for developing brain metastases are still unclear, and there are newer drugs being tested in clinical trials. For now, this is the regimen approved by the US Food and Drug Administration for this population.

The Q&A was edited for clarity and length.

References

  1. Slamon D, Eiermann W, Robert N, et al; Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14):1273-1283. doi:10.1056/NEJMoa0910383
  2. von Minckwitz G, Huang CS, Mano MS et al; KATHERINE Investigators. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628. doi:10.1056/NEJMoa1814017
  3. Chan A, Delaloge S, Holmes FA et al; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17(3):367-377. doi:10.1016/S1470-2045(15)00551-3
  4. Pivot X, Romieu G, Debled M, et al; PHARE Trial Investigators. 6 months versus 12 months of adjuvant trastuzumab in early breast cancer (PHARE): final analysis of a multicentre, open-label, phase 3 randomised trial. Lancet. 2019;393(10191):2591-2598. doi:10.1016/S0140-6736(19)30653-1
  5. Earl HM, Hiller L, Vallier A-L, et al; PERSEPHONE Steering Committee and Trial Investigators. 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial. Lancet. 2019;393(10191):2599-2612. doi:10.1016/S0140-6736(19)30650-6
  6. Cameron D, Piccart-Gebhart MJ, Gelber RD, et al; Herceptin Adjuvant (HERA) Trial Study Team. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet. 2017;389(10075):1195-1205. doi:10.1016/S0140-6736(16)32616-2
  7. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609  
  8. Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB Trial. J Clin Oncol. 2020;38(23):2610-2619. doi:10.1200/JCO.20.00775
  9. FDA approves tucatinib for patients with HER2-positive metastatic breast cancer.  Press release. US Food and Drug Administration. April 20, 2020. Accessed March 20, 2021. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tucatinib-patients-her2-positive-metastatic-breast-cancer

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Oncology Nurse Advisor had no role in this content’s preparation.

Reviewed March 2021