There was a close to 100% concordance charge between gastric and breast most cancers HER2 scoring algorithms in a retrospective evaluation of the section 2 MOUNTAINEER trial (NCT03043313), suggesting that both algorithm can be utilized to determine HER2-positivity in sufferers with metastatic colorectal most cancers (mCRC ). These outcomes, which have been offered on the 2023 Gastrointestinal Most cancers Symposiumcould also be helpful in serving to suppliers decide which sufferers could profit from therapy with tucatinib (Tukysa) plus trastuzumab (Herceptin), in response to investigators.one
Amongst 105 sufferers who have been enrolled within the section 2 MOUNTAINEER trial, the concordance charge between central laboratory confirmed HER2 standing by breast and gastric most cancers algorithms was 100%. For the central laboratory confirmed HER2 immunohistochemistry (IHC) rating by breast and gastric algorithms, there was a 99% concordance charge between algorithms.one
“With out established finest practices, each the breast and gastric algorithms are generally utilized by pathologists to find out HER2 standing within the CRC affected person inhabitants to find out HER2 standing in mCRC,” wrote Andrea Cercek, MD, a medical oncologist at Memorial Sloan Kettering Most cancers Heart, in New York, New York, and co-investigators within the poster. “This concordance evaluation helps the usage of both algorithm to determine sufferers who could reply to therapy with tucatinib together with trastuzumab till an FDA-approved HER2 assay is offered for mCRC.”
On January 19, 2023, the FDA accredited tucatinib together with trastuzumab for the therapy of sufferers with RAS wild-type, HER2-positive mCRC, based mostly on findings from MOUNTAINEER.2 Within the poster presentation at ASCO GI, examine authors defined that there are a number of testing strategies obtainable to find out HER2 standing, though there aren’t any at present established finest practices for HER2 testing and interpretation in mCRC.one
For these with HER2 positivity, major resistance and poor responses to anti-EGFR remedy are frequent. HER2 amplification has been recognized as an oncogenic driver in breast and gastric cancers and has lately been recognized as a clinically related goal in mCRC.
The speed of HER2 overexpression, together with, or HER2 amplification is estimated to be about 3%-5% amongst sufferers with mCRC, though, for sufferers with RAS/BRAF wild-type mCRC tumors, these charges can improve. For sufferers with mCRC, the present normal of care is multi-agent chemotherapy, each with or with out a VEGF- or EGFR-inhibitor. Nevertheless, these therapies aren’t healing, and the survival outcomes are poor.2-10 MOUNTAINEER investigators have expressed hope that the approval of tucatinib/trastuzumab will considerably enhance outcomes for sufferers with HER2+ illness.eleven
MOUNTAINEER is a world, open-label, section 2 trial which enrolled sufferers with mCRC who had already obtained at the very least 2 strains of systemic remedy—together with fluoropyrimidines, oxaliplatin, irinotecan, and anti-VEGF monoclonal antibody remedy.one These sufferers had confirmed HER2-positivity, per IHC/in situ hybridization (ISH)/next-generation sequencing (NGS) testing, RAS-wild-type illness. There have been 3 cohorts; cohort A (n = 45) obtained each tucatinib and trastuzumab; cohort B obtained (n = 41) tucatinib and trastuzumab; and cohort C obtained tucatinib alongside (n = 31). The first finish factors have been confirmed goal response charge (cORR) in cohorts A and B. Secondary finish factors included length of response per blinded impartial central assessment (BICR), progression-free survival, per BICR, and general survival (OS), in cohorts A and B.
Topline outcomes from the trial confirmed that the cORR with tucatinib plus trastuzumab was 38.1%, the median length of response was 12.4 months, the median PFS was 8.2 months, and the median OS was 24.1 months. Moreover, topline outcomes confirmed that there have been no deaths due to hostile occasions (AEs). Diarrhea was the most typical AE; 60.5% of sufferers skilled grade 1 or 2 diarrhea, and three.5% of sufferers skilled grade 3 diarrhea. Investigators deemed the AE-related discontinuation charge to be low, at 5.8%.
Within the trial, HER2 screening occurred previous to enrollment with at the very least 1 native methodology used to determine overexpression or amplification, together with IHC, ISH, and/or NGS. Following enrollment, archival or contemporary tumor tissue was submitted to sponsor-designated central laboratories. Later, retrospective HER2 testing with IHC/FISH was scored by each breast and gastric algorithms for HER2.
The breast and gastric scoring standards have been as follows:
- IHC Rating of 0: Detrimental IHC standing; FISH End result Not Wanted; FISH Standing Not obtainable; and Detrimental general HER2 Standing.
- IHC Rating of 1+: Detrimental IHC standing; FISH End result Not Wanted; FISH Standing Not obtainable; and Detrimental Total HER2 Standing.
- IHC Rating of two+: Equivocal IHC Standing; FISH End result Not Wanted; FISH Standing Not Amplified; and Detrimental Total HER2 Standing.
- IHC Rating of two+: Equivocal IHC standing; FISH Results of HER2/CEN-17 ratio lower than 2; FISH Standing Amplified; and Detrimental Total HER2 Standing.
- IHC Rating of three+: Constructive IHC standing; FISH End result HER2/CEN-17 ratio much less equal to or larger than 2; FISH Standing Not Obtainable; and Detrimental Total HER2 Standing.
Moreover, the HER2 check scoring standards have been as follows:
- IHC Rating of 0:
- No staining or membrane staining in lower than or a most of 10% of tumor cells for breast most cancers tips,
- and no reactivity or membranous exercise in lower than 10% of tumor cells for gastric most cancers tips.
- IHC Rating of 1+:
- Incomplete or faint membrane staining in at the very least 10% of cells for breast most cancers tips,
- and faint or barely perceptible membranous reactivity in at the very least 10% of tumor cells for gastric most cancers tips.
- IHC 2+:
- Weak to average full membrane staining over 10% of tumor cells, ISH obligatory for breast most cancers tips,
- And weak to average full, basolateral, or lateral membranous reactivity in at the very least 10% of tumor cells for gastric most cancers tips.
- IHC 3+:
- Greater than 10% robust full membrane staining for breast most cancers tips,
- and robust full, basolateral, or lateral membranous reactivity in over 10% of tumor cells for gastric most cancers tips.
Total, amongst 114 enrolled sufferers with HER2-positive illness in response to at the very least 1 native testing methodology, 69 sufferers underwent NGS, 46 underwent IHC 3+, and 363 underwent ISH. On this inhabitants, there have been 9 sufferers with out tissue obtainable for central HER2 testing. The remaining 105 did have tissue obtainable for central HER2 testing. Amongst these, 98 had legitimate central HER2 outcomes, and 82 out of these 98 went on to have their tumor centrally confirmed as HER2-positive (83.7%).
Of the 7 sufferers that didn’t have legitimate central HER2 outcomes, 3 have been examined outdoors of the manufacturer-specific 28-day stability window and had inconclusive HER2 outcomes. The remaining 4 had tissue that was deemed not evaluable by the central lab pathologists. As well as, 10 sufferers who have been examined past the manufacturer-specified 28-day stability window and have been thought-about HER2-positive with an IHC of three+ or 2+/FISH-amplified based mostly on the scientific rationale that HER2 ICH staining depth could be anticipated to lower over time. HER2+ outcomes included all tissue samples which have been analyzed with an IHC of three+ or 2+/FISH-amplified consequence.
In the end, 16 sufferers have been deemed adverse by each breast and gastric algorithms, 82 have been categorised as optimistic by each algorithms, and seven sufferers have been labeled “not decided” by each algorithms. There have been no sufferers who scored adverse, optimistic, or not decided by breast with out receiving the identical rating by gastric requirements. And vice versa.
For IHC scoring, there have been 5 sufferers who obtained a rating of 0 in response to each the gastric and breast algorithms, together with 8 who obtained a rating of 1+ in response to each algorithms, 22 who obtained a 2+ rating, 63 who obtained a 3+ rating, and 6 “not decided”. Of notice, 1 affected person did obtain a rating of 0 within the breast algorithm and a 1 within the gastric algorithm, negating 100% concordance the pattern.
As well as, one affected person did have an IHC rating of two+ and subsequently didn’t have a sound FISH consequence, leading to 7 “Not Decided” for HER2 standing however solely 6 “not decided” for IHC rating.
- Cercek A, Ng Kimmie, Strickler JH, et al. HER2 testing in colorectal most cancers: concordance evaluation between breast and gastric scoring algorithms from the MOUNTAINEER trial. J Clin Oncol. 2023;41(suppl 4):198. doi:10.1200/JCO.2023.41.3_suppl.198
- Seagen publicizes FDA accelerated approval of Tukysa (tucatinib) together with trastuzumab for individuals with beforehand handled RAS wild-type, HER2-positive metastatic colorectal most cancers. Information launch. Seagen, Inc.; January 19, 2023. Accessed January 23, 2023. bit.ly/3wbKV45
- Benson AB, Venook AP, Al-Hawary MM, et al. Colon most cancers, model 2.2021, NCCN medical apply tips in oncology. J Natl Compr Canc Netw. 2021;19(3):329-359. doi:10.6004/jnccn.2021.0012
- Strickler J, Ng Okay, Cercek A, et al. MOUNTAINEER: open-label, section II examine of tucatinib mixed with trastuzumab for HER2-positive metastatic colorectal most cancers (SGNTUC-017, trial in progress). J Clin Oncol. 2021;39(suppl 3): TPS153. doi:10.1200/JCO.2021.39.3_suppl.TPS153
- Sartore-Bianchi A, Amatu A, Porcu L, et al. HER2 positivity predicts unresponsiveness to EGFR-targeted therapy in metastatic colorectal most cancers. Oncologist. 2019;24(10):1395-1402. doi:10.1634/theoncologist.2018-0785
- Heinemann V, Singh M, Hardtstock F, et al. Evaluation of metastatic colorectal ancer sufferers’ preferences for biologic therapies in germany utilizing a discrete alternative experiment. Clin Colorectal Most cancers. 2022;21(2):122-131. doi:10.1016/j.clcc.2021.12.002
- Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus tips for the administration of sufferers with metastatic colorectal most cancers. Ann Oncol. 2016;27(8):1386-1422. doi:10.1093/annonc/mdw235
- Jeong JH, Kim J, Hong YS, et al. HER2 amplification and cetuximab efficacy in sufferers with metastatic colorectal most cancers harboring wild-type RAS and BRAF. Clin Colorectal Most cancers. 2017;16(3):e147-e152. doi:10.1016/j.clcc.2017.01.005
- Raghav Okay, Loree JM, Morris JS, et al. Validation of HER2 amplification as a predictive biomarker for anti-epidermal development issue receptor antibody remedy in metastatic colorectal most cancers. JCO Summary Oncol. 2019;3:1-13. doi:10.1200/PO.18.00226
- Ross JS, Fakih M, Ali SM, et al. Focusing on HER2 in colorectal most cancers: The panorama of amplification and brief variant mutations in ERBB2 and ERBB3. Most cancers. 2018;124(7):1358-1373. doi:10.1002/cncr.31125
- Flaherty C. Tucatinib plus trastuzumab might handle want for brand new normal of care in HER2+ metastatic CRC. January 18, 2023. Accessed January 23, 2023. https://bit.ly/3Xu0HTZ