NeoSTAR - ADCs in Neoadjuvant Triple Negative Breast Cancer?
Hello everyone! It has been a minute!
First of all, apologies for the lack of posting on the OftiM Newsreel over the last eight months; as is so often the case, life has gotten in the way. However, we are back and better than ever, planning on regular blog posts on all things oncology. We kick things off with a recent publication examining neoadjuvant therapy in triple-negative breast cancer.
In the modern world of oncology, anti-cancer treatments, new and old, are being tested earlier and earlier in the treatment paradigm. Perioperative pembolizumab recently demonstrated a benefit in resectable melanoma, neoadjuvant immunotherapy has established itself in the treatment of breast and lung cancers and novel antiandrogen agents in the hormone-sensitive prostate cancer (HSPC) space are now standard of care. However, there has not been a strong push towards using antibody-drug conjugates (ADCs) in the neoadjuvant space.
Perhaps NeoSTAR will signal a change in this area.
Published in the Annals of Oncology on 12 December 2023 by Spring, Tolaney, Fell et al., NeoSTAR examined the use of Sacituzumab govitecan (SG) in the neoadjuvant treatment of triple-negative breast cancer (TNBC). It epitomises the current movement of using novel agents earlier in the treatment queue. But first a bit of a recap:
ADCs covalently bind a monoclonal antibody with a cytotoxic agent. The idea is the cytotoxic agent – usually a form of chemotherapy – is released into the cancer cell upon attachment and internalisation. This, in theory at least, increases the specificity of previously indiscriminate therapies, increasing the anti-cancer efficacy and decreasing cytotoxicity to non-cancerous cells. Again, in theory.
SG combines SN-38, an active metabolite of the commonly used topoisomerase I inhibitor irinotecan, with an anti-Trop-2 monoclonal antibody. Trop-2 was selected as it is widely expressed in several solid tumour types, including breast and lung cancer. SG has a high drug-antibody ratio (DAR) (7.6:1) and is thought to have an anti-cancer bystander effect, that is an effect against cancer cells adjacent to that directly affected by the govitecan. In the TNBC space, SG has demonstrated efficacy in the phase III ASCENT trial, improving overall survival (OS) from 6.7 months with clinicians-choice chemotherapy to 12.1 months. It has since become a standard of care in this space.
NeoSTAR is an investigator-initiated non-randomised platform clinical trial that evaluated neoadjuvant SG (NA SG) for participants with localised TNBC. Patients had to have TNBC confirmed via biopsy, measuring ≥1cm, ECOG performance status (PS) of ≤1, with adequate organ and bone marrow function. The primary endpoint was pathological complete response (pCR) rate, which has been established as an accurate surrogate for overall survival in early breast cancer for many years. Secondary endpoints included overall response rate (ORR), safety and tolerability. Exploratory endpoints included evaluation of predictive biomarkers (e.g. baseline Ki67, tumour-infiltrating lymphocytes [TILs] and TROP2 expression).
Enrolled patients received single-agent SG at 10mg/kg on D1 and D8 of a 21-day cycle for four cycles before undergoing imaging at week 12 of treatment. If imaging demonstrated a near-complete or complete radiological response, patients proceeded to definitive surgery.
However, if there was suspicion of poor response or progressive disease, patients underwent a biopsy. If residual disease was confirmed, patients could receive additional neoadjuvant therapy. Additional therapy was determined by the investigator, but usually meant dose-dense doxorubicin and cyclophosphamide or combination taxane and carboplatin.
NeoSTAR study design. Courtesy of Annals of Oncology
Following definitive surgery, patients had the option to receive additional adjuvant therapy, again at the treating oncologist’s discretion. All patients who had residual disease at surgery underwent adjuvant therapy. After completion of treatment, patients were followed up every six months, as per standard clinical practice.
50 patients were enrolled in NeoSTAR. The median age was 48.5years and the majority of patients (84%) were Caucasian ethnicity. There was a roughly even split of menopausal status (52% pre-menopausal, 46% post-menopausal). The majority of patients (52%) had stage II disease, with most having T2 primary (58%) and node-negative (78%) disease. 9 patients (18%) had a known BRCA mutation.
