Gastrointestinal oncologists weigh HER2 testing practices, the order of HER2-directed therapies, and emerging agents for metastatic colorectal cancer.
With tucatinib (Tukysa) plus trastuzumab (Herceptin) and fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) both available for the treatment of patients with HER2-positive metastatic colorectal cancer (mCRC), the challenge in clinical practice is finding eligible patients early in their disease course and choosing the optimal order of therapy.¹
“We still see [approximately] 30% of patients in the community who don’t get tested at all,” Michael Cusnir, MD, of Mount Sinai Medical Center in Florida, said during a recent OncLive® Scientific Interchange and Workshop. John H. Strickler, MD, of Mayo Clinic in Jacksonville, Florida, moderated the panel of gastrointestinal oncologists.
The panelists said that the commonly cited 3% to 5% prevalence of HER2 positivity in mCRC was overstated. Among several hundred patients screened for the phase 3 MOUNTAINEER-03 trial (NCT05253651) at Cusnir’s center, the HER2 positivity rate was below 1% in Hispanic patients and 2% to 3% in non-Hispanic patients.
The faculty regarded HER2 positivity as a practical label for treatment eligibility rather than a single biologic entity, defined by immunohistochemistry (IHC) 3+, IHC 2+ with positive in situ hybridization, or amplification on next-generation sequencing (NGS). T-DXd eligibility requires IHC 3+ expression, but eligibility for tucatinib plus trastuzumab needs only HER2 positivity.²
In the phase 2 MOUNTAINEER trial, tucatinib plus trastuzumab (n = 84) produced a median progression-free survival (PFS) of 8.1 months (95% CI, 4.2-10.2) and a median overall survival of 23.9 months (95% CI, 18.7-28.3).³ However, the panelists agreed that circulating tumor DNA (ctDNA) testing is most helpful for clinical decision-making when the result is positive.1
Many centers test for HER2 at diagnosis, but insurance protocols can hold up NGS on specimens collected during a hospital stay, according to the panelists. Common workarounds include ordering reflex IHC testing from pathology, using in-house panels, and ordering NGS at the first outpatient visit.
Aron Simkins, MD, of Mount Sinai Medical Center, and other faculty favored reflex IHC plus ctDNA as the quickest route to a complete first-line treatment decision. Tissue NGS results have a turnaround time of approximately 2 weeks, whereas this is shortened to 5 to 10 days with ctDNA assays. The panelists were split on whether to begin treatment sooner than the return of the tissue NGS results. Manish A. Shah, MD, of Weill Cornell Medicine in New York, New York, said he starts treating patients with chemotherapy within 1 week of testing based on IHC and adds other agents later; other experts agreed that they wait for the full panel of results to come back.
HER2-Positive mCRC Management
The faculty agreed that patients should receive tucatinib plus trastuzumab first and T-DXd after disease progression, generally after repeating HER2 testing by liquid biopsy. Treatment durability drove that choice. In the phase 2 DESTINY-CRC01 trial (NCT03384940), T-DXd at 6.4 mg/kg produced a cORR of 45.3% (95% CI, 31.6%-59.6%) in patients with HER2-positive mCRC (n = 53), but the median duration of response (DOR) was 7.0 months (95% CI, 5.8-9.5), and grade 3 or higher interstitial lung disease or pneumonitis was observed.⁴ Conversely, in MOUNTAINEER, tucatinib plus trastuzumab yielded a median DOR of 15.2 months (95% CI, 8.9-20.5).³
“The responses seem to be more transient with T-DXd than we got out of MOUNTAINEER,” Strickler said, cautioning the limitations of cross-trial comparisons.¹
However, community practice patterns often run in reverse, which Cusnir attributed to many generalist oncologists’ familiarity with T-DXd from treating patients with breast cancer. The panelists saw this as the widest gap between academic and community care.
The MOUNTAINEER-03 trial is randomly assigning patients with HER2-positive, RAS wild-type disease to receive first-line modified FOLFOX6 (mFOLFOX6; oxaliplatin, leucovorin, and fluorouracil) plus tucatinib and trastuzumab or mFOLFOX6 alone or combined with bevacizumab (Avastin) or cetuximab (Erbitux); the primary end point is PFS.⁵ The panelists expect a positive result to change first-line treatment selection, and several questioned whether chemotherapy is needed.¹
Turning their attention to emerging agents, the panelists reported that in a randomized phase 3 trial, trastuzumab rezetecan (SHR-A1811; n = 86) improved median PFS vs standard of care (n = 44) in patients with HER2-positive advanced CRC (HR, 0.33; 95% CI, 0.21-0.53; P < .0001).6 However, they judged the efficacy of this antibody-drug conjugate to be equivalent to that of T-DXd.1
Additionally, the experts highlighted that in a pooled analysis of patients with HER2-positive CRC (n = 19), zongertinib (Hernexeos) produced a cORR of 42% (95% CI, 23.1%-63.7%).⁷ Zanidatamab-hrii (Ziihera) drew the most interest from the panelists, as they viewed a bispecific antibody as a logical partner for a TKI.¹
The panelists identified education about genomic sequencing and early HER2 testing as the clearest need in the mCRC treatment field, as Cusnir warned that a rare amplification is easily overlooked once RAS wild-type status is noted.1 For future first-line trials, the panelists proposed enrolling patients based on the results of local testing with parallel confirmation and accepting PFS as a registrational end point.
