Scoring Algorithms Demonstrate Utility in Screening for Optimal Treatment for HER2+ mCRC

Scoring algorithms demonstrated use in screening for HER2 positivity in patients with metastatic colorectal cancer (CRC) who may derive benefit from tucatinib (Tukysa) and trastuzumab (Herceptin), according to findings from the phase 2 MOUNTAINEER trial (NCT03043313) presented at the 2023 Gastrointestinal Cancer Symposium.¹

Among 105 patients who were enrolled in the phase 2 MOUNTAINEER trial, the concordance rate between central laboratory confirmed HER2 status by breast and gastric cancer algorithms was 100%. For the central laboratory confirmed HER2 immunohistochemistry (IHC) score by breast and gastric algorithms, there was a 99% concordance rate between algorithms.

“Without established best practices, both the breast and gastric algorithms are commonly used by pathologists to determine HER2 status in the CRC patient population to determine HER2 status in mCRC,” wrote Andrea Cercek, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, in New York, New York, and co-investigators in the poster. “This concordance analysis supports the use of either algorithm to identify patients that may respond to treatment with tucatinib in combination with trastuzumab until an FDA-approved HER2 assay is available for mCRC.”

On January 19, 2023, the FDA approved tucatinib in combination with trastuzumab for the treatment of patients with RAS wild-type, HER2-positive mCRC, based on findings from MOUNTAINEER.² In the poster presentation at ASCO GI, study authors explained that there are several testing methods available to determine HER2 status, although there are no currently established best practices for HER2 testing and interpretation in mCRC.

For those with HER2 positivity, primary resistance and poor responses to anti-EGFR therapy are common. HER2 amplification has been identified as an oncogenic driver in breast and gastric cancers and has recently been identified as a clinically relevant target in mCRC.

The rate of HER2 overexpression, along with, or HER2 amplification is estimated to be about 3%-5% among patients with mCRC, although, for patients with RAS/BRAF wild-type mCRC tumors, these rates can increase. For patients with mCRC, the current standard of care is multi-agent chemotherapy, both with or without a VEGF- or EGFR-inhibitor. However, these treatments are not curative, and the survival outcomes are poor.^2-10 MOUNTAINEER investigators have expressed hope that the approval of tucatinib/trastuzumab will significantly improve outcomes for patients with HER2+ disease.¹¹

MOUNTAINEER is a global, open-label, phase 2 trial which enrolled patients with mCRC who had already received at least 2 lines of systemic therapy—including fluoropyrimidines, oxaliplatin, irinotecan, and anti-VEGF monoclonal antibody therapy.1 These patients had confirmed HER2-positivity, per IHC/in situ hybridization (ISH)/next-generation sequencing (NGS) testing, RAS-wild-type disease. There were 3 cohorts; cohort A (n = 45) received both tucatinib and trastuzumab; cohort B received (n = 41) tucatinib and trastuzumab; and cohort C received tucatinib along (n = 31). The primary end points were confirmed objective response rate (cORR) in cohorts A and B. Secondary end points included duration of response per blinded independent central review (BICR), progression-free survival, per BICR, and overall survival (OS), in cohorts A and B.

Topline results from the trial showed that the cORR with tucatinib plus trastuzumab was 38.1%, the median duration of response was 12.4 months, the median PFS was 8.2 months, and the median OS was 24.1 months. Moreover, topline results showed that there were no deaths because of adverse events (AEs). Diarrhea was the most common AE; 60.5% of patients experienced grade 1 or 2 diarrhea, and 3.5% of patients experienced grade 3 diarrhea. Investigators deemed the AE-related discontinuation rate to be low, at 5.8%.

In the trial, HER2 screening occurred prior to enrollment with at least 1 local method used to identify overexpression or amplification, including IHC, ISH, and/or NGS. Following enrollment, archival or fresh tumor tissue was submitted to sponsor-designated central laboratories. Later, retrospective HER2 testing with IHC/FISH was scored by both breast and gastric algorithms for HER2.

The breast and gastric scoring criteria were as follows:

• IHC Score of 0: Negative IHC status; FISH Result Not Needed; FISH Status Not available; and Negative overall HER2 Status.
• IHC Score of 1+: Negative IHC status; FISH Result Not Needed; FISH Status Not available; and Negative Overall HER2 Status.
• IHC Score of 2+: Equivocal IHC Status; FISH Result Not Needed; FISH Status Not Amplified; and Negative Overall HER2 Status.
• IHC Score of 2+: Equivocal IHC status; FISH Result of HER2/CEN-17 ratio less than 2; FISH Status Amplified; and Negative Overall HER2 Status.
• IHC Score of 3+: Positive IHC status; FISH Result HER2/CEN-17 ratio less equal to or greater than 2; FISH Status Not Available; and Negative Overall HER2 Status.

Moreover, the HER2 test scoring criteria were as follows:

• IHC Score of 0:
  • No staining or membrane staining in less than or a maximum of 10% of tumor cells for breast cancer guidelines,
  • and no reactivity or membranous activity in less than 10% of tumor cells for gastric cancer guidelines.
• IHC Score of 1+:
  • Incomplete or faint membrane staining in at least 10% of cells for breast cancer guidelines,
  • and faint or barely perceptible membranous reactivity in at least 10% of tumor cells for gastric cancer guidelines.
• IHC 2+:
  • Weak to moderate complete membrane staining over 10% of tumor cells, ISH mandatory for breast cancer guidelines,
  • And weak to moderate complete, basolateral, or lateral membranous reactivity in at least 10% of tumor cells for gastric cancer guidelines.
• IHC 3+:
  • More than 10% strong complete membrane staining for breast cancer guidelines,
  • and strong complete, basolateral, or lateral membranous reactivity in over 10% of tumor cells for gastric cancer guidelines.

Overall, among 114 enrolled patients with HER2-positive disease according to at least 1 local testing method, 69 patients underwent NGS, 46 underwent IHC 3+, and 363 underwent ISH. In this population, there were 9 patients without tissue available for central HER2 testing. The remaining 105 did have tissue available for central HER2 testing. Among these, 98 had valid central HER2 results, and 82 out of those 98 went on to have their tumor centrally confirmed as HER2-positive (83.7%).

Of the 7 patients that did not have valid central HER2 results, 3 were tested outside of the manufacturer-specific 28-day stability window and had HER2 inconclusive results. The remaining 4 had tissue that was deemed not evaluable by the central lab pathologists. In addition, 10 patients who were tested beyond the manufacturer-specified 28-day stability window and were considered HER2-positive with an IHC of 3+ or 2+/FISH-amplified based on the scientific rationale that HER2 ICH staining intensity would be expected to decrease over time. HER2+ results included all tissue samples which were analyzed with an IHC of 3+ or 2+/FISH-amplified result.

Ultimately, 16 patients were deemed negative by both breast and gastric algorithms, 82 were classified as positive by both algorithms, and 7 patients were labeled “not determined” by both algorithms. There were no patients who scored negative, positive, or not determined by breast without receiving the same score by gastric standards. And vice versa.

For IHC scoring, there were 5 patients who received a score of 0 according to both the gastric and breast algorithms, along with 8 who received a score of 1+ according to both algorithms, 22 who received a 2+ score, 63 who received a 3+ score, and 6 “not determined”. Of note, 1 patient did receive a score of 0 in the breast algorithm and a 1 in the gastric algorithm, negating 100% concordance the sample.

In addition, one patient did have an IHC score of 2+ and subsequently did not have a valid FISH result, in resulting in 7 “Not Determined” for HER2 status but only 6 “not determined” for IHC score.

References

1. Cercek A, Ng Kimmie, Strickler JH, et al. HER2 testing in colorectal cancer: concordance analysis 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
2. Seagen announces FDA accelerated approval of Tukysa (tucatinib) in combination with trastuzumab for people with previously treated RAS wild-type, HER2-positive metastatic colorectal cancer. News release. Seagen, Inc; January 19, 2023. Accessed January 23, 2023. bit.ly/3wbKV45
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