Focus on These Data When Making Treatment Decisions in Breast Cancer

Komal Jhaveri, MD

During a Targeted Oncology^TM Case-Based Roundtable event, Komal Jhaveri, MD, the section head of the Endocrine Therapy Research Program, clinical director, of Early Drug Development Service, and a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, NY, discussed the case of a 63-year-old patient with HER2-positive metastatic breast cancer.

Targeted Oncology^TM: How typical is the presentation of this patient in your clinical practice, and what data are most relevant to you in choosing a treatment approach?

JHAVERI: According to the recently updated NCCN [National Comprehensive Cancer Network] guidelines in systemic therapy options for recurrent stage IV disease, we use a taxane with a dual HER2 blockade, which is trastuzumab and pertuzumab in the first line.¹ This is obviously based on the unprecedented progression-free survival [PFS] and overall survival [OS] benefit in the CLEOPATRA trial [NCT00567190].² The paclitaxel was based out of a phase 2 trial that was conducted by my colleague, Chau Dang, MD, here at Memorial Sloan Kettering Cancer Center, and we did not see any febrile neutropenia with the paclitaxel, so that has really become our go-to regimen in the first line.³

What data support treatment options in the second-line setting?

In the second-line setting, we have data from the EMILIA trial (NCT00829166), which led to T-DM1, or ado-trastuzumab emtansine, an antibody-drug conjugate [ADC], the first one for breast cancer.⁴ This is despite this trial not having patients progressing on trastuzumab, but in clinic this is our contemporary choice...for our patients. Additionally, we have a plethora of options that patients can receive on the third line and beyond. These include tucatinib [Tukysa] plus trastuzumab plus capecitabine [Xeloda] and fam-trastuzumab deruxtecan-nxki [Enhertu].1 We also have other chemotherapies with trastuzumab, such as capecitabine with trastuzumab and capecitabine with other TKIs [tyrosine kinase inhibitors]. There are targeted therapies, including a recent approval for margetuximab-cmkb [Margenza], an Fc-optimized antibody that was approved for use with chemotherapy in this last year.⁵

We have these many options, but what we do not know is the optimal sequence for third-line therapy and beyond.

Now, what is interesting here is that the triplet of tucatinib plus trastuzumab plus capecitabine, per the NCCN guidelines, is preferred in patients with both systemic and CNS progression on ado-trastuzumab emtansine.1 However, it may be given even in the second-line setting. Fam-trastuzumab deruxtecan is preferred in patients with visceral metastases [if there is disease] progression on ado-trastuzumab emtansine. [However, it is] contraindicated for patients with known pneumonitis or interstitial lung disease.

What makes this ADC special? Why is it distinct from T-DM1?

I think there are a few key attributes that we might want to think of [in] T-DXd [trastuzumab deruxtecan]. One is that the drug-to-antibody ratio [DAR] is 8 molecules of chemotherapy that can be delivered. Now, to put this into context when we think of T-DM1 therapy, that DAR is 3.5. So we are delivering more chemotherapy to the tumor cell. The payload itself is a topoisomerase I inhibitor, which we do not regularly use for our HER2- positive patients.

It is a highly potent payload, which the patients have not seen...in their regimens, and it has a very short half-life, so the free payload has a very short half-life, which is great. The linker is stable, and it is a tumor selective cleavable linker. Once this is delivered to the tumor, it is the pepsin in the tumor that makes the linker cleave and then deliver the payload. It is very tumor selective, so one can potentially expect less off-target toxicity.

And another important attribute to keep in mind is the bystander effect. It has membrane permeability, and so this payload can be membrane permeable and go to the neighboring cells, which might not necessarily be HER2 overexpressing. But that is why we have also seen activity in what we now call HER2 low, which is HER2 IHC 1+ and 2+ patients who have shortened benefit with T-DXd and other novel inhibitors that are also being developed and have this bystander effect. Of note, T-DM1 does not have that. And as we know, we do not utilize T-DM1 for patients who do not have HER2-amplified or HER2- expressive tumors.

Please discuss how the DESTINY-Breast01 trial [NCT03248492] has affected decisions for this patient.

[These data that] led to the approval of trastuzumab deruxtecan [were from] an open-label, multicenter, phase 2 trial [that enrolled] patients 18 [years] or older with unresectable metastatic breast cancer who had centrally confirmed HER2-positive disease and who had prior T-DM1.6,7 Patients with a history of interstitial lung disease were excluded.

This was because [of what] we had already learned from an adjudication committee that was put in place with the phase 1 experience of this agent. And stable, treated brain metastases were allowed to enroll on this trial. These patients were then enrolled in 2 parts. Part 1 included a PK [pharmacokinetic] stage and a dose-finding stage. In the PK stage, we studied 3 doses of which two, 5.4 mg/kg and the 6.4 mg/kg, moved on to the dose-finding stage. Based on the PK data and the safety data, the 5.4 mg/kg [dose] was selected to move forward and is the current recommended and approved dose.

This was the dose that moved into the continuation stage, where most of the patients had TDM-1 resistant disease. There were 4 patients who had TDM-1 intolerance, for a total of 184 patients [who] were treated with this dose, 5.4 mg/kg, with a primary end point of ORR [overall response rate]. One thing that I would like to highlight is that these patients have received up to 6 prior lines of therapy, and [approximately] two-thirds received prior pertuzumab therapy.

Additional baseline characteristics [also should be considered]. Median age was [approximately] 55 years. These were patients predominantly with a good performance state. [Approximately] 50% of these patients were hormone receptor positive. [Approximately] 84% had HER2 positivity by IHC 3+ expression. The remaining were IHC 2+ or 1+ or ISH [in situ hybridization] positive. Visceral disease was present in 92% of patients, of whom 57% had lung metastases. This is important to remember for the discussion of our case. Liver metastases were present in 30%, and the rest also had bone disease. There were 24 [13%] of these patients enrolled in the trial who also had stable, treated brain metastases.

How do the updated data from the DESTINY-Breast01 trial affect treatment decisions?

In the updated DESTINY-Breast01 trial data from June 2020, all but 4 patients had tumor shrinkage.⁸ The overall response rate, despite this [population being] heavily treated with a median of 6 prior lines of therapy, was 61.4%, including patients who had a complete response. The median duration of response, which is also very important to understand for our patients who are heavily pretreated, was 21 months in this phase 2 trial. And this response was seen rather early: time to response was 1.6 months. So if you are really worried about somebody with extensive disease or burdened disease, this was a quick response with this drug.

The median PFS in DESTINY-Breast01 was 19.4 months. This is rather impressive for such a heavily pretreated population. Just to put this into context and into perspective, when we think of other trials in the third line and beyond, whether it was the TH3RESA trial [NCT01419197] that studied TDM-1 with physician choice therapy, the NALA study [NCT01808573], the HER2CLIMB study [NCT02614794], or the SOPHIA trial [NCT02492711], the median PFS for the patient population [in the] third line [was approximately] 7 to 8 months.^9-12 The PFS [in DESTINY-Breast02] of 19.4 months—in such a heavily pretreated population, I think it is really unprecedented.8 The median OS data at 21 months was 25 months, but what I would really like to highlight here is that this is just 35% maturity of data, and we really need follow-up maturity now to understand the implications. [Approximately] 119 patients were already censored, and 17 were thought to have events at month 2, so at 18 months we had 74% alive, but [these are] still immature data.

Did these data show progression of disease in other areas?

A subgroup analysis for the 24 patients [13%] in the CNS subgroup was presented at ASCO [American Society of Clinical Oncology Annual Meeting] this year.¹³ Seventeen patients had brain lesions at baseline, and the data [were] available to evaluate responses in the brain for 15 of the 17. Though this was a small subgroup, it was important that there were responses seen in patients with stable brain metastases; 41% had a partial response and another 41% had disease stabilization in the brain. Again, this subgroup also had median of 6 lines of therapy, the same as the total population. Median follow-up here was 11 months, and...in the CNS subgroup, the ORR, PFS, and duration of response were comparable to those in the total patient population treated at the same dose. The median PFS in this population with brain metastases was 18 months [95% CI, 6.7-18.1]. There was also an additional case report where we saw 55% regression of a metastatic brain lesion.

The most common sites when we looked at progression were the liver, lung, and lymph nodes, which was similar in all patients total and the CNS subgroup. Meaning, once you were in the CNS subgroup or the total patient population and then you progressed, the common types of progression were within the liver, lungs, and lymph nodes. Progression in the brain was not as common. There were only 4 of 48 patients who had progressed in the brain, including 2 out of the 8 patients with baseline CNS metastases.

What is the safety profile of T-DXd?

I think the most common adverse events [AEs] that we see, and that were seen in more than 10% of the patients in the study, were nausea, vomiting, alopecia, fatigue, and neutropenia.¹⁴ But an important AE that we want to keep in mind is the drug-related ILD [interstitial lung disease] or pneumonitis. The ILD incidence that was reported initially with the August 2019 data cutoff was 25 patients [13%] who developed ILD or pneumonitis. The majority had grade 1 or grade 2 ILD or pneumonitis; however, there were 4 fatal events. The median time to developing ILD was 4.1 months. At the additional 1-year cutoff, and overall median cutoff, there were 3 additional ILD cases determined by the independent adjudication committee.

ILD events were seen mostly within the first 12 months, and after the 12-month mark, only 1 patient developed ILD, perhaps suggesting that ILD is not a cumulative AE. But this is something that we really must be aware of, and not just us, but also our frontline nursing staff who are fielding the calls when the patient calls in. [If there are symptoms that may indicate ILD or pneumonitis,] whether they have shortness of breath, a new cough, extreme fatigue, [we need] to quickly interrupt therapy, get pulmonology involved, and give patients steroids. [There are] patients who are asymptomatic, [so we have] to keep a very close eye on this to make sure that we are not missing anything.

We have become more trained look for these [potential AEs] given that there are so many classic agents with breast cancer that cause pneumonitis: checkpoint inhibitors and everolimus, and [also] CDK4/6 inhibitors....I think we all have become a little more vigilant about keeping a close eye on symptoms for our patients and for also for keeping an eye on the scans to make sure that we are not missing the so-called ground glass opacities for which we might want to interrupt or discontinue therapy. Fortunately, the heart events or cardiac events were very low, including left ventricular ejection fraction decreases or cardiac failure, as is seen with trastuzumab.

What was the design of the HER2CLIMB phase 2 trial?

[Let’s move on] then to the phase 2 HER2CLIMB trial of tucatinib [Tukysa] and capecitabine and trastuzumab, which studied patients with HER2-positive metastatic disease who had prior treatment with trastuzumab, pertuzumab, and T-DM1.¹⁵ What was key in the study was that active brain metastases not needing local therapy were allowed, but they were not required. So you could have had treated, stable brain metastases, but you were also allowed to have active brain metastases. What is important to remember here is that these are patients with small tumors, less than 2-cm tumors, who do not have symptoms warranting local therapy. They did not require immediate radiation and they were [still] considered eligible.

[More than] 600 patients were enrolled—410 in the tucatinib arm and 202 in the placebo arm.15 And they were well-balanced groups with a median age of [approximately] 55 years, all with predominantly good performance status; 60% were hormone receptor positive; overall, they had received 4 prior lines of therapy. Forty-eight percent had a history of brain metastasis. Of these 48%, 60% [of the brain metastases] were stable and treated. The remaining were what was called active, which could be untreated brain metastases. Untreated [meant] no local therapy or systemic therapy or [that they had been] treated in the past with some kind of local therapy but [were] progressing again. Even though they are progressing again, they are not symptomatic enough to warrant additional local therapy.

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_{8. Modi S, Saura C, Yamashita T, et al. Updated results from DESTINY-breast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd) in HER2 positive metastatic breast cancer. Abstract presented at: San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Accessed August 20, 2021. https://www. sabcs.org/Portals/SABCS2016/2020%20SABCS/ALL%20ABSTRACTS%202-9. pdf?ver=2020-12-09-104626-337}

_{9. Krop IE, Kim SB, Martin AG, et al. Trastuzumab emtansine vs treatment of physician’s choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol. 2017;18(6):743-754. doi:10.1016/S1470-2045(17)30313-3}

_{10. Saura C, Oliveira M, Feng YH, et al. Neratinib plus capecitabine vs lapatinib plus capecitabine in HER2-Positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: phase III NALA trial. J Clin Oncol. 2020;38(27):3138-3149. doi:10.1200/JCO.20.00147}

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_{12. Rugo HS, Im SA, Cardoso F, et al. Efficacy of margetuximab vs trastuzumab in patients with pretreated ERBB2-positive advanced breast cancer: a phase 3 randomized clinical trial. JAMA Oncol. 2021;7(4):573-584. doi:10.1001/jamaoncol.2020.7932}

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_{15. Enhertu. Prescribing information. Daiichi Sankyo, Inc; 2021. Accessed August 20, 2021. https://bit.ly/3hkf3mN}