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An important question is how to better treat and prevent brain metastases in patients with HER2-positive MBC. At some point, more than 50% of these patients will develop brain metastases. We have noted a higher odds of CNS metastasis in patients who are Hispanic/Latino, black, or older. Furthermore, those with an Eastern Cooperative Oncology Group performance status ≥ 2, those with de novo MBC, and those with hormone receptor–positive disease are more likely to develop CNS metastasis.
The standard of care in this setting has been lapatinib plus capecitabine, which is FDA approved. However, data from a pooled analysis show that this combination is associated with low response rates (~ 20%). The pooled median PFS and OS were 4.1 months and 11.2 months, respectively. These are important data to keep in mind as new agents are evaluated and approved. Indeed, neratinib plus capecitabine has now been approved in this setting.
Now, the reason that lapatinib plus capecitabine may be more active against CNS disease than T-DM1, trastuzumab, and pertuzumab is that, under normal conditions, lapatinib and capecitabine can pass through the blood–brain barrier and penetrate the CNS. By contrast, antibodies are too large to pass the blood–brain barrier.
Hurvitz and colleagues, including myself, conducted an analysis of survival by CNS metastasis status in patients with HER2-positive MBC drawn from the SystHERs registry. As shown here, in the modern chemotherapy era, the median PFS is 9-10 months in those with CNS metastases vs approximately 19 months in those without CNS metastases. Similarly, median OS was 30-38 months in those with CNS metastases vs not reached in those without CNS metastases.
It is striking that we can achieve such good disease control in women who develop CNS metastases after being diagnosed with MBC. Patients can have more than 3 years of life after the diagnosis of CNS metastases, which I believe reflects effective control of systemic disease. That being said, our goal is to prevent metastases to the CNS in the first place.
CEREBEL was a randomized, open-label phase III study comparing lapatinib plus capecitabine vs trastuzumab plus capecitabine in patients with HER2-positive MBC and no CNS metastasis (N = 540). The primary endpoint was CNS metastasis as first site of relapse.
CNS was the first site of progression for 3% of patients in the lapatinib arm vs 5% in the trastuzumab arm. The incidence of CNS progression at any time was comparable between arms (7% vs 6%, respectively). The median time to first CNS progression was slightly longer in the lapatinib arm (5.7 vs 4.4 months in the trastuzumab arm).
Of note, the median PFS was longer in the trastuzumab arm vs in the lapatinib arm (8.1 vs 6.6 months, respectively; P = .021), as was median OS (27.3 vs 22.7 months, respectively; P = .095). As a result, this trial was closed early due to futility in the lapatinib plus capecitabine arm and improved benefits in the trastuzumab arm. One of the reasons lapatinib was less effective was the increased incidence of AEs—diarrhea, in particular—that impeded patients from receiving optimal doses for extended periods.
Neratinib is a next-generation TKI that binds to HER4, HER2, and HER1; by contrast, lapatinib binds just to HER1 and HER2, and both pertuzumab and trastuzumab are specific to HER2. Both neratinib and lapatinib can cross the blood–brain barrier.
Neratinib was originally approved by the FDA as a single agent for extended adjuvant therapy of early HER2-positive breast cancer previously treated with trastuzumab. It is also now approved in combination with capecitabine for patients with advanced or metastatic HER2-positive breast cancer who have received at least 2 previous HER2-targeted regimens for metastatic disease.
Two of the most important trials evaluating neratinib in MBC are NefERT-T and TBCRC 022. In the phase III NEfERT-T study, the combination of trastuzumab/paclitaxel was compared with neratinib/paclitaxel in patients with previously untreated, HER2-positive locally recurrent or metastatic breast cancer (N = 479).
Although the median PFS was 12.9 months in both arms (HR: 1.02), there were far fewer CNS progression events in the neratinib arm vs the trastuzumab arm (20 vs 41, respectively). This suggests that a HER2 TKI can prevent or delay the onset of CNS metastases in HER2-positive MBC.
The phase II TBCRC 022 trial evaluated neratinib plus capecitabine in patients with HER2-positive MBC and brain metastases. The study had 3 cohorts: Cohort 1 evaluated neratinib in patients with HER2-positive brain metastases; cohort 2 evaluated neoadjuvant use of neratinib; and cohort 3, which will be discussed here, evaluated neratinib plus capecitabine in patients with or without previous lapatinib treatment. Most of the patients had received, and progressed on, stereotactic radiosurgery as well.
