AstraZeneca’s Enhertu demonstrated a 72% reduction in the risk of disease progression or death in HER2-positive metastatic breast cancer according to trial results presented at the European Society for Medical Oncology (ESMO) congress, while early trial results of another two-drug combination has been shown to shrink tumours in half in patients with low-grade serous ovarian cancer.
The phase 1 ovarian cancer trial, led by a team at the Institute of Cancer Research (ICR) in London and the Royal Marsden NHS Foundation Trust, tested the drugs VS-6766 and defactinib in patients with low-grade serous ovarian cancer. The results were so successful a phase 2 trail is already under way.
The pair of drugs, which work together to block the signals cancer cells need to grow, could offer a new treatment option for women with a specific type of ovarian cancer that rarely responds to chemotherapy or hormone therapy.
Researchers are “delighted with the outcome”, and hope it will offer a significant advance in treatment if the results are replicated in larger trials.
This type of cancer tends to develop at a younger age, less than 13% of patients respond to chemotherapy, and less than 14% respond to hormone therapy. Trial results show that of the 24 patients evaluated, 46% saw their tumours shrink significantly in response to the treatment.
The outcomes were even better in patients with a particular mutation, with 64% who have KRAS-driven tumours seeing them shrink after treatment. The researchers said this indicated that tumour profiles could be used to identify which patients are most likely to benefit from the new treatment.
Participants in the trial, aged from 31 to 75, lived for an average of 23 months before their cancer progressed.
“Overcoming cancerʼs ability to evolve resistance to treatment is a huge challenge for cancer research,” said Prof Kristian Helin, the chief executive of the ICR. “This study has turned a deep understanding of how cancer fuels its growth and develops resistance into a highly targeted treatment for patients who currently have few treatment options.”
Dr Susana Banerjee, also from the ICR and consultant medical oncologist and research lead at the Royal Marsdenʼs gynaecology unit, said: “If these findings are confirmed in larger trials, theyʼll represent a significant advance in low-grade serous ovarian cancer treatment.”
The combination treatment worked even in patients who had already received an MEK inhibitor – something which can cause tumours to shrink but tends to stop working as tumours develop resistance to treatment – before the study, Banerjee said.
Separately at the congress, the DESTINY-Breast03 trial of new drug Enhertu (trastuzumab deruxtecan) to treat a form of breast cancer was hailed as “groundbreaking”, with results said to suggest a strong trend towards improved overall survival.
AstraZeneca said Enhertu demonstrated a 72% reduction in the risk of disease progression or death in women with HER2-positive metastatic breast cancer compared with a different medicine.
The trial, involving about 500 patients in Asia, Europe, North America, Oceania and South America, found “a strong trend towards improved overall survival” with Enhertu. But it was also pointed out that this analysis was “not yet mature and is not statistically significant”.
Dr Kotryna Temcinaite, a senior research communications manager at Breast Cancer Now, said: “These are incredibly promising results, and we now hope that further research will show whether this treatment could also offer patients precious extra time to live and be there for more moments that matter.
“It is fantastic to see that Enhertu could give hundreds of people with HER2 positive incurable secondary breast cancer the chance of more time before their disease progresses.”
After 15.5 and 13.9 months of follow-up in the Enhertu and trastuzumab emtansine (T-DM1) arms, respectively, the median progression-free (PFS) for patients treated with Enhertu was not reached compared to 6.8 months for T-DM1 as assessed by blinded independent central review (BICR).
Three-fold improvement in PFS
In the key secondary endpoint of PFS assessed by investigators, patients treated with Enhertu, which is being developed with Japan’s Daiichi Sankyo , Enhertu experienced a three-fold improvement in PFS of 25.1 months versus 7.2 months for T-DM1. A consistent PFS benefit was observed in key subgroups of patients treated with Enhertu, including those with a history of stable brain metastases.
There was a strong trend towards improved overall survival (OS) with Enhertu, however this analysis is not yet mature and is not statistically significant. Nearly all patients treated with Enhertu were alive at one year (94.1%) compared to 85.9% of patients treated with T-DM1.
Could become the new standard of care
Dr Javier Cortés, head, International Breast Cancer Center (IBCC), Barcelona, Spain, said: “Patients with previously treated HER2-positive metastatic breast cancer will typically experience disease progression in less than a year with available HER2-directed treatments. The high and consistent benefit seen across efficacy endpoints and key subgroups of patients receiving Enhertu in DESTINY-Breast03 is remarkable and supports the potential of Enhertu to become the new standard of care for those who have previously been treated for HER2-positive metastatic breast cancer.”
Susan Galbraith, executive vice president, Oncology R&D at AstraZeneca, said: “Today’s results are ground-breaking. Enhertu tripled progression-free survival as assessed by investigators, and provided a disease control rate exceeding 95% compared to 77% for T-DM1 in DESTINY-Breast03. In addition, the safety profile was encouraging with no Grade 4 or 5 interstitial lung disease events in this trial. These unprecedented data represent a potential paradigm shift in the treatment of HER2-positive metastatic breast cancer, and illustrate the potential for Enhertu to transform more patient lives in earlier treatment settings.”
