Key Data Illuminate New Directions in HER2-Positive Metastatic Breast Cancer Landscape

Virginia G. Kaklamani, MD

An abundance of riches in the form of new data for HER2-targeted agents continues to drive progress for patients with metastatic breast cancer. Efforts to address disease have resulted in the repurposing and movement of established agents in lines of therapy, the designing of basket and adaptive trials used to explore therapeutic avenues, and the development of novel agents to fill clinical gaps for patients with limited options.

There was no shortage of data for patients with HER2-positive metastatic breast cancer at the 2021 San Antonio Breast Cancer Symposium (SABCS). Investigators arrived with updates from several key trials, including the following:

• DESTINY-Breast03 (NCT03529110): a phase 3 study evaluating fam-trastuzumab deruxtecan-nxki (Enhertu) vs ado-trastuzumab emtansine (T-DM1; Kadcyla) in patients with HER2-positive, unresectable and/or metastatic breast cancer, previously treated with trastuzumab (Herceptin) and a taxane¹;
• PHOEBE (NCT03080805): a phase 3 trial examining pyrotinib plus capecitabine vs lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer²; and
• SUMMIT (NCT01953926): a phase 2 basket study evaluating the efficacy of neratinib added to trastuzumab with or without fulvestrant among patients with triple-negative breast cancer (TNBC) and those with hormone receptor–positive, HER2-negative, HER2-mutant breast cancer.³

As part of an OncLive^® Breast Cancer Talk, Virginia G. Kaklamani, MD, moderated a discussion of the top takeaways from SABCS 2021 with a panel of breast cancer experts including Anne P. O’Dea, MD; Yara Abdou, MD; and Heather McArthur, MD.

In addition to discussing updated data from the landmark trials, the panel shared insights on 2 novel bispecific agents and how the landscape may be shifting toward leveraging these agents in the future. Data from 2 phase 1 trials were discussed:

• NCT03619681: evaluating KN026, a f irst-in-human HER2 bispecific antibody in combination with chemotherapy for patients with HER2-positive advanced breast cancer,⁴ and
• NCT02892123: evaluating zanidatamab in combination with chemotherapy for patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab (Perjeta), and T-DM1.⁵

Finally, the panel turned their attention to a read out from the I-SPY 2 Trial (NCT01042379), in which investigators explored the rationale of adding tucatinib to a taxane and dual HER2 blockade.⁶ Results ranged from promising to null and void, leaving investigators with clear directions on which avenues are worth pursuing in future endeavors and which ones are proving to be dead ends.

O'Dea: [Prior to SABCS 2021], Sara Hurvitz, MD, presented [data from] key subgroups for DESTINY-Breast03 at the European Society for Medical Oncology [ESMO] Annual Congress 2021. She specifically talked about the patients who had clinically stable brain metastasis [at baseline]—15% of the overall trial population [n = 524].¹ She reminded us that in some of the data presented at ESMO the objective response rate was much better, of course, for trastuzumab deruxtecan regardless of subgroup. Whether you look at estrogen receptor status, presence of visceral metastasis, or number of lines of prior therapy, whatever subgroup you look at the objective response rate was much better with trastuzumab deruxtecan compared with T-DM1. The objective response rate was 79.7% [with trastuzumab deruxtecan (n = 261)] with a very impressive hazard ratio of 0.28.

What they then looked at in more detail and [and presented at SABCS] was the key subgroup of patients with brain metastasis…and they gave us a lot of granularity on the data in terms of [, for instance, the] intracranial [results (Table¹)]. If we look at the median progression-free survival [PFS] with trastuzumab deruxtecan, it was 15 months compared with 3 months with T-DM1 with a hazard ratio of 0.25. If we look specifically at intracranial responses, of the 72 patients with brain metastasis [who had target or nontarget lesions at baseline by imaging], the intracranial objective response rate was 63.9% with trastuzumab deruxtecan. Importantly, 28% of patients had complete responses [(CRs), which is], very exciting for these patients. This was compared with an intracranial response of 33.4% with T-DM1, with a CR rate for T-DM1 of 3%.

Table. Response in CNS Subgroups of DESTINY-Breast03 Trial¹

We know that interstitial lung disease [ILD] is a potential toxicity with this compound, and in the earlier phases of [the DESTINY] studies we’ve seen some grade 5 [events in the data]. In DESTINY-Breast03, however, there were no cases of grade 5 ILD. In fact, there was no grade 4 ILD [either]. The overall rate of ILD was 10.5% [and] that was a very important safety signal.

Kaklamani: This was one of the most important trials presented this year, not just at SABCS, and I wanted to put [the data] into perspective. What are your thoughts about trastuzumab deruxtecan and where it sits in metastatic HER2-positive breast cancer?

Abdou: [The data are] remarkable, … magnificent, and [have] definitely changed the treatment paradigm for patients with HER2-positive metastatic breast cancer. I would definitely [use] this drug in the second-line setting. Even though T-DM1 was our effective easy-to-give therapy, trastuzumab deruxtecan has remarkable data [and] is going to change the outcomes for these patients.

As Dr O’Dea alluded, the safety signal was quite reassuring. I think as part of that we’re a little more comfortable with identifying these adverse effects and maybe giving this drug in an earlier setting where patients are less vulnerable to developing pulmonary toxicity. That being said, [on account of] the lower ILD signal and the remarkable data that were presented, I would definitely change my treatment paradigm to use trastuzumab deruxtecan in the second-line setting.

Kaklamani: Dr McArthur, based on the results presented here and the pretty impressive response rate and PFS in patients with stable brain metastasis, how are you thinking about these patients in that second-line setting if you’re finding brain metastasis?

McArthur: [Trastuzumab deruxtecan] has really become a standard of care in the second line and these are really exciting data in a subset of patients. Again, these are patients with clinically stable and treated brain metastasis, so a slightly different population than the patients with brain metastasis who participated in the HER2CLIMB study [NCT02614794].

One question that came up in the Q&A after the session was around the potential for radiation necrosis. There had to be at least 2 weeks between the end of whole brain radiation and study treatment, and those data are forthcoming. There will be some interest around CNS [central nervous system]-specific toxicity.

But it is particularly interesting to me because an antibody-drug conjugate we think of as being such a large molecule and the blood-brain barrier as being impenetrable to these large molecules. It challenges our thinking [on] how, historically, we’ve thought about how drugs get into the CNS—whether there are transportation mechanisms that we don’t understand [or] whether it’s systemic release of the drug that somehow penetrates the CNS has yet to be determined. But overall, [these are] really exciting data.

Kaklamani: Let’s move on to our second abstract, which [concerns] updated overall survival results from the phase 3 PHOEBE trial, pyrotinib vs lapatinib in combination with capecitabine in patients with HER2-positive metastatic breast cancer. Dr Abdou, would you like to help us understand the trial?

Abdou: Pyrotinib is a second-generation irreversible pan-HER tyrosine kinase inhibitor [TKI], targeting HER1, HER2, and HER4. PHOEBE [investigators] evaluated pyrotinib plus capecitabine vs lapatinib plus capecitabine among patients with previously treated HER2-positive metastatic breast cancer. In the interim analysis, [whose findings were] published in Lancet Oncology, the pyrotinib combination significantly improved PFS compared with lapatinib, but the overall survival data were still immature.

At SABCS, we [listened to findings from] the updated analysis of the overall survival from this trial at the data cut-off, which was approximately 33 months’ follow-up. Among 267 patients enrolled in the study, patients who were treated with pyrotinib plus capecitabine had a 31% lower risk of death than those treated with lapatinib plus capecitabine. The [median] overall survival was not reached in the pyrotinib arm compared with 26.9 [months] in the lapatinib arm, [and] the hazard ratio was 0.69. The subgroup analysis of overall survival and PFS confirmed the benefit of pyrotinib across most of the clinically relevant subgroups.

I do want to point out though that…neither pertuzumab nor T-DM1 [had been] approved in China at the time of patient enrollment, and therefore the study was unable to assess the efficacy of the combination regimen in patients previously treated with either of those therapies, making it hard to extrapolate data to the US population. However, this is a reasonable second-line option in countries and regions where access to HER2-targeted therapies is scarce.

Kaklamani: As you mentioned, T-DM1 [is available] in China but agents such as trastuzumab deruxtecan or tucatinib [are not available]. So for that patient population, pyrotinib would be a wonderful option.

Our third abstract, [focuses on data of] neratinib with fulvestrant and trastuzumab for hormone receptor–positive mutant metastatic breast cancer, and neratinib plus trastuzumab for triple-negative breast cancer. [These are the] latest updates from the SUMMIT trial [NCT01953926], another important trial we’re all looking forward to seeing data from. Dr McArthur, what are your thoughts about the trial?

McArthur: Komal Jhaveri, MD, from Memorial Sloan Kettering Cancer Center, gave a fantastic update from the SUMMIT trial. HER2 mutations in the absence of gene amplification or protein overexpression are a unique mechanism of oncogenic addiction to HER2 signaling. They’re rare, they occur only in approximately 2% to 12% of tumors, and [Jhaveri] gave a nice breakdown…actually of incidence in specific subsets of breast cancer—2% in primary breast tumors, 2% to 4% in metastatic breast cancer overall.

[The] update from that study is a little bit complicated [Figure³]. There are multiple different arms, [including] a TNBC arm comprising 18 patients who were treated with the doublet, neratinib with trastuzumab. There was an overall response rate in those 18 patients of 33% with a median PFS of 6.2 months.

Figure. Trial Schema and Updated Outcomes in HER2-mutant SUMMIT Population³

The rest of the study focused on the hormone receptor–positive, HER2-negative, HER2-mutant population. There was 1 nonrandomized arm that combined neratinib with fulvestrant and trastuzumab and that population had an overall response rate of 46%, which I thought was impressive, and a median PFS of 8.2 months. In a second part of that study, there was randomization of patients with hormone receptor–positive, HER2-negative, HER2-mutant [disease], and [this arm] was designed to tease out the contributions of each of the components of the triplet regimens.

Seven patients were randomized to receive the triplet, 7 patients received fulvestrant with trastuzumab, and another 7 patients received fulvestrant alone. What I thought was remarkable was that [patients in the] 2 arms of the 3-arm randomization who did not receive neratinib had a 0% overall response rate, whereas those in the triplet arm, again a small group, [had] an overall response rate of 29%.

Combining both the nonrandomized arm and [those in the] randomized arm who received the triplet, the overall response rate with that triplet was 42%. The median PFS was 7 months and, interestingly, [these data were] after prior CDK exposure. It appears, based on the absence of response rate without neratinib, that neratinib [is] critical for inhibition of HER2-mutant breast cancer. [It is] worth noting that there is a cost in the form of toxicity—approximately 90% of patients experienced diarrhea of any grade and just over 80% of patients experienced nausea. Loperamide prophylaxis is critically important when these combinations are to be administered.

O'Dea: Dr McArthur, did [investigators] use dose escalation for the neratinib in that trial or was it just loperamide prophylaxis?

McArthur: It was responsive loperamide. There was not a prophylactic regimen which is why the rate was so high at 90%.

Kaklamani: That’s a great point, Dr O’Dea. We know from the control trial that if we give neratinib at the dose escalation, patients do significantly better because the diarrhea is just so dreadful. The ER-positive group was impressive but I kept looking at the triple-negative group—no chemotherapy and a monoclonal antibody, trastuzumab, plus neratinib giving us a response rate of 33.3%. That’s pretty impressive as well, right?

McArthur: It’s amazing. I mean, [these are] small numbers again, only 18 patients participating in that triple-negative cohort. But it is incredible that you could have…a nonchemotherapeutic regimen to treat triple-negative disease and that’s one more thing, potentially, [for] our arsenal.

Kaklamani: If next week you send a patient for molecular testing and they come back with a HER2 mutation, would you consider giving neratinib?

McArthur: [I had a patient] enrolled on the SUMMIT trial when I was [at Memorial] Sloan Kettering and she did exceptionally well after progressing very quickly on prior lines of therapy. So I have used neratinib in selected patients. Again, these mutations are relatively rare, but I have used [the drug] in selected patients with success. [However], as Dr Jhaveri said, it’s not ready for prime time based on these relatively small numbers.

