Year after year, researchers, oncologists and other health professionals, industry representatives, and patient advocates descend upon Chicago, Illinois (when not virtual) early in the month of June to attend the American Society of Clinical Oncology (ASCO) annual conference and hear the latest research findings in cancer care. You may have heard through varied news sources over the past few weeks, that some of the research highlights presented this year are “practice-changing.” In fact, one plenary presentation for a breast cancer treatment clinical trial received a rarely given standing ovation. In breast cancer, what is worthy of a standing ovation? Unfortunately, it appears not very much. What should change practice? The answer should be high levels of evidence. However, much less than that does.
As breast cancer advocates, we are pushing for treatments that work. What does “work” mean to NBCC? It means that the treatment someone is given has been shown by high-quality evidence to extend life (i.e., you live longer). However, it should NOT be at an unacceptable quality of life or result in financial toxicity. Regarding the latter, until our government and society act to control runaway high-priced drugs, financial toxicity is a given for all new drugs, whether they work or not. With that said, there were some notable breast cancer clinical trial results and other research findings presented at ASCO this year. We will report on several of those over the next couple of weeks.
About Antibody Drug Conjugates (ADCs)
An ADC is a highly targeted drug that combines a monoclonal antibody specific to an antigen or receptor on the surface of a tumor cell (e.g., the HER2 receptor) with a cytotoxic anti-cancer agent. So, you hone in on the cancer cell with the antibody and then deliver very toxic chemotherapy internally to that cell. Usually, the chemotherapy attached to the antibody is too toxic to be delivered systemically. Unlike systemic chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells, thereby limiting the toxicity that often accompanies systemic chemotherapy. Ado-trastuzumab emtansine (also called TDM-1 or Kadcyla) is one such drug that has been approved to treat some patients with HER2-positive breast cancer. The monoclonal antibody is trastuzumab (Herceptin) which binds to the HER2 receptor which is overexpressed in HER2+ breast cancer. The expectation is that once the antibody portion of TDM-1 binds to the HER2 receptor on cancer cells, emtansine (a form of chemotherapy) is released into the cell and causes the cell to die.
Antibody Drug Conjugates
There has been increasing interest in antibody drug conjugates (ADCs) for the treatment of cancer, and at this year’s ASCO, results were presented for several breast cancer trials employing ADCs. The most talked-about ADC in breast cancer is called trastuzumab deruxtecan (T-DXd or Enhertu®), which is being studied in dozens of clinical trials. A key difference between T-DXd and TDM-1, is the chemotherapy delivered. The antibody is the same (trastuzumab).
T-DXd first received accelerated approval in 2019 from the FDA for the treatment of certain patients with metastatic HER2+ breast cancer based on a single-arm trial (Destiny-Breast01) in a cohort of heavily pretreated patients. A total of 61% of patients demonstrated partial or complete tumor shrinkage that lasted for a median of 21 months. Of note, approximately 10% of patients treated with Enhertu developed interstitial lung disease (ILD), some resulting in death.
T-DXd went on to receive regular approval by the FDA on May 4, 2022[i] for the treatment of a different subset of patients with metastatic HER2+ breast cancer and became the standard of care in the second-line setting. This approval was based on the results of the DESTINY-Breast03 trial (the confirmatory trial for DESTINY-Breast01), which we reported on in October 2021. The primary endpoint that led to the approval was a statistically significant improvement in progression-free survival. Data on overall survival, a secondary endpoint, was still immature at the time of approval. Updated safety data for Breast03 and key findings from Breast04 were presented at ASCO.
DESTINY-Breast03 Safety Profile Update
Per prior reported results, T-DXd resulted in superior progression-free survival (PFS) with 75.8% of participating patients progression-free at 12 months vs. 34.1% progression-free on T-DM1.[ii]
T-DXd is a very toxic drug. All grades of treatment-related toxicity were high for both drugs (99.6% and 95.4%); Twice as many patients discontinued T-DXd (14.8%; n=38) vs T-DM1 (7.3%; n=19) because of adverse events, mainly due to ILD in the T-DXd arm which occurred in 8% (n=21) of patients. Dose reductions were also higher for patients treated with T-DXd vs. TDM-1 (23% vs. 13.8%). Nausea, vomiting, fatigue, neutropenia, anemia, and alopecia were far more prevalent with T-DXd, and these side effects last the length of treatment. Patients are on T-DXd longer and thus experience the side effects for longer. Given earlier findings from DESTINY-Breast 01, study investigators monitored patients closely for the development of signs of ILD. ILD of any grade developed in 10.9% of patients on T-DXd though none resulted in death during Breast03.
Background. HER2 status of breast tumors is traditionally classified as either positive (3+) or negative. More recently, a new classification of HER2 low breast cancer has been suggested. The term has been defined in clinical trials and research to describe HER2- tumors that test 1+ or 2+ based on immunohistochemistry (IHC) tests of HER2 status, but that test negative by fluorescent in situ hybridization (FISH). NBCC has written about this previously. Read more about it here.
HER2 low tumors constitute approximately 50% of all breast cancers, including both hormone receptor-positive (HR+) and triple-negative breast cancers (TNBC). Currently available HER2-targeted therapies have not proven effective for patients with HER2-low expression.
Trial Results. DESTINY-Breast04 sought to examine the efficacy of T-DXd in HER2 low expressing patients. Patients were randomized two to one to T-DXd (373 patients) vs. treatment of physicians’ choice (184) (i.e., capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel), the majority of whom received eribulin. The primary endpoint was PFS, and the secondary endpoint was overall survival. The Median follow-up was 18.4 months.
PFS was improved in the T-DXd arm by 4.8 months, going from 5.1 months for patients receiving treatment of physicians’ choice (control arm) compared to 9.9 months for patients receiving T-DXd. Overall survival was similarly improved, going from 16.8 months in the treatment of physicians’ choice arm to 23.4 months in the T-DXd arm (a ~6.6-month improvement). Improvements were seen in both the HR+ and the TNBC subgroups of patients, though there were far fewer patients with TNBC included in the trial, and the benefits in this subgroup are exploratory.
Approximately 16% of patients on T-DXd, discontinued treatment due to side effects, with 8.2% because of ILD. Eight percent of patients discontinued in the control group because of treatment-related side effects (2.3% due to peripheral sensory neuropathy). The most common side effects requiring dose reduction were nausea and fatigue (4.6%) for the T-DXd group and neutropenia (14%) for the control group.
What Do We Make of These Results?
T-DXd has extended progression-free survival in the metastatic setting of HER2+ and HER2-low breast cancer (including HR+) by many months and has also extended overall survival in the HER2-low metastatic setting. PFS of course is of no clinical benefit. The drug comes with significant toxicity, both physical and financial at ~$15k every three weeks. Even though it is targeted to the HER2 receptor on tumor cells, it causes toxicity in the lungs and results in substantial gastrointestinal-related side effects. There is still the question of when in the treatment cycle it should be given. It has been moved to the second line in HER2+ metastatic disease, and an ongoing global head-to-head phase 3 trial (DESTINY-BREAST09) is evaluating T-DXd with or without pertuzumab compared to the standard of care (taxane, trastuzumab, and pertuzumab) as a potential first-line treatment. It is not yet approved in the HER2-low setting, but that is a matter of time. Additionally, we heard a lot of ongoing discussion at the meeting about studying this drug in the early stage setting of breast cancer where outcomes, especially among HR+ and HER2+ patients are relatively very good with much less toxic therapy. The benefit-to-risk tradeoffs given the toxicities associated with this drug will be far different in early-stage breast cancer than in the metastatic setting.
Advocates should closely monitor trials with this drug as it advances into earlier lines of treatment for metastatic disease and into the early stages of breast cancer. At this time, we don’t know whether earlier is better than later, especially given its toxicities. Real-world monitoring of these drugs will also be important to ensure that the ILD-associated toxicity is effectively managed in community-based oncology practice outside of clinical trials.
[ii] Cortés J, Kim SB, Chung WP, Im SA, Park YH, Hegg R, Kim MH, Tseng LM, Petry V, Chung CF, Iwata H, Hamilton E, Curigliano G, Xu B, Huang CS, Kim JH, Chiu JWY, Pedrini JL, Lee C, Liu Y, Cathcart J, Bako E, Verma S, Hurvitz SA; DESTINY-Breast03 Trial Investigators. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. N Engl J Med. 2022 Mar 24;386(12):1143-1154. doi: 10.1056/NEJMoa2115022. PMID: 35320644.