In the 49 patients comprising cohort 3, the CNS response rate was 49%. Of importance, 12 patients in this cohort had previous lapatinib and the response in these women was 33%. Overall, most patients achieved at least stable disease. Clearly, neratinib can benefit patients with CNS metastases.
The efficacy of neratinib plus capecitabine was compared with lapatinib plus capecitabine in 621 patients with HER2-positive MBC following at least 2 lines of HER2-targeted therapies in the registrational phase III NALA trial, which was presented at ASCO 2019. Patients with stable brain metastases were permitted to enroll on the study. Of note, the capecitabine dose was lower in the neratinib arm to decrease the risk of diarrhea (1500 mg/m2 vs 2000 mg/m2 in the lapatinib arm). The coprimary endpoints were OS and centrally confirmed PFS, with secondary endpoints including locally determined PFS, response, safety, and patient-reported outcomes.
Baseline patient characteristics were well balanced between arms, with 59% having hormone receptor–positive disease and approximately 44% having de novo metastatic disease. Most patients (79%) were younger than 65 years of age. Approximately 70% of patients had received 2 previous HER2-targeted therapies, with the other 30% having received 3 or more. Of the available HER2-targeted agents, approximately 40% of patients had received trastuzumab only. The remaining 60% of patients had received trastuzumab as well as pertuzumab (~ 8%), T-DM1 (~ 20%), or both pertuzumab and T-DM1 (~ 34%).
Because both the PFS and OS curves separated late, there was a prespecified comparison of mean survival (a restricted means analysis) instead of median survival. This analysis found a significant PFS benefit of 2.2 months favoring neratinib and capecitabine (mean PFS: 8.8 vs 6.6 months for lapatinib and capecitabine; P = .0003). There was a numerical improvement in mean OS, but it was not statistically significant (24.0 vs 22.2 months, respectively; HR: 0.88).
Time to intervention for CNS metastases is a reasonable surrogate for progression of CNS metastatic disease. In this study, 55 patients needed intervention (primarily radiotherapy) in the neratinib arm vs 75 in the lapatinib arm, representing, in relative terms, an approximately 20% reduction. Clearly, in the NALA trial, neratinib plus capecitabine was more beneficial in reducing CNS metastasis.
The main AE of interest with neratinib is grade 3 diarrhea that, in this study, affected 24% of patients in the neratinib arm vs 13% in the lapatinib arm. Because diarrhea is a common AE associated with HER2-targeted TKIs, this disparity may be due in part to the longer median duration of treatment with neratinib vs lapatinib (5.7 vs 4.4 months, respectively). The rate of discontinuations due to treatment-emergent AEs was 11% with neratinib vs 14.5% with lapatinib.
Of importance, the diarrhea was self-limiting. We did not initially allow for prophylactic loperamide, although the trial protocol was eventually amended to allow for a tapered dose (3 times daily for 1-2 weeks, twice daily for 1 week, then once daily for 1 week before stopping).
As shown here, the time to onset of diarrhea with neratinib was fairly quick, within the first 2 weeks. The median number of cumulative days of grade 3 diarrhea was 4 per patient, which is similar to lapatinib and capecitabine. A total of 2.6% of patients discontinued due to diarrhea in the neratinib arm vs 2.3% in the lapatinib arm.
Because diarrhea is such a concern with neratinib, the phase II CONTROL study was designed to evaluate antidiarrheal prophylaxis in patients with early HER2-positive breast cancer who are receiving neratinib after adjuvant trastuzumab (N = 501). The 3 sequential prophylaxis cohorts were loperamide, budesonide plus loperamide, and colestipol plus loperamide. All patients received neratinib 240 mg/day for 1 year. An added dose-escalation cohort (n = 60) received neratinib at 120 mg/day, then 160 mg/day, and then 240 mg/day with loperamide prophylaxis as needed.
The earlier phase III ExteNET study of neratinib, which was conducted in patients with HER2-positive early breast cancer who had received adjuvant trastuzumab (N = 1408), was used as a historical control to assess the benefit of antidiarrheal prophylaxis in CONTROL.
As shown here, the incidence of grade 3 diarrhea was 40% in ExteNET. In the CONTROL study, the addition of loperamide prophylaxis decreased this to 31%. The use of both loperamide and budesonide reduced the rate to 27%, and the combination of colestipol and loperamide reduced it to 11%, with a discontinuation rate due to diarrhea of 1.7%.
In my opinion, we can achieve even lower rates of diarrhea in our patients receiving neratinib by using dose-escalation strategies. That said, I anticipate that there will always be a fraction of patients who will have sufficiently severe diarrhea that they will need to discontinue neratinib.
Tucatinib is a novel HER2-targeted TKI that is uniquely selective for HER2 compared with other HER2-directed TKIs. This table shows that tucatinib and neratinib both have an IC50 of approximately 7-8 nM, which means they are essentially equivalent in binding the HER2 tyrosine kinase. Lapatinib has a higher IC50 of 49 nM for HER2, meaning it does not bind as well. The more important difference between these agents is that neratinib binds to EGFR whereas tucatinib does not. Thus, tucatinib is much more selective for the HER2 tyrosine kinase than neratinib, even though it is probably just as potent in its HER2-related effects. A key implication of tucatinib binding poorly to EGFR is that this agent may result in less EGFR-associated toxicity, such as diarrhea and skin AEs.
In a phase Ib study in HER2-positive MBC, the vast majority of patients responded to the combination of T-DM1 plus tucatinib. Likewise, early data on this agent combined with trastuzumab and capecitabine showed quite promising response rates in heavily pretreated patients with HER2-positive MBC, including patients with brain metastases.[28,29] Tucatinib plus capecitabine/trastuzumab was associated with an ORR of 61%, with a median duration of response of 10 months in 23 patients. Of importance, in the 12 patients with CNS disease, the ORR was 42%.
Although limited by the small numbers of patients, these early results do suggest promising activity with this triplet, including CNS activity. These data helped provide the rationale for the important HER2CLIMB study.
The phase II HER2CLIMB study was aimed at confirming these early results. This was a randomized, placebo-controlled trial comparing tucatinib plus capecitabine and trastuzumab vs placebo plus capecitabine and trastuzumab in patients with heavily pretreated HER2-positive MBC (N = 612).[30,31] Patients had to have received previous trastuzumab, pertuzumab, and T-DM1. The primary endpoint was PFS, with secondary endpoints including OS and PFS in patients with brain metastases.
Slightly fewer than one half of the patients had a history of brain metastases; 60% of those patients had treated metastases that were stable, but 40% had untreated or progressive brain metastases. The median number of previous lines of therapy in the metastatic setting was 3, ranging from 1-14. More than one third of patients had stage IV disease at initial diagnosis.
The study met its primary endpoint of PFS: In the overall population, the median PFS was 7.8 months with the addition of tucatinib vs 5.6 months with placebo (HR: 0.54; P < .00001), corresponding to a 46% reduction in the risk of progression.[30,31] At 1 year, 33.1% of patients in the tucatinib arm had not progressed vs 12.3% in the placebo arm. In the other subgroups analyzed, tucatinib was consistently superior to placebo.
At the same time, results also showed an OS improvement, which is extraordinary in the first analysis of a study; this analysis occurred after the first 410 patients were randomized to the tucatinib arm.[30,31] The median OS was 21.9 months with the addition of tucatinib vs 17.4 months with trastuzumab plus capecitabine alone (HR: 0.66; P = .0048), corresponding to a 34% reduction in the risk of death. The 2-year OS rate was 45% with tucatinib vs 26% with placebo, which is quite dramatic.
The median OS was also significantly improved in the women with baseline brain metastases (HR: 0.58; 95% CI: 0.40-0.85).
The median PFS in patients with brain metastases was 7.6 months with tucatinib vs 5.4 months with placebo (HR: 0.48; P < .0001).[30,31] Of importance, by 1 year, 25% of patients in the tucatinib arm still had not progressed vs 100% in the placebo arm. Updated data are expected to be presented at ASCO 2020.
The major AE associated with the tucatinib combination regimen in HER2CLIMB was diarrhea, which occurred in approximately 80% of patients. The diarrhea could be severe and was mostly due to the capecitabine. Even in the placebo arm, the rate was quite high (> 50%). In fact, only a small percentage of the more-severe diarrhea was attributed to tucatinib (~ 4%). The incidence of hand–foot syndrome was also notably higher in the tucatinib arm, most likely because the patients were on this regimen longer. Nausea also was more common with tucatinib. Most other AEs occurred at lower frequencies and at more comparable rates between arms.
Tucatinib clearly has a substantial benefit for both OS and PFS, with fewer AEs than other HER2 TKIs. As of March 2020, the FDA has granted priority review to tucatinib, and I hope it will be approved for MBC.