Anti-HER2 Agents Gain Ground in Colorectal Cancer

The genome sequencing of cancers has revolutionized the field of cancer therapy by identifying novel genomic changes and driver events in human malignancies with prognostic and therapeutic value.¹ One such genetic alteration is ERBB2 (also known as HER2) gene amplification. Approximately 20% of breast cancer cases and 15% of gastric cancer cases are significantly inluenced by HER2 status, so antiHER2 therapy has become a standard treatment.² In the wave of its major influence on these malignancies, anti-HER2 therapy for various cancers—notably colorectal cancer (CRC)—has been thoroughly investigated.³

“HER2 amplification or overexpression occurs in 3% of all patients with metastatic CRC (mCRC), and those rates are a bit higher in patients who have RAS and BRAF wild-type disease, John H. Strickler, MD, said in an interview with Targeted Therapies in Oncology™. Strickler is an associate professor of medicine and member of the Duke Cancer Institute at Duke University School of Medicine in urham, North Carolina. Currently, however, the prognostic value of HER2 in CRC is unclear.⁴ “From a prognostic standpoint, its unclear whether HER2 confers a negative outcome on patients, Stricler said. Although some studies have shown that patients with HER2-positive malignancies had a worse overall survival (OS) rate than those with HER2-negative tumors, other studies have found no association between HER2 status and survival outcomes.^5,6

However, HER2 status may predict disease behavior. Theres a uniue pattern of metastasis from HER2-positive mCRC, Strickler noted. Specifically, its more likely to metastasize to the brain and lung than nonHER2-positive mCRC. Additionally, for a subgroup of patients, HER2 amplification may predict resistance to certain standard therapies. hats been shown in preclinical work and retrospective studies is that HER2 overexpression drives resistance to our current standard of care for patients with RAS therapies, Stricler said. However, these patients may benefit from anti-HER2 therapies.⁷

Currently, HER2-directed antibodies and tyrosine kinase inhibitors (TKIs) are the major anti-HER2 therapeutic options in mCRC.⁸

Small Molecule TKIs

Tucatinib

Tucatinib (Tuysa) is an orally available, reversible HER2-targeted TI. It selectively inhibits HER2 enzymatic activity, distinguishing it from other TIs such as neratinib (Nerlynx), which is a potent inhibitor of both HER2 and EGFR.⁹

"Whats uniue about tucatinib compared with other TKIs is that it has a minimal inhibitory effect on other HER-family receptors, like EGFR. As a result, rash or diarrhea is observed less with tucatinib than other nonselective TKIs,ܺ Strickler said.

In 2020, tucatinib was approved for the treatment of advanced unresectable or metastatic HER2-positive breast cancer in combination with trastuzumab (Herceptin) and capecitabine for adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.¹⁰ In HER2-amplified CRC, it displayed considerable anticancer efficacy in patient-derived xenograft models. The effect was amplified when combined with the HER2-directed antibody, trastuzumab.⁹

The combination of tucatinib and trastuzumab was further evaluated in the phase 2 MOUNTAINEER trial (NCT03043313; FIGURE¹¹) in patients with HER2-positive mCRC. At a median follow-up of 20.7 months, the 86 patients with RAS wild-type mCRC with HER2 amplification treated with the combination drug therapy had a 38.1% confirmed objective response rate (ORR) and a disease control rate ('CR) of 71.4%.^{11 ܹ}

The duration of response was pretty interesting,ܺ Tanios S. Bekaii-Saab, MD, FACP, said. Bekaii-Saab is leader of the Gastrointestinal Cancer Program and medical director of the Clinical Research Office at Mayo Clinic Comprehensive Cancer Center and vice chair and section chief of medical oncology in the Department of Internal Medicine at Mayo Clinic in Phoenix, Arizona. “It was above a year, and the median OS was 24 months.” A smaller cohort of patients who received tucatinib monotherapy had a response rate of 3.3% and a DCR of 80.0% at 12 weeks.¹¹

In addition, the combination treatment was well tolerated.¹¹ The most frequent treatment-emergent adverse events (TEAEs) were diarrhea, fatigue, nausea, and infusion-related symptoms. Hypertension was the most prevalent grade 3 or greater toxicity in 7% of patients.¹¹ Regarding tucatinib monotherapy, the most common adverse events included diarrhea, fatigue, nausea, and dermatitis acneiform. The most common grade 3 or greater treatment-related toxicities were increased alanine aminotransferase levels and diarrhea, both occurring in 2% of patients.^{11 ܹ}

This combination [tucatinib/trastuzumab drug therapy] has recently been FDA approved for RAS wild-type, HER2-positive unresectable or metastatic CRC in the second line and beyond],” Bekaii-Saab said,¹² adding that another study evaluating combination tucatinib trastuzumab treatment is underway. ܹThereܼs a follow-up study called MOUNTAINEER-03 (NCT05253651), which is essentially looking at moving trastuzumab with tucatinib to the first-line and combining it with chemotherapy versus chemotherapy plus biologic of choice.”

