DESTINY Calls For Daiichi Sankyo/AZ’s Enhertu In Other Indications
Gastric, Lung And Colorectal Data Promising
Executive Summary
Daiichi Sankyo and AstraZeneca’s ambitions to expand the use of their HER-2 targeted antibody-drug conjugate product beyond breast cancer are looking realizable on the back of new results presented at ASCO, but toxicities remain an issue.
New Phase II data for Daiichi Sankyo Co. Ltd./AstraZeneca PLC’s HER2-directed antibody-drug conjugate (ADC) Enhertu (trastuzumab deruxtecan) presented at ASCO reinforce its potential in three more tumor types where HER2 can play a role – gastric, lung and colorectal.
Enhertu was first launched for use in breast cancer in the US at the start of the year, but its potential in other cancer indications was a major factor in the multi-billion dollar deal the two companies struck in March last year.
Overall, the new data suggest that Enhertu has effective antitumor activity in all three HER2-positive tumor types, but as with the breast cancer indication, the drug comes with toxicities of myelosuppression and interstitial lung disease that will require careful management. The companies have instituted guidelines since the drug’s launch to increase awareness of the problems and say they are hopeful that they will be able to reduce their impact.
Enhertu seems to be able to take the efficacy of the original HER2-targeting agent, trastuzumab (Herceptin and biosimilars), which has had considerable success in breast and gastric cancers, a step further. The second-generation antibody drug conjugate consists of a humanized, monoclonal, anti-HER2 antibody bound to a cytotoxic topoisomerase I inhibitor (the drug ‘payload’) using a proprietary cleavable, tetrapeptide-based linker. The linker is stable in plasma but after internalization, it is cleaved by lysosomal enzymes such as cathepsins, which are overexpressed in cancer cells.
Enhertu is differentiated from Roche’s ADC Kadcyla (trastuzumab emtansine (trastuzumab-DM1) – which uses the tubulin inhibitor DM1 as the payload – in that it has a higher drug-antibody ratio (7-8 drug molecules per antibody, compared with 3-4 for Kadcyla) and the payload has a far higher membrane permeability, meaning it is able to exert a killing effect on neighboring tumor cells.
AstraZeneca’s oncology R&D chief José Baselga told Scrip all Enhertu’s attributes contributed to the clinical effects seen. “We have the combination of a good target and then you have an incredibly potent payload. This antibody is an engineering masterpiece: being able to put eight to ten payloads per antibody.” Then, he added, there was the bystander effect: the ability of the payload to reach neighboring cells that might not overexpress HER2 is an advantage in gastric cancer, for example, where there is heterogenous expression of the protein within the tumor.
Gastric Cancer
Gastric cancer is the most advanced of the additional disease settings under investigation, and the full results from the 187-patient registrational Phase II trial DESTINY-Gastric01 presented at ASCO expand the topline data in the third-line metastatic setting reported in January.
An estimated 15%-20% of advanced gastric and gastroesophageal junction cancers have overexpression or amplification of HER2. The DESTINY-Gastric01 study included patients from east Asia (Japan and South Korea) where HER2-positive gastric cancer is most prevalent and these data support the recent supplemental submission to the Ministry of Health, Labour and Welfare in Japan, where Enhertu has a Sakigake designation for this indication.
The ASCO data reveal the endpoint of confirmed objective response rate (ORR) was 42.9% with Enhertu monotherapy (6.4mg/kg) compared with 12.5% with investigator’s choice of chemotherapy (paclitaxel or irinotecan) in patients with HER2-positive unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma whose disease had progressed following two or more treatment regimens including Herceptin and chemotherapy. Unconfirmed ORR is the primary endpoint of the trial (51.3% [95% CI 41.9–60.5] versus 14.3% [95% CI 6.4–26.2]; p<0.0001). Both confirmed and unconfirmed ORR were assessed by independent central review.
