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We will next discuss ADCs, which consist of a monoclonal antibody specific to a cell surface protein (ideally one abundant in tumors and absent in normal tissues) conjugated to a potent cytotoxic agent through a linker. Once bound to its antigen on a tumor cell, the ADC is internalized and the linker releases the toxin, leading to tumor cell death. Some linkers are enzymatically cleavable whereas others are not, but in either case, the cytotoxic payload has to be relatively potent because only a limited amount of the drug will enter the cells.
An illustrative HER2-targeted ADC is T-DM1, which consists of trastuzumab conjugated via a stable thioether linker to DM1 (emtansine), a highly potent tubulin destabilizer.
This slide shows the mechanism of action of HER2-targeted ADCs. As mentioned, the antibody will bind to the receptor, the ADC will be endocytosed, and it will then release the cytotoxic payload into the cell.
One benefit to using an ADC with a cleavable linker is that it may be more active in cells with lower levels of HER2 expression (ie, IHC 1+, 2+). In addition, these agents may have CNS activity. Lastly, these ADCs can potentially kill nearby cells through a “bystander effect” where the ADC binds the target but releases the payload before internalization. Alternatively, if the internalized drug readily passes through the cell membrane, the drug may escape from the cell into the intercellular space, where it can then affect neighboring cells.
The most notable differences between the early ADCs and the new generation of ADCs are, first, that the newer compounds have reduced immunogenicity because they are chimeric or humanized antibodies rather than mouse antibodies. Second, the new ADCs are stable in circulation. Third, the new ADCs have linkers that can release the drug within the cell. Fourth, the drugs have moved away from typical chemotherapy agents (eg, doxorubicin) and toward highly potent cytotoxic agents such as auristatin, maytansine, and calicheamicin. In addition, the newer agents have a higher drug:antibody ratio.
T-DXd (formerly DS-8201) is a humanized anti-HER2 monoclonal antibody conjugated to an exatecan derivative via a tetrapeptide-based cleavable linker.[40-42] This payload is a topoisomerase inhibitor like irinotecan, but 10 times more potent. T-DXd is very stable in plasma and has high potency. In addition, it provides the bystander killing effect because it has a cleavable linker. T-DXd is unique in that it has a high drug:antibody ratio of 8:1, meaning on average of 8 molecules of the cytotoxic payload are attached to each antibody. By comparison, T-DM1 has a drug:antibody ratio of approximately 3.5 emtansine molecules attached to each antibody.
T-DXd was granted accelerated approval on December 20, 2019, by the FDA for the treatment of adults with unresectable or metastatic HER2-positive breast cancer who have received at least 2 previous lines of anti–HER2-based regimens for metastatic disease. The approval was based on the results from the DESTINY-Breast01 trial, which we will review now.
In DESTINY-Breast01, 249 patients with heavily pretreated, relapsed, HER2-positive, unresectable breast cancer or MBC received T-DXd every 3 weeks.[44,45] This was a 2-part study, with part 1 assessing doses ranging from 5.4-7.4 mg/kg and part 2 evaluating just the 5.4-mg/kg dose (n = 184).
Patients enrolled on this trial had a median of 6 previous lines of therapy, and all patients had received trastuzumab and T-DM1; 66% had received pertuzumab. Also, more than one half of the patients were ER positive. Most (83.7%) had high HER2 expression (IHC 3+).
In the patients treated with 5.4 mg/kg, the ORR was 60.9%, with 11 patients (6%) achieving a CR.[44,45] The disease control rate was 97% and the median duration of response was nearly 15 months. These are dramatic results in such a heavily pretreated patient population, and substantially better than what we have seen with other HER2 TKIs or trastuzumab with chemotherapy.
A subgroup analysis of responses showed that previous pertuzumab did not preclude responding to T-DXd. In fact, responses were seen across all subgroups analyzed, including patients with brain metastases and those with HER2-positive tumors that were IHC 1+ or 2+.
With the caveat that this is an early phase I/II study with a median follow-up of 11.1 months, the median PFS was more than 16 months (and more than 18 months in the 24 patients with brain metastases). The median OS has not yet been reached. Even with the short follow-up, these are some of the best results seen in this setting to date.
The safety profile was fairly tolerable, with the exception of ILD, which we will discuss next.[44,45] Other common AEs included grade 1/2 nausea, fatigue, alopecia, vomiting, and constipation. There was some diarrhea, predominantly low grade. Grade ≥ 3 anemia and neutropenia were also observed, but this regimen was fairly well tolerated overall.
On this study, there were 25 ILD events, of which 4 resulted in death. The median time to ILD onset was 193 days (range: 42-535). Seventeen of 20 patients with grade ≥ 2 ILD received corticosteroids. At the time of analysis, 7 patients had recovered, 2 are recovering, and the fates of 12 are unknown.
Regarding the grading of ILD, grade 1 is asymptomatic—essentially disease found on CT scans. In my experience, it is important not to assume that infiltrate seen on CT is benign disease in patients receiving T-DXd. Grade ≥ 2 is symptomatic ILD, with symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms.
Even in an asymptomatic patient, if there is any evidence of ILD on CT, we have to taper off the drug and start the patient on steroids. If the ILD resolves within 28 days, treatment can be restarted. If the patient has symptomatic ILD, we have to stop the drug and start the patient on steroids. In either case, a pulmonary consultation is required as well.
As mentioned, T-DXd was granted accelerated approval on December 20, 2019, by the FDA for the treatment of adults with unresectable or metastatic HER2-positive breast cancer who have received at least 2 previous lines of anti–HER2-based regimens for metastatic disease.
The approved dose is 5.4 mg/kg IV every 3 weeks. Clinicians should monitor blood counts before each administration and assess left ventricle ejection fraction both before and during treatment. And of course, clinicians need to remain highly alert for any signs of ILD.
DESTINY-Breast02 is a randomized, open-label phase II trial comparing T-DXd vs chemotherapy in patients with HER2-positive MBC who had progressed on at least 3 lines of therapy including T-DM1 and other HER2-targeted agents (planned N = 600). This trial excludes those with CNS metastases. Patients will be randomized to T-DXd at 5.4 mg/kg every 3 weeks (planned n = 400) or to physician’s choice of trastuzumab plus capecitabine or lapatinib plus capecitabine (planned n = 200). The primary endpoint is PFS with secondary endpoints including OS and responses.
This trial is an FDA-required confirmatory study that has almost completed accrual (March 2020). Hopefully, we will see the results soon.
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