Abdou: It would be interesting to look at the molecular biology of these tumors, specifically in TNBC, to see if they have a specific heterogeneity depending on that mutation.

Kaklamani: Most mutations happen in the kinase part of HER2 as well, which is also important. [But] there did not seem to be much of a difference in response, depending on where those mutations were.

Our next abstract, [has data for] a first-in-human HER2-targeted bispecific antibody, KN026, for the treatment of patients with HER2-positive metastatic breast cancer, results from a phase 1 trial. Dr O’Dea, would you like to go over this poster with us?

O'Dea: This was looking at a novel bispecific antibody that binds to 2 distinct HER2 epitopes. It was given as monotherapy for HER2-positive metastatic breast cancer in a phase 1 dose escalation [trial] using a 3 + 3 dose escalation rule followed by a dose-expansion cohort. There were 63 patients [evaluated and the] recommended phase 2 dose was 20 mg every 2 weeks or 30 mg every 3 weeks. [At that] dose the overall response rate was 28.1% and the median PFS was 6.8 months among 57 patients.

Investigators completed a series of translational studies in 20 of the patients with confirmed coamplification of CDK12. They found that to be a promising biomarker. If you looked at the patients that had coexpression of CDK12, the overall response rate was 50% compared with 0% without the coexpression, so [that is] very encouraging. And if you looked at the median PFS in the group with the coexpression, it was 8.2 months vs lack of coexpression, [for which it was] 2.7 months. The authors’ conclusions were that KN026 was well tolerated overall [and it] achieved comparable efficacy [with the] trastuzumab and pertuzumab doublet even in a more heavily pretreated population. It appears that the coamplification of HER2 and CDK12 may predict who will derive benefit from this new compound.

Kaklamani: Some of the adverse reactions [included] fever, diarrhea, and some liver toxicity, [and] most of them were grade 1 and 2. That 50% [response rate] is impressive [for] an antibody.

The next abstract looks at [data from a phase 1 study] of another bispecific antibody, zanidatamab, or ZW25, in combination with chemotherapy for HER2-positive breast cancer. Dr Abdou, would you like to give us your thoughts on this trial?

Abdou: Zanidatamab is a HER2-targeted bispecific antibody which is directed at 2 domains of the HER2 protein—EZD4 and EZD2—and simultaneously binds to 2 distinct sites on the HER2 resulting in increased antibody binding, receptor clustering, and then downregulation of the HER2 receptor. The data presented at SABCS are results from an ongoing phase 1 clinical trial [in which] 20 patients with heavily pretreated HER2-positive metastatic breast cancer were enrolled and had received zanidatamab in combination either with Navelbine, or capecitabine, or paclitaxel.

I would like to point out that 9 of these patients had stable brain metastasis at the time of enrollment, which was allowed on the trial, and patients [had] received a median of 3 prior HER2 regimens. In 16 of the patients evaluable for efficacy, treatment with zanidatamab and chemotherapy resulted in an objective response rate of 36.4% and a disease control rate of 86.4%. The median PFS was 7.3 months across all the treatment arms, and the median duration of response was not reached.

Among all patients [n = 20]…zanidatamab with chemotherapy was pretty well tolerated. …A majority of adverse effects [were] considered mild to moderate and the most common…were diarrhea, nausea, and peripheral neuropathy, which I suspect…were [mostly] due to chemotherapy, not the anti-HER2 agent. These data definitely support further investigation of zanidatamab as a novel therapeutic agent for HER2-positive breast cancer, and my understanding is they’re also evaluating the combination with tucatinib, which will be interesting to see.

Kaklamani: Another impressive bispecific antibody. They’re becoming a little more common in our phase 1 trials, right? When I looked at these data, this disease control rate of 86.4% really caught my attention. In these heavily pretreated patients, that’s a good number to have.

Let’s move on to the poster discussion of tucatinib plus paclitaxel [and] pertuzumab-trastuzumab followed by AC in [patients with] high-risk HER2-positive breast cancer with stage II or III disease, [the] results from the I-SPY trial. Dr McArthur, what were your thoughts here?

McArthur: As you know, the I-SPY 2 study [has] an adaptive design to identify potentially promising strategies to move them forward into phase 3 studies. It’s not designed to look at arms head to head, but to look at signals. In the HER2-positive cohort, the control arm is the paclitaxel with trastuzumab and pertuzumab followed by anthracycline with cyclophosphamide which would be administered either every 2 or 3 weeks. In this case, tucatinib was administered together with the taxane and dual HER2 blockade antibodies.

Investigators started out administering tucatinib at 300 mg once daily in the first 8 patients. Three of those patients experienced grade 3 hepatoxicity and 2 experienced grade 3 diarrhea. That was a high toxicity rate at that dose level, so investigators subsequently [initiated] 2 additional cohorts, 1 [in which] tucatinib was administered at 250 mg once daily and [1 in which] tucatinib was administered in an adaptive fashion—150 mg once daily on days 1 to 28 and then 250 mg once daily on days 29 to 84 to complete the coadministration with paclitaxel.

Ultimately, the toxicity was very similar in those 2 subsequent arms. One patient of 5 in the 250-mg arm experienced grade 3 hepatoxicity and 1 experienced grade 3 diarrhea. Among the 7 patients who participated in the adaptive tucatinib design, 2 experienced grade 3 hepatoxicity and 2 experienced grade 3 diarrhea. So even with the dose reduction and adaptive strategy, there was unacceptable toxicity and ultimately that arm was suspended.

Investigators did not have pathologic CR data to present at the time of the meeting; they did, however, present some of the MRI substudy data. …Fifteen of the 17 patients had more than an 80% reduction in tumor volume by MRI, indicating that there were active responses to the prescribed regimen but again unacceptable toxicity.

Kaklamani: This is why we do clinical trials, right? This is a prime example of a trial really showing unacceptable toxicity with a combination of a taxane and tucatinib. I guess the investigators’ thought was, if you want to combine tucatinib with something, you want to combine it maybe with an antibody-drug conjugate but not with paclitaxel because of that toxicity. There are trials looking at tucatinib in the adjuvant setting to try to see whether we can actually move this drug forward.

References

1. Hurvitz S, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd; DS-8201a) vs trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Abstract presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Accessed January 31, 2022. https://www.abstractsonline.com/pp8/#!/10462/presentation/649 
2. Xu B, Yan M, Ma F, et al. Updated overall survival (OS) results from the phase 3 PHOEBE trial of pyrotinib versus lapatinib in combination with capecitabine in patients with HER2-positive metastatic breast cancer. Abstract presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Accessed January 31, 2022. https://www.abstractsonline.com/pp8/#!/10462/presentation/650 
3. Jhaveri K, Park H, Waisman J, et al. Neratinib + fulvestrant + trastuzumab for hormone receptor-positive, HER2-mutant metastatic breast cancer and neratinib + trastuzumab for triple-negative disease: latest updates from the SUMMIT trial. Abstract presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Accessed January 31, 2022. https://www.abstractsonline.com/pp8/#!/10462/presentation/2080 
4. Zhang J, Ji D, Cai L, et al. First-in-human HER2-targeted bispecific antibody KN026 for the treatment of patients with HER2-positive metastatic breast cancer: results from a phase I study. Poster presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Accessed January 31, 2022. https://www.abstractsonline.com/pp8/#!/10462/presentation/1041 
5. Bedard PL, Im SA, Elimova E, et al. Zanidatamab (ZW25), a HER2-targeted bispecific antibody, in combination with chemotherapy (chemo) for HER2-positive breast cancer (BC): results from a phase 1 study. Poster presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Accessed January 31, 2022. https://www.abstractsonline.com/pp8/#!/10462/presentation/1038 
6. Potter DA, Roesch E, Yau C, et al. Evaluation of tucatinib + (paclitaxel +pertuzumab +trastuzumab) followed by AC in high-risk HER2-positive (HER2+) stage II/III breast cancer: results from the I-SPY 2 TRIAL. Abstract presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Accessed January 31, 2022. https://www.abstractsonline.com/pp8/#!/10462/presentation/2071