The phase 3 MOUNTAINEER-03 trial is expected to finish by 2028.¹¹

Pyrotinib

Pyrotinib is an irreversible pan-HER TKI targeting HER2, EGFR, and HER4. In 2018, it was approved to treat HER2-positive recurrent or metastatic breast cancer in China and has shown antitumor effect in other solid tumors in lung and gastric cancer.¹³ A retrospective study evaluating the safety and effectiveness of pyrotinib in HER2-positive advanced nonbreast solid tumors showed potent antitumor activity and a satisfactory safety profile.¹⁴ Li et al found that pyrotinib monotherapy can be effective in salvage therapy settings for patients with mCRC with HER2 amplification who have developed resistance to trastuzumab and lapatinib (Tykerb).¹⁵

Findings from the HER2-FUSCC-G study (NCT04960943) demonstrated that the combination of pyrotinib and trastuzumab was effective in treatment-refractory HER2-positive RAS wild-type mCRC. Median progression-free survival (PFS) and OS at 11.2 months were 7.53 and 16.8 months, respectively. In addition, patients with wild-type RAS/BRAF had prolonged survival compared with patients with RAS/BRAF mutations (7.53 vs 1.63 months, respectively; P = .02) The most common TEAE was diarrhea.¹⁶

Results from another study assessing the safety and efficacy of pyrotinib in combination with trastuzumab for treating HER2-positive recurrentܘmetastatic CRC showed an ORR and DCR of 22.2% and 61.1%, respectively. Approximately 22% of patients achieved a confi rmed partial response, and 39% had stable disease. The ORR and DCR in patients with wild-type RAS/BRAF were 33.3% and 83.3%, respectively. The most common adverse events were diarrhea, fatigue, hand-foot syndrome, and anemia.¹⁷

Neratinib

Neratinib, like pyrotinib, is an irreversible pan-HER TKI targeting HER2, EGFR, and HER4.In cell lines and xenografts, neratinib was more potent than the TKI lapatinib.¹⁸ Findings from another study showed that across several tumor types harboring HER2 mutations, neratinib resulted in promising levels of activity.¹⁹

Jacobs et al demonstrated that the combination therapy of neratinib and cetuximab (Erbitux) in 11 patients with quadruple wild-type (KRAS/NRAS/BRAF/PIK3CA) HER2-positive tumors was well tolerated, with a low incidence of grade 3 or greater adverse events. Patients were required to have prior treatment with oxaliplatin and irinotecan chemotherapy and anti-EGFR therapy with either cetuximab or panitumumab (Vectibix). Results indicated that no patients achieved enough tumor shrinţage to meet the Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 criteria for an objective response. However, 44% of patients had stable disease at all neratinib doses, and 4 showed HER2 amplification in the initial tumor or enrollment biopsy.¹⁸

BDTX-189 

BDTX-189 is a potent, selective, irreversible TKI that is highly selective against uniơue oncogenic driver mutations of the ERBB family—including extracellular, transmembrane, and ţinase domain allosteric mutations of HER2 and EGFR—while sparing wild-type EGFR. ²⁰

In the ongoing Masterkey-01 trial (NCT04209465), the safety, tolerability, pharmacoţinetics, and antitumor activity of BDTX-189 are being assessed in patients with advanced solid malignancies, including CRC, non–small cell lung cancer, and breast, ovary, biliary, pancreas, and cervical cancers.²¹ Initial trial data have revealed a favorable toxicity profile for BDTX-189 therapy. Most TEAEs were medically manageable and low grade in nature. TEAEs included diarrhea, nausea, vomiting, elevated alanine transaminase and aspartate aminotransferase (AST) levels, and fatigue. Moreover, evidence of anticancer activity was observed in heavily pretreated patients, including those who received prior HER2 TKI therapy.²¹

Fruquintinib

Other TKIs, besides those targeting HER2, also have shown good responses in treating mCRC. Fruơuintinib is an oral TKI that targets VEGFR ^{-1, -2,} and ^-3.22. In the phase 3 FRESCO trial (NCT02314819), it was shown to improve both OS and PFS compared with placebo in patients with mCRC. It also demonstrated a satisfactory safety and tolerability profile. Based on the result from this trial fruơuintinib was approved in China for the treatment of patients with mCRC who had undergone at least 2 prior standard anticancer therapies.²³

Recently, data from the phase 3 FRESCO-2 trial (NCT04322539) demonstrated that patients with refractory mCRC treated with fruơuintinib plus best supportive care had a significant and clinically meaningful improvement in OS compared with those who received placebo plus best supportive care. Fruquintinib was also well tolerated and had an acceptable safety profile consistent with data from the FRESCO trial. The study authors asserted that fruơuintinib should be considered a new treatment option for this patient population.^23,24

Combination HER2-Targeting Therapy

Numerous other noteworthy trials have evaluated the safety and effectiveness of combined HER2-targeting treatment in mCRC. One such study is HERACLES (NCT03225937), which demonstrