Expert Discusses HER2 Selective Kinase Inhibitors in Heavily Pretreated Breast Cancer

Lee Schwartzberg, MD

During a Targeted Oncology Case-Based Peer Perspectives virtual event, Lee Schwartzberg, MD, medical oncologist, West Cancer Center and Research Institute, discussed the therapeutic options for a 39-year-old woman with HER2-positive breast cancer who was heavily pretreated.

Targeted Oncology^TM: What are this patient’s therapeutic options at this point?

SCHWARTZBERG: We have a lot of treatment options to consider, including tucatinib [Tukysa], trastuzumab, or capecitabine. These are category 1 treatments according to the National Comprehensive Cancer Network [NCCN] breast cancer guidelines.¹ Based on the DESTINY-Breast01 trial [NCT03248492] results, we also have T-DX [fam-trastuzumab deruxtecan-nxki; Enhertu] and neratinib [Nerlynx] and capecitabine.

What was the rationale for developing tucatinib?

Tucatinib is a HER2 selective kinase inhibitor that is a very specific kinase, compared with neratinib. From a biochemical perspective, tucatinib is highly selective for HER2 relative to EGFR. Neratinib strongly inhibits at the same level as tucatinib for HER2, but it also inhibits EGFR. Lapatinib [Tykerb], a previously developed kinase that we were using for the last 10 years until the emergence of these newer agents, is much less potent. It’s really about 20 times less potent than either of the other 2 [agents].

Please describe for us the HER2CLIMB study.

The HER2CLIMB study [NCT02614794] evaluated tucatinib, capecitabine, and trastuzumab.² [It included] patients who had undergone prior treatment with trastuzumab, pertuzumab, and T-DM1. Patients were allowed to have been treated with lapatinib, but not in the last 12 months and [with] no other investigational or approved TKIs [tyrosine kinase inhibitors]. They were randomized with tucatinib given twice a day continuously, capecitabine 1000 mg/m2 twice a day on days 1 to 14 every 3 weeks, andtrastuzumab in the standard dose. This was a placebo-controlled study. PFS [progression-free survival] by BICR [blinded independent central review] was the primary end point, with multiple other end points.

The demographics were well balanced between the groups. It was a 2:1 randomization, a fairly large trial for a late line HER2- positive group of 600 patients. Half the patients had brain metastases in this study.

Investigators reported a 2.2-month improvement in median PFS for the whole population [HR, 0.54; P <.00001]. The median overall survival [OS] was almost 22 months versus 17, so [there was] about a 5-month improvement in OS [HR, 0.66; P < .00480]. PFS benefit was noted in all subgroups by subgroup analysis.

There were some additional end points. The response rate was about doubled with the addition of tucatinib compared with the placebo group [41% vs 23%; P = .00008], and for the initial report of brain metastases there was also a 2.2-month improvement in PFS for patients with brain metastases, similar to that seen for the whole group [7.6 months vs 5.4 months; HR, 0.48; P < .00001].

Describe the adverse events (AEs) that investigators observed in the trial.

The most common AEs of greater than 20% in the tucatinib arm were diarrhea, elevated liver function test results, and PPE [palmar-plantar erythrodysesthesia]. Grade 3 diarrhea was reported in 13% of patients compared with 9% in the control arm. There was a modest increase in liver function, particularly grade 3, at around 5% for tucatinib versus 0.5%; the PPE syndrome was a bit higher and really [with] no major difference in grade 3 at 13% versus 9%. In terms of AEs leading to tucatinib or placebo discontinuation, investigators reported 6% in the tucatinib arm and 3% in the placebo arm.

Regarding intracranial CNS [central nervous system] responses, the confirmed overall response rate is 47% in the tucatinib arm compared with 20% in the placebo arm. Also, importantly, the duration of response in those patients who responded was more than doubled—6.8 months compared with 3.0 months.³

How would you describe the survival responses?

If you look at all patients with brain metastases, the risk of death was decreased by 42%, so, a hazard ratio of 0.58 for the patients who had brain metastases. The median OS was increased substantially to 18 months compared with 12 months per patients who received placebo.³

In patients with active brain metastases, similar OS findings were reported. In that subpopulation, the hazard ratio was 0.59 and the median OS was a little longer—20.7 months versus 11.6 months for patients in the placebo arm. The agent seemed to confer the same amount of benefit in patients with activebrain metastases as in those who had treated brain metastases.

The HER2CLIMB-02 trial [NCT03975647] is a randomized phase 3 trial of tucatinib plus T-DM1 versus [placebo plus] T-DM1. In this trial, we will determine if tucatinib adds [benefit] to T-DM1. Importantly...patients are eligible with or without brain metastases.

What are the highlights of the NALA study (NCT01808573)?

The NALA study randomized patients to neratinib plus capecitabine using prophylaxis with loperamide.⁴ The lapatinib plus capecitabine [regimen] was the previous standard of care in patients who had had 2 or more lines of HER2-directed therapy. Most of these patients had had 2 lines of therapy. Only a third had had prior trastuzumab, pertuzumab, and T-DM1, which is our standard today.

The centrally confirmed PFS was the coprimary end point. The restricted analysis of 24 months showed a 2.2-month improvement in disease PFS, which was highly statistically significant. There was a hazard ratio of 0.76 for the whole curve.

Time to intervention for CNS metastases was evaluated, but this was not a primary or a secondary end point. The time was reduced from 29% to 23% with neratinib compared with lapatinib [and was] statistically significant.

The response rate was 33% versus 27%. The clinical benefit rate was somewhat higher and statistically significant. The median duration of response was 8.5 months versus 5.6 months, [with a] hazard ratio of 0.5 for the duration of response.

The most common AEs observed were again diarrhea, it was 24% grade 3 versus 13% for lapatinib, and there was no real difference in hand-foot syndrome. In fact, it was worse with lapatinib.

There was more all-grade nausea and vomiting for neratinib, a little bit more than lapatinib, and more decreased appetite. Treatment discontinuation, however, due to treatment-emergent AEs, was 11% versus 15% favoring neratinib.

If you look at the maximum toxicity grade 3, it was 24% versus 13%. Eleven percent of patients had grade 3 diarrhea first onset and the median cumulative duration was 3 to 4 days. Treatment discontinuation was similar for diarrhea between the 2 arms.

What were the findings of the CONTROL study (NCT02400476), which looked at the effect of prophylaxis on neratinib-associated diarrhea?

The CONTROL study looked at prophylaxis with a variety of different regimens including loperamide and other regimens.⁵ This was a sequential cohort study with 5 treatment arms. The last arm evaluated as-needed loperamide. Everyone agrees that this does not always take care of diarrhea and, in fact, can cause constipation, leading to a vicious cycle. In this case, loperamide was given as needed, but the strategy was to do a neratinib dose escalation and to start at typically half dose, then three-quarter dose, then full dose.

The grade 3 toxicity for diarrhea was much lower at 12%, although the all grade remains high for all of these strategies. There was no grade 4 diarrhea reported in any of the arms, including just using loperamide on a routine basis. But the grade 3 diarrhea was lower in each of the cohorts.

Can you discuss trastuzumab deruxtecan? What’s unique about it?

Trastuzumab deruxtecan is a novel antibody-drug conjugate (ADC). It has 3 components. The backbone is trastuzumab, so like T-DM1 it is composed of the trastuzumab molecule. What’s different here are 2 other aspects of the molecule.

First of all, there is a different linker. It’s a tetrapeptide linker that is cleavable and has different properties than the linkers that are used in some of the other ADCs. Secondly, it has a different type of payload—an exatecan derivative—[and] this makes it very different.

Please discuss the DESTINY-Breast01 study.

That was a 2-part study.⁶ Part 1 was a dose expansion study; in part 2, patients were resistant or refractory to, or intolerant of, T-DM1. So these patients were progressing on T-DM1. Investigators had tested 3 different doses [5.4 mg/kg, 6.4 mg/kg, and 7.4 mg/kg]. The [7.4- mg/kg] dose was dropped at the end of phase 1. Patients in part 2 received the 5.4-mg/kg dose, which is the [standard] dose since the trial. The data cutoff was a year ago, with many patients [42%] continuing. The primary end point was response rate in this phase 2 study.

This was a heavily pretreated population, patients [with] mainly an ECOG 0 and 1 [score] who were hormone receptor positive, and most of them were IHC [immunohistochemistry] [HER2- positive] 3 in this particular population. Thirteen percent of patients did have brain metastases on this study.

All patients had to have prior trastuzumab and T-DM1; two- thirds had pertuzumab and, interestingly, another half had other anti-HER2 therapies.

The confirmed overall response rate by independent review was 61% and most of those were PRs [partial responses], but 6% were CRs [complete responses]. The disease control rate was 97% and the clinical benefit rate was 76%. The median duration of response was almost 15 months with a rapid time to response of 1.6 months.

What were the survival benefits and AEs?

Median PFS was 16.4 months. The median follow-up here was relatively short, at only 11 months at the time of publication.⁶ The median PFS in the 24 patients with brain metastases was 18.1 months. And the median survival has not yet been reached, with only a median follow-up of 11 months.

The treatment-emergent AE profile was a little different. Here, nausea was the most common toxicity, in addition to fatigue and alopecia. Remember, there was only grade 1 or 2 alopecia that occurred in half the patients with vomiting and some other GI toxicity. Neutropenia was seen in grade 3 or greater in about 15% or 20% of patients and some anemia grade 3 or 4 was reported in under 10% of patients.

The AE of special interest for deruxtecan is interstitial lung disease [ILD], and this was found in about 14% of patients; [it was] mostly grade 1 and 2, but there were 4 grade 5 or deaths due to ILD. The median time to ILD was almost 6 months and a little over 6 months. Only 13 of the 20 patients with grade 2 [ILD] received corticosteroids and the outcomes for some were not known. Of the fatal cases, 3 received steroids and the death occurred sometime after that. The recommendation was to monitor for symptoms of ILD, hold the drug, and start steroids as soon as ILD is suspected.

Can you provide details about the development program for trastuzumab deruxtecan?

There are 3 upcoming trials in breast cancer. The DESTINY- Breast02 study [NCT03523585] is evaluating patients after treatment with T-DM1. We’ve already seen the phase 2 study, which is Breast01. This is a phase 3 trial evaluating T-DM1 versus investigator’s choice of chemotherapy plus anti-HER2 therapy.

The DESTINY-Breast03 trial [NCT03529110] evaluates patients in the second line who have been treated with first-line trastuzumab and taxane therapy and are then going to be randomized to an upfront head-to-head comparison of trastuzumab-deruxtecan with T-DM1.

DESTINY-Breast04 trial [NCT03734029] looks at patients with HER2 low who are IHC 1+ or 2+ but in situ hybridization [ISH]- negative, at least ISH-negative for 2+; most of the IHC 1+ are not tested. The experimental arm is [fam-] trastuzumab deruxtecan and the comparator arm is physician’s choice without anti-HER2 therapy. Investigators are determining whether or not [fam-] trastuzumab deruxtecan has activity.

_REFERENCES:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 6.2020. Accessed January 7, 2021. https://bit.ly/2XgEAmt}

_{2. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2- positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. doi:10.1056/ NEJMoa1914609}

_{3. Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol. 2020;38(23):2610-2619. doi:10.1200/JCO.20.00775}

_{4. Saura C, Oliveira M, Feng YH, et al. Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: findings from the multinational, randomized, phase III NALA trial. J Clin Oncol. 2019;37(suppl 15):1002. doi:10.1200/JCO.2019.37.15_suppl.1002}

_{5. Barcenas CH, Hurvitz SA, Di Palma JA, et al. Effect of prophylaxis on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer: phase II CONTROL trial. J Clin Oncol. 2019;37(suppl 15):548. doi:10.1200/JCO.2019.37.15_suppl.548}

_{6. Modi S, Saura C, Yamashita T, et al; DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610-621. doi:10.1056/NEJMoa1914510}