DESTINY-Breast03 is the first global phase 3 head-to-head trial of Enhertu against an active control and supports the potential of this medicine to become the new standard of care for patients with HER2-positive metastatic breast cancer following initial treatment with trastuzumab and a taxane, said Ken Takeshita, global head, Research and Development at Daiichi Sankyo.
“We believe this highly sophisticated and specifically engineered ADC is fulfilling its promise to reshape the treatment of HER2-positive metastatic breast cancer, with the goal to move into earlier lines of treatment for HER2-positive breast cancer and many other HER2-expressing tumour types across our broad clinical trial programme.”
Trastuzumab deruxtecan is already an FDA-approved agent for adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. It was granted accelerate approval in 2020 based on results from the DESTINY-Breast01 trial, in which trastuzumab deruxtecan clinically meaningful and durable activity in a heavily pretreated patient population with HER2-positive metastatic breast cancer.
First study details
725MO Phase I study of the combination of the dual RAF/MEK inhibitor VS-6766 and the FAK inhibitor defactinib: Results of efficacy in low grade serous ovarian cancer
Presented at the ESMO Congress by Susana Banerjee, 19 September 2021
Patients with low grade serous ovarian cancer (LGSOC) have limited response to conventional chemotherapy and hormonal therapy. Recently, MEK inhibitors have shown an overall response rate (ORR) 15-26%. Activation of p-FAK is a possible mechanism of resistance to MEK inhibitors and we hypothesised combination of a RAF/MEK inhibitor with a FAK inhibitor would overcome this.
We explored the safety, pharmacokinetics and pharmacodynamics in the dose escalation study and recommended a phase two dose of the combination of RAF/MEK inhibitor VS-6766 3.2 mg twice a week and the FAK inhibitor defactinib 200 mg twice daily, both administered 3 out of 4 weeks in 28 day cycles in a highly intermittent dosing schedule. We evaluated confirmed responses using RECIST 1.1. We present the efficacy of the combination in patients with LGSOC in this trial so far.
Currently, 25 patients with LGSOC have been treated with 24 evaluated for response, median age 57 (range 31 to 75 years) and median previous lines of therapy 4 (range 1 to 9). Of the 24 evaluable patients, 11 (46%) had KRAS mutations and 10 (42%) received prior MEK inhibitor treatment. The most common adverse events were rash and CK elevation which were predominantly grade 1/2. The overall response rate in all patients was 46% (11/24, 95% CI: 28% to 65%), with ORR of 64% (7/11, 95% CI: 35% to 85%) in patients with KRAS mutations, and 44% (4/9, 95% CI: 19% to 73%) in patients with KRAS wildtype tumours. Four patients had undocumented KRAS status. Responses were observed in patients with and without prior MEK inhibitor treatment. The median progression free survival was 23 months for the whole cohort, 13/24 patients are still on study and updated results will be presented.
An intermittent dosing schedule of the combination of VS-6766 and defactinib has shown encouraging clinical activity in patients with recurrent LGSOC. These data support an ongoing registration-directed study of VS-6766 ± defactinib in patients with recurrent LGSOC (ENGOT-ov60/NCRI/GOG-3052; NCT04625270).
Second study details
Trastuzumab Deruxtecan shows superior PFS versus T-DM1 in HER2+ unresectable/metastatic breast cancer
Presented at the ESMO Congress by Javier Cortés on 18 September 2021
T-DXd is a HER2-targeting antibody–drug conjugate approved for pts with advanced HER2+ mBC based on the results from DESTINY-Breast01 (NCT03248492). This is the first report of DESTINY-Breast03 (NCT03529110), a multicenter, open-label, randomized phase 3 study comparing the efficacy and safety of T-DXd vs T-DM1 in pts with HER2+ mBC previously treated with trastuzumab and taxane. This is the first reported randomised study of T-DXd in BC.
Pts were randomised 1:1. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR). Secondary endpoints include overall survival (OS), objective response rate (ORR), duration of response, PFS by investigator, and safety.
As of May 21, 2021, 524 pts were randomised. Median age was 54 years (range, 20-83). The hazard ratio (HR) for PFS was 0.2840 (P = 7.8 x 10-22); median PFS not reached for T-DXd vs 6.8 mo for T-DM1. The estimated 12-month OS event rates were 94.1% (95% CI, 90.3-96.4) for T-DXd and 85.9% (95% CI, 80.9-89.7) for T-DM1; HR: 0.5546 (95% CI, 0.3587-0.8576; P = 0.007172 did not cross pre-specified boundary for significance). Median treatment duration was 14.3 mo (range, 0.7-29.8) with T-DXd vs 6.9 mo (range, 0.7-25.1) with T-DM1; similar rates of TEAEs were observed. No drug-related deaths occurred in either arm. Adjudicated drug-related interstitial lung disease (ILD) occurred in 10.5% of pts with T-DXd (most [9.7%] grade 1/2; 0 grade 4/5) vs 1.9% with T-DM1 (all grade 1/2).
ESMO presentation of LBA1 – Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (Pts) with HER2+ metastatic breast cancer (mBC): Results of the randomised phase III DESTINY-Breast03 study (Open access)
Oncology congress article – 725MO – Phase I study of the combination of the dual RAF/MEK inhibitor VS-6766 and the FAK inhibitor defactinib: Results of efficacy in low grade serous ovarian cancer (Open access)
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