Enhertu-treated patients had a 41% reduction in the risk of death compared with chemotherapy (hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.39-0.88; p=0.0097) at a pre-specified interim analysis. The median OS was 12.5 months versus 8.4 months with chemotherapy. See table for full data.
The safety and tolerability profile for the drug was consistent with that observed in the Phase I gastric cancer trial and previously reported studies The most common adverse events of grade 3 or higher were a decreased neutrophil count (in 51% of the trastuzumab deruxtecan group and 24% of the physician’s choice group), anemia (38% and 23%, respectively), and decreased white-cell count (21% and 11%). A total of 12 patients had Enhertu–related interstitial lung disease or pneumonitis (grade 1 or 2 in nine patients and grade 3 or 4 in three), as adjudicated by an independent committee.
Biomedtracker/Datamonitor Healthcare analysts said the data “certainly bode well” for the ongoing Phase II DESTINY-Gastric02 study which will be used to support planned filings in the US and Europe, “especially considering the unmet need presented by the trial’s patient population.” The product has recently received a US breakthrough therapy designation and orphan drug status for the gastric cancer indication, reflecting the poor prospects for these patients.
“Although Enhertu would not be the first HER2-targeting agent in the indication, the impressive objective response and OS data revealed indicate a high degree of efficacy in heavily pre-treated HER2-positive stomach cancer patients,” they said, adding that the “strong response seen in Enhertu-treated gastric cancer is an encouraging sign for the drug’s future in the indication.”
However, Enhertu is not the only HER2 antagonist in development for gastric cancer. Kadcyla was discontinued for use in gastric cancer but MacroGenics Inc.’s margetuximab, a Herceptin 'biobetter' is being investigated in the pivotal Phase II/III MAHOGANY trial in metastatic or locally advanced, treatment-naive, HER2-positive gastric or gastroesophageal junction cancer. The two may not go into direct competition any time soon though, the Biomedtracker analysts pointed out, as MAHOGANY is exploring margetuximab in frontline disease, whereas Enhertu is being initially investigated in heavily pre-treated patients.
Lung Cancer
Meanwhile, data from the ongoing 170-patient Phase II DESTINY-Lung01 trial also presented at ASCO show Enhertu produced clinically meaningful tumor responses in patients with HER2-mutant unresectable and/or metastatic non-squamous non-small cell lung cancer (NSCLC) whose disease had progressed following one or more systemic therapies.
Enhertu was recently granted US breakthrough therapy designation for the treatment of HER2-mutant metastatic NSCLC.
Daiichi Sankyo and AstraZeneca are positioning Enhertu as a therapy for patients with HER2-mutated NSCLC who have previously been treated with PD-1/PD-L1 inhibitors, an area of great unmet need for these patients who have few, if any, treatment options left.
The primary endpoint of confirmed ORR, assessed by independent central review, was 61.9% for patients treated with Enhertu monotherapy (6.4mg/kg). Patients achieved a disease control rate (DCR) of 90.5% with an estimated median progression-free survival (PFS) of 14.0 months. Median duration of response (DoR) and overall survival (OS) had not been reached at the time of data cut-off.
While the role of anti-HER2 treatment has been established in breast and gastric cancers, there are no HER2-directed therapies specifically approved for lung cancer, and this may work in Enhertu’s favor given the high toxicity burden also seen in this study.
As was the case in breast cancer, the promising efficacy profile is associated with a significant toxicity cost. The most common grade 3 or higher treatment-emergent adverse events were decreased neutrophil count (26.2%) and anemia (16.7%). There were five cases (11.9%) of confirmed treatment-related interstitial lung disease (ILD) and pneumonitis.
“With 64.3% of patients experiencing grade 3 or higher treatment-emergent adverse events (TEAEs), the side effect profile is concerning,” said the Biomedtracker/Datamonitor Healthcare analysts. “Additionally, there were high rates of dose interruption (59.5%), dose reduction (38.1%), and treatment discontinuation (23.8%) due to TEAEs. A path forward in this indication will likely require finding a way to balance Enhertu’s safety and efficacy.”