The overall pCR rate with SG alone was 30%. pCR rates were highest among participants with clinical stage I disease (50%), followed by stage II disease (27%) and stage III (18%), which is perhaps not surprising. Patients with a BRCA mutation appeared to response well, with 6 out of 9 achieving a pCR. The ORR with SG alone was 64%, again the highest for those with stage I disease (54%).
21 patients received additional neoadjuvant chemotherapy. Of those, 7 patients (33%) achieved a pCR.
At a median follow-up of 18.9 months, the two-year EFS was 95% for all participants. Among patients who achieved a pCR from SG alone, 2-year EFS was 100%, versus 92% in patients who had residual disease. However, there were only two EFS events during follow-up, so the numbers remain small and are likely not statistically significant.
Waterfall plot demonstrating best response by RECIST 1.1. Courtesy of Annals of Oncology
Of the exploratory biomarkers that were analysed, presence of a higher-than-average proportion of TILs or a high ki67 appeared to correlate with a greater magnitude of response. The baseline ki67 was 16.2% higher in patients with pCR (p=0.007), while 3/5 evaulable patients who achieved a radiological CR had a higher-than average ki67. Baseline TIL value was 24% higher in patients who achieved a pCR (p=0.002), and 4/5 patients who achieved a pCR had a high TILs percentage. There was no significant correlation between Trop-2 expression (p=0.440) or H-score (0.626).
In a study such as this it is also important to examine the additional systemic therapies patients received. Among patients who achieved pCR with SG alone:
Adjuvant doxorubicin + cyclophosphamide: 2
Adjuvant carboplatin + taxane: 5
Adjuvant docetaxel + cyclophosphamide: 7
No adjuvant systemic therapy: 1
The Bottom Line: first of all, we must address the limitations of NeoSTAR. Most obviously, it is a single-arm, investigator-led, non-controlled study, that only enrolled 50 patients. SG was not compared to standard therapies. Notably the current standard of care for neoadjuvant TNBC – ddAC + taxane + carboplatin + pembrolizumab as per KEYNOTE-522 and BrighTNess– was used in one patient who did not achieve a pCR with SG alone. So very few conclusions can be drawn about where SG may fit into the treatment paradigm of early TNBC. In addition, the broad array of additional neoadjuvant and subsequent adjuvant treatments muddy the waters, and the EFS data is very difficult to interpret given the small number of events.
However, there are several notable results are worth from NeoSTAR:
The overall pCR rate of patients was 30%. This is significantly lower than the 64.8% in KEYNOTE-522, despite on average patients being of higher risk in the latter study
For patients with stage I disease, the pCR rate was 50%. This emphasises the fact that risk of residual disease and treatment resistance is not solely a factor of tumour size or nodal involvement.
The treatment schema, where patients underwent neoadjuvant SG first, then underwent assessment for residual disease was interesting, and potentially opens the door for de-escalation of systemic treatment in patients with a good response to initial therapy. This could save patients both time and exposure to neoadjuvant therapy and raises the possibility of treatment personalisation, something that has not been possible in the NA TNBC space before.
However, it is worth noting that 14 participants proceeded directly to surgery after SG and were found to have residual disease, so imaging alone does not appear to be adequate in the assessment of residual disease.
The 2-year EFS rate was 95%, emphasising the overall effectiveness of treatments at our current disposal.
While it does not help us draw any definitive conclusions, NeoSTAR raises several important questions. Is it possible to move an ADC such as SG into the neoadjuvant space? Might we see neoadjuvant T-DM1 or T-Dxd for patients with HER-2 positive breast cancer in the future (a question currently under investigation with the phase II SHAMROCK study)? And is it possible to personalise and de-escalate therapy in the neoadjuvant space? This last question will doubtless raise many scientific and philosophical debates amongst clinicians, which will be fascinating to watch.
For now, all we can do is watch this space.
Source: Spring LM, Tolaney SM, Fell G et al. Response-guided neoadjuvant sacituzumab govitecan for localized triple-negative breast cancer: results from the NeoSTAR trial. Annals of Oncology. Vol 35 (3). Available from: https://www.annalsofoncology.org/article/S0923-7534(23)05107-4/fulltext
