Tanios S. Bekaii-Saab, MD, FACP
The addition of trastuzumab (Herceptin) to tucatinib (Tukysa) considerably improves results, maintains high quality of existence, and is easily tolerated in sufferers with HER2-positive metastatic colorectal most cancers (mCRC), supporting its use as the primary HER2-targeted routine for this affected person inhabitants. If authorized by means of the FDA, in style adoption of the doublet will supply sufferers with a much-needed remedy selection, in step with Tanios S. Bekaii-Saab, MD, FACP.
On September 19, 2022, the FDA granted precedence evaluation standing to tucatinib together with trastuzumab for grownup sufferers with HER2-positive CRC who’ve gained no less than 1 prior remedy routine for unresectable or metastatic illness.1
The applying used to be supported by means of findings from the segment 2 MOUNTAINEER trial (NCT03043313), the place the routine demonstrated an function reaction fee (ORR) of 38.1% (n = 84; 95% CI, 27.7%-49.3%), with an average length of reaction (DOR) of 12.4 months (95% CI, 8.5-20.5). Additionally, sufferers who gained the doublet skilled an average progression-free survival (PFS) of 8.2 months (95% CI, 4.2-10.3) and an average total survival (OS) of 24.1 months (95% CI, 20.3-36.7).2,3
The regulatory company is anticipated to make a decision at the supplemental new drug utility for the mix by means of January 19, 2023 below the Prescription Drug Person Price Act.
“The [FDA approval of this regimen will be] a significant win for sufferers with HER2-positive metastatic CRC, [as] we’ll have the ability to be offering tucatinib and trastuzumab to our sufferers who already failed on no less than 1 prior line of treatment,” stated Bekaii-Saab, who’s the chief of the Gastrointestinal Most cancers Program on the Mayo Health facility Complete Most cancers Middle, scientific director of the Most cancers Medical Analysis Place of work, and the vice chair and segment leader for scientific oncology within the Division of Inside Medication at Mayo Health facility in Phoenix, Arizona.
In an interview with OncLive®, Bekaii-Saab expanded on key efficacy and protection knowledge reported with the routine from the MOUNTAINEER trial, the possible results of this routine’s approval at the present remedy panorama, and the ongoing investigation of this and different focused approaches in mCRC.
OncLive®: How would the FDA popularity of tucatinib plus trastuzumab in mCRC impact scientific handle this inhabitants?
Bekaii-Saab:This [will be] the primary popularity of any focused technique in sufferers with HER2-overexpressing mCRC. We’ve in the past had some smaller, single-arm research that instructed get advantages [with targeted therapy–based combinations] and [these regimens] had been incorporated within the tips, however there used to be no FDA popularity of any of those mixtures.
It’s additionally essential to notice that [this] subgroup of sufferers [makes up] about 2% to three% of all sufferers with colon most cancers, [which is] a vital quantity. [Moreover], sufferers with HER2-amplified, RAS wild-type most cancers don’t reply [well] to EGFR inhibitors, so they’ve much less choices than different RAS wild-type sufferers, except for for the ones [with] BRAF-mutated tumors. Having a extensively authorized mixture treatment [will be] a significant acquire for sufferers with HER2-positive mCRC [whose disease is] additionally RAS wild form.
May just you make bigger at the trial design of MOUNTAINEER, and the affected person inhabitants incorporated?
MOUNTAINEER used to be an international, open-label segment 2 trial. It began with 45 sufferers [in] cohort A. There used to be an investigator-initiated element of the trial run during the Accrual Analysis Consortium, supported by means of Mayo Health facility, with John Strickler, MD, of [Duke Cancer Institute], as major investigator [and myself] as co-principal investigator.
[Along with] Seagen, we then [turned] this right into a randomized find out about with 41 sufferers [in] cohort B and  sufferers in cohort C. Sufferers had been randomized to tucatinib [plus] trastuzumab or tucatinib on my own. Apparently, in cohort C, [patients] on tucatinib on my own had been allowed to pass over to tucatinib and trastuzumab [regardless of whether] they skilled radiographic development at any level or had now not accomplished a [partial response (PR) or complete response (CR)] by means of week 12.
The find out about incorporated sufferers with RAS wild-type illness [who had received] an average of three prior traces of systemic treatment in any surroundings. Those sufferers had been closely pretreated.
