Tanios S. Bekaii-Saab, MD, FACP, expands on key data reported from the MOUNTAINEER trial, the potential effects of this regimen’s approval on the current treatment landscape, and the continued investigation of this and other targeted approaches in metastatic colorectal cancer.
Tanios S. Bekaii-Saab, MD, FACP
The addition of trastuzumab (Herceptin) to tucatinib (Tukysa) significantly improves outcomes, maintains quality of life, and is well tolerated in patients with HER2-positive metastatic colorectal cancer (mCRC), supporting its use as the first HER2-targeted regimen for this patient population. If approved by the FDA, widespread adoption of the doublet will provide patients with a much-needed treatment alternative, according to Tanios S. Bekaii-Saab, MD, FACP.
On September 19, 2022, the FDA granted priority review status to tucatinib in combination with trastuzumab for adult patients with HER2-positive CRC who have received at least 1 prior treatment regimen for unresectable or metastatic disease.1
The application was supported by findings from the phase 2 MOUNTAINEER trial (NCT03043313), where the regimen demonstrated an objective response rate (ORR) of 38.1% (n = 84; 95% CI, 27.7%-49.3%), with a median duration of response (DOR) of 12.4 months (95% CI, 8.5-20.5). Moreover, patients who received the doublet experienced a median progression-free survival (PFS) of 8.2 months (95% CI, 4.2-10.3) and a median overall survival (OS) of 24.1 months (95% CI, 20.3-36.7).2,3
The regulatory agency is expected to decide on the supplemental new drug application for the combination by January 19, 2023 under the Prescription Drug User Fee Act.
“The [FDA approval of this regimen will be] a major win for patients with HER2-positive metastatic CRC, [as] we’ll be able to offer tucatinib and trastuzumab to our patients who already failed on at least 1 prior line of therapy,” said Bekaii-Saab, who is the leader of the Gastrointestinal Cancer Program at the Mayo Clinic Comprehensive Cancer Center, medical director of the Cancer Clinical Research Office, and the vice chair and section chief for medical oncology in the Department of Internal Medicine at Mayo Clinic in Phoenix, Arizona.
In an interview with OncLive®, Bekaii-Saab expanded on key efficacy and safety data reported with the regimen from the MOUNTAINEER trial, the potential effects of this regimen’s approval on the current treatment landscape, and the continued investigation of this and other targeted approaches in mCRC.
Bekaii-Saab:This [will be] the first approval for any targeted strategy in patients with HER2-overexpressing mCRC. We’ve previously had some smaller, single-arm studies that suggested benefit [with targeted therapy–based combinations] and [these regimens] were included in the guidelines, but there was no FDA approval for any of these combinations.
It’s also important to note that [this] subgroup of patients [makes up] about 2% to 3% of all patients with colon cancer, [which is] a significant number. [Moreover], patients with HER2-amplified, RAS wild-type cancer do not respond [well] to EGFR inhibitors, so they have less options than other RAS wild-type patients, except for those [with] BRAF-mutated tumors. Having a widely approved combination therapy [will be] a major gain for patients with HER2-positive mCRC [whose disease is] also RAS wild type.
MOUNTAINEER was a global, open-label phase 2 trial. It started with 45 patients [in] cohort A. There was an investigator-initiated component of the trial run through the Accrual Research Consortium, supported by Mayo Clinic, with John Strickler, MD, of [Duke Cancer Institute], as principal investigator [and myself] as co-principal investigator.
[Along with] Seagen, we then [turned] this into a randomized study with 41 patients [in] cohort B and  patients in cohort C. Patients were randomized to tucatinib [plus] trastuzumab or tucatinib alone. Interestingly, in cohort C, [patients] on tucatinib alone were allowed to cross over to tucatinib and trastuzumab [regardless of whether] they experienced radiographic progression at any point or had not achieved a [partial response (PR) or complete response (CR)] by week 12.
The study included patients with RAS wild-type disease [who had received] a median of 3 prior lines of systemic therapy in any setting. These patients were heavily pretreated.
The study met its primary end point, showing positive efficacy results, and [tucatinib plus trastuzumab was] also relatively well tolerated. Cohorts A and B [showed an] ORR of [38.1%], including 3 patients who had a CR. [Notably], the DOR was [greater] than 12 months. In other words, if a patient [achieved] a response, it tended to be durable and averaged more than 1 year. Only [3.3%] of patients responded with tucatinib monotherapy, [which equals] 1 patient. This is interesting, because we know that the ORR for HER2-expressing cancers with trastuzumab alone is [between] 10% and 15%.
We also looked at the tucatinib and trastuzumab [arm] post-crossover and [saw] that 18% of patients responded. [These results] emphasize the importance of combining tucatinib and trastuzumab for patients with HER2-overexpressing, mCRC, and [echo] the principle of ‘hit early and hit strong to get your best results.’
To continue building [on these results], we presented some quality-of-life [QOL] data on patient-related outcomes at [the 2022 ESMO Congress]. Ultimately, in this group of chemotherapy-refractory patients, tucatinib combined with trastuzumab [is] not only well tolerated [with] clinically meaningful antitumor activity but [allows] patients [to] maintain QOL throughout the treatment period. There were consistent trends that were observed for patients treated with tucatinib monotherapy, as well.
Together with the efficacy and safety data from MOUTAINEER, this QOL component further supports the overall tolerability profile of the regimen. At this point in time, [these results] make the combination of tucatinib and trastuzumab the preferred option for patients with HER2-positive mCRC.
Overall, this was a very safe regimen. Although there were some adverse effects [AEs], severe AEs were less common. [Most] patients [experienced AEs], but only [about] 38% experienced grade 3 or greater AEs. The [rate of AE-related] treatment discontinuation is one of the lowest we’ve seen, [at 5.8%]. There were [also] no deaths due to AEs.
About [2.3%] of patients had increased [alanine aminotransferase (ALT)], and COVID-19–[related] pneumonia, cholangitis, and fatigue [discontinuation rates were each 1.2%]. We know that fatigue can be problematic in patients receiving TKIs, but this is such a low rate compared with what we see with other TKIs.
Treatment-emergent AEs linked to trastuzumab [reflected a] very similar [incidence of] liver function abnormalities, as well as COVID-19–related pneumonia. This event itself is unlikely to be related to tucatinib and trastuzumab [due to] the pandemic. Overall, [there was a] significant and positive tolerability profile for patients.
[Notably,] when you look at cardiotoxicity, which is important since we’re targeting HER2, there were asymptomatic left ventricular ejection fraction decreases leading to dose modification or discontinuation in 3.5% of patients. [This is] as would be expected for this class of agents.
Diarrhea was predominantly low grade and manageable with prophylaxis. Severe diarrhea was observed in less than 4% of patients. We didn’t mandate antidiarrheal prophylaxis in the study, but I do in my clinic. [It’s] the standard protocol that we use in CRC and tends to control more significant diarrhea in these patients.
In my clinic, everyone gets next-generation sequencing [NGS] and [they are tested] for microsatellite instability–high [MSI-H] status. Patients who [have] RAS wild-type, HER2-amplified tumors [are typically given] FOLFOXIRI plus bevacizumab [Avastin] if they can tolerate it. Those patients should be excluded from receiving EGFR inhibitors based on [previous] data. If I can, I use the combination in the second line but [it is] acceptable to use it in [the] third line if those patients go through the typical FOLFOX, followed by FOLFOX or FOLFIRI to establish a first line of defense.
The good news is that we also have another agent that’s recommended in colon cancer based on [findings from] the [DESTINY-CRC01 study (NCT03384940) of] fam-trastuzumab dertuxtecan-nxki [Enhertu]. [This drug is] a chemotherapy agent that has a targeted moiety and [it] has been shown to be active whether patients receive prior anti-HER2 targeted therapy or not.
The biggest concern with [trastuzumab deruxtecan] is its significant toxicities. [There are] not only chemotherapy-related toxicities such as fatigue, nausea, vomiting, neutropenia, and thrombocytopenia, but interstitial lung disease in about 6% to 10% of patients. In my clinic, we deprioritize this agent in the HER2-targeted strategy, meaning [that] patients will go on chemotherapy in the first line, tucatinib and trastuzumab in the second line, and trastuzumab deruxtecan in the third line. We’ve created multiple targeted options [for] those patients.
MOUNTAINEER-03 [was] based on the interesting findings from MOUNTAINEER. [It aims to] move a therapy that was found to be very promising in later lines into the first line. Tucatinib plus trastuzumab will be added to standard chemotherapy with FOLFOX and will be compared with FOLFOX plus drug or biologic of choice, depending on [region. Patients with] RAS wild-type, HER2-amplified tumors [will] be randomized to [these regimens]. I see a lot of value for bringing this [regimen] into the first line. If the study ends up being positive, it will continue to transform the way we treat patients with [this disease].
We [are] continuing to break down CRC into subgroups and work with HER2, BRAF and RAS pathways. A lot of work [has] been done around KRAS G12C, [and we are now focusing on] other common KRAS alterations. [We achieved] meaningful responses in CRC when the KRAS G12C inhibitor adagrasib [Krazati] was added to cetuximab [Erbitux]. [We have also seen] some interesting data with sotorasib [Lumakras] and panitumumab [Vectibix]. We are seeing the same elevation of approved combinations for BRAF V600E mutations, [with] encorafenib [Braftovi] and cetuximab moving from later lines to the first line [either with] chemotherapy or alone.
We’re also starting to look at less-common alterations. [About] one-third of patients with [tumors harboring] BRAF V600E will also have MSI-H [disease]. The question is, how do we go after [both] targets at the same time? The phase 2 SEAMARK study [(NCT05217446) aims to figure that out].
We’re collaborating with our [colleagues] in Japan through the Gozila platforms [and are] looking at collaborations across the board to understand [how to best] apply next lines of targeted therapy to smaller subsets of patients with colon cancer. In [the field] of colon cancer, we [hope to] move away from random assignment of chemotherapy to all patients and [have] a more targeted approach with molecularly targeted agents and immunotherapeutic strategies [for] patient subgroups.