There are a number of other therapies in development for this setting, but Enhertu’s efficacy data look competitive. “Although these data are still preliminary and there are some patient population differences, the overall response rate (ORR) of 61.9% compares very favorably to other pipeline therapies such as the combination of [Mirati Therapeutics Inc.'s small molecule multi-target kinase inhibitor] sitravatinib plus Opdivo (nivolumab) (ORR = 28.6%), and [Sanofi’s antibody-drug conjugate], SAR408701 (ORR = 22.7%),” the analysts added. “If Enhertu demonstrates a better risk/benefit profile in patients with HER2-mutated NSCLC, which accounts for approximately 2–4% of the NSCLC market, it could dominate in this subgroup of patients.”
Colorectal Cancer
In colorectal cancer, the first results from the 78-patient Phase II DESTINY-CRC01 trial showed clinically meaningful activity in patients with HER2-positive unresectable and/or metastatic colorectal cancer who received at least two prior lines of standard treatment.
Like the lung indication, there are currently no drugs specifically approved for HER2-positive colorectal cancer, which affects approximately 2-5% of patients with colorectal cancer.
The primary endpoint of confirmed ORR, assessed by independent central review, showed 45.3% of patients with HER2-positive (defined as IHC3+ or IHC2+/ISH+) advanced colorectal cancer treated with Enhertu monotherapy (6.4mg/kg) achieved a tumor response.
A disease control rate (DCR) of 83.0% was observed with a median progression-free survival (PFS) of 6.9 months. Median duration of response (DoR) and OS have not yet been reached.
However, no responses were seen in two exploratory cohorts enrolled patients with tumors with lower levels of HER2 expression (IHC2+/ISH- and IHC1+, respectively).
The ORR of 45.3% and disease control rate of 83.0% in 53 patients with HER2-positive colorectal tumors, did not quite match the ORR of 60.9% reported in Enhertu’s similar Phase II trial in breast cancer, but is nonetheless indicative of “remarkable” anti-tumor activity in HER2-positive metastatic colorectal cancers, the Biomedtracker/Datamonitor Healthcare analysts said.
“This will no doubt build off the drug’s strong performance in breast cancer, and while HER2 is not as common a therapeutic target in colorectal cancer, with only 2–5% of all patients overexpressing the protein, the resistance to conventional EGFR and HER1-based interventions such as Erbitux and Vectibix seen in such patients presents a high unmet need,” they added.
Again, Enhertu is unlikely to be without competition in metastatic colorectal cancer. Other HER2-targeting drugs also in Phase II development in HER2-positive CRC patients include Puma Biotechnology Inc.’s kinase inhibitor, Nerlynx (neratinib) and Seattle Genetics Inc.’s Tukysa (tucatinib).
Tukysa, a tyrosine kinase inhibitor of the HER2 protein, has just been launched in the US for breast cancer following a swift approval by the US FDA under Project Orbis, a collaborative effort between multiple international regulators to simultaneously review new oncology drugs. (Also see "Seattle Genetics Win Early US FDA Approval For Tukysa, Plans Rapid Launch" - Scrip, 17 Apr, 2020.)
Seattle Genetics also recently reported interim results from its Phase II MOUNTAINEER trial in colorectal cancer of an ORR of 52.2%, slightly better than that seen in DESTINY-CRC01, albeit with a smaller sample size. The MOUNTAINEER regimen also incorporates trastuzumab, noted the Biomedtracker analysts. “This dual blockade approach may potentially be more active, but the greater specificity granted by the targeted nature of Enhertu’s conjugate of trastuzumab and deruxtecan may also result in lower toxicity.
“A full appraisal of the ADC in colorectal cancer and of how it compares with other HER2-targeting agents will thus require more mature data from both Enhertu’s ongoing study and those of its rivals.”
Editor's note: This article was updated on 8 June to clarify the primary endpoint for the DESTINY-Gastric01of unconfirmed ORR