What had been the important thing efficacy knowledge noticed with tucatinib plus trastuzumab within the trial, and what updates had been offered on the 2022 ESMO Congress?
The find out about met its number one finish level, appearing advantageous efficacy effects, and [tucatinib plus trastuzumab was] additionally moderately neatly tolerated. Cohorts A and B [showed an] ORR of [38.1%], together with 3 sufferers who had a CR. [Notably], the DOR used to be [greater] than 365 days. In different phrases, if a affected person [achieved] a reaction, it tended to be sturdy and averaged greater than 1 yr. Best [3.3%] of sufferers answered with tucatinib monotherapy, [which equals] 1 affected person. That is attention-grabbing, as a result of we all know that the ORR for HER2-expressing cancers with trastuzumab on my own is [between] 10% and 15%.
We additionally regarded on the tucatinib and trastuzumab [arm] post-crossover and [saw] that 18% of sufferers answered. [These results] emphasize the significance of mixing tucatinib and trastuzumab for sufferers with HER2-overexpressing, mCRC, and [echo] the main of ‘hit early and hit robust to get your easiest effects.’
To proceed development [on these results], we offered some quality-of-life [QOL] knowledge on patient-related results at [the 2022 ESMO Congress]. In the long run, on this staff of chemotherapy-refractory sufferers, tucatinib mixed with trastuzumab [is] now not most effective neatly tolerated [with] clinically significant antitumor task however [allows] sufferers [to] handle QOL all through the remedy length. There have been constant developments that had been noticed for sufferers handled with tucatinib monotherapy, as neatly.
Along with the efficacy and protection knowledge from MOUTAINEER, this QOL element additional helps the entire tolerability profile of the routine. At this day and age, [these results] make the mix of tucatinib and trastuzumab the most popular choice for sufferers with HER2-positive mCRC.
May just you make bigger at the protection profile and remedy discontinuation charges related to the tucatinib/trastuzumab routine?
General, this used to be an overly protected routine. Despite the fact that there have been some antagonistic results [AEs], critical AEs had been much less normal. [Most] sufferers [experienced AEs], however most effective [about] 38% skilled grade 3 or larger AEs. The [rate of AE-related] remedy discontinuation is among the lowest we’ve noticed, [at 5.8%]. There have been [also] no deaths because of AEs.
About [2.3%] of sufferers had larger [alanine aminotransferase (ALT)], and COVID-19–[related] pneumonia, cholangitis, and fatigue [discontinuation rates were each 1.2%]. We all know that fatigue may also be problematic in sufferers receiving TKIs, however that is the sort of low fee when compared with what we see with different TKIs.
Remedy-emergent AEs related to trastuzumab [reflected a] very identical [incidence of] liver serve as abnormalities, in addition to COVID-19–connected pneumonia. This match itself is not going to be associated with tucatinib and trastuzumab [due to] the pandemic. General, [there was a] vital and advantageous tolerability profile for sufferers.
[Notably,] while you have a look at cardiotoxicity, which is essential since we’re focused on HER2, there have been asymptomatic left ventricular ejection fraction decreases resulting in dose amendment or discontinuation in 3.5% of sufferers. [This is] as could be anticipated for this elegance of brokers.
Diarrhea used to be predominantly low grade and manageable with prophylaxis. Critical diarrhea used to be noticed in lower than 4% of sufferers. We didn’t mandate antidiarrheal prophylaxis within the find out about, however I do in my sanatorium. [It’s] the usual protocol that we use in CRC and has a tendency to regulate extra vital diarrhea in those sufferers.
How would possibly this mix have compatibility into present remedy methods for this affected person inhabitants?
In my sanatorium, everybody will get next-generation sequencing [NGS] and [they are tested] for microsatellite instability–top [MSI-H] standing. Sufferers who [have] RAS wild-type, HER2-amplified tumors [are typically given] FOLFOXIRI plus bevacizumab [Avastin] if they are able to tolerate it. The ones sufferers must be excluded from receiving EGFR inhibitors according to [previous] knowledge. If I will, I take advantage of the mix in the second one line however [it is] appropriate to make use of it in [the] 0.33 line if the ones sufferers pass during the conventional FOLFOX, adopted by means of FOLFOX or FOLFIRI to determine a primary defensive line.
The excellent news is that we even have some other agent that’s advisable in colon most cancers according to [findings from] the [DESTINY-CRC01 study (NCT03384940) of] fam-trastuzumab dertuxtecan-nxki [Enhertu]. [This drug is] a chemotherapy agent that has a focused moiety and [it] has been proven to be energetic whether or not sufferers obtain prior anti-HER2 focused treatment or now not.
The largest worry with [trastuzumab deruxtecan] is its vital toxicities. [There are] now not most effective chemotherapy-related toxicities reminiscent of fatigue, nausea, vomiting, neutropenia, and thrombocytopenia, however interstitial lung illness in about 6% to ten% of sufferers. In my sanatorium, we deprioritize this agent within the HER2-targeted technique, that means [that] sufferers will pass on chemotherapy within the first line, tucatinib and trastuzumab in the second one line, and trastuzumab deruxtecan within the 0.33 line. We’ve created more than one focused choices [for] the ones sufferers.
What used to be the explanation for comparing this mix within the ongoing segment 3 MOUNTAINEER-03 trial (NCT05253651)?
MOUNTAINEER-03 [was] according to the attention-grabbing findings from MOUNTAINEER. [It aims to] transfer a treatment that used to be discovered to be very promising in later traces into the primary line. Tucatinib plus trastuzumab will probably be added to straightforward chemotherapy with FOLFOX and will probably be when compared with FOLFOX plus drug or biologic of selection, relying on [region. Patients with] RAS wild-type, HER2-amplified tumors [will] be randomized to [these regimens]. I see a large number of worth for bringing this [regimen] into the primary line. If the find out about finally ends up being advantageous, it’ll proceed to turn into the way in which we deal with sufferers with [this disease].
What deliberate or ongoing research at Mayo Health facility do you want to spotlight?
We [are] proceeding to damage down CRC into subgroups and paintings with HER2, BRAF and RAS pathways. Numerous paintings [has] been completed round KRAS G12C, [and we are now focusing on] different normal KRAS alterations. [We achieved] significant responses in CRC when the KRAS G12C inhibitor adagrasib [Krazati] used to be added to cetuximab [Erbitux]. [We have also seen] some attention-grabbing knowledge with sotorasib [Lumakras] and panitumumab [Vectibix]. We’re seeing the similar elevation of authorized mixtures for BRAF V600E mutations, [with] encorafenib [Braftovi] and cetuximab transferring from later traces to the primary line [either with] chemotherapy or on my own.
We’re additionally beginning to have a look at less-common alterations. [About] one-third of sufferers with [tumors harboring] BRAF V600E may even have MSI-H [disease]. The query is, how will we pass after [both] objectives on the identical time? The segment 2 SEAMARK find out about [(NCT05217446) aims to figure that out].
We’re taking part with our [colleagues] in Japan during the Gozila platforms [and are] taking a look at collaborations around the board to know [how to best] follow subsequent traces of focused treatment to smaller subsets of sufferers with colon most cancers. In [the field] of colon most cancers, we [hope to] transfer clear of random project of chemotherapy to all sufferers and [have] a extra focused way with molecularly focused brokers and immunotherapeutic methods [for] affected person subgroups.
- Seagen declares Tukysa (tucatinib) together with trastuzumab granted precedence evaluation by means of FDA for in the past handled HER2-positive metastatic colorectal most cancers. Information unencumber. Seagen Inc. September 19, 2022. Accessed January 17, 2023. https://bit.ly/3DyydRB
- Strickler JH, Ng Ok, Cercek A, et al. MOUNTAINEER: open-label, segment II find out about of tucatinib mixed with trastuzumab for HER2-positive metastatic colorectal most cancers (SGNTUC-017, trial in growth). J Clin Oncol. 2021;39(suppl 3):TPS153. doi:10.1200/JCO.2021.39 .3_suppl.TPS153
- Strickler JH, Cercek A, Siena S, et al: Further analyses of MOUNTAINEER: a segment II find out about of tucatinib and trastuzumab for HER2-positive mCRC. Ann Oncol. 2022;33(suppl 7):S1394. doi:10.1016/j.annonc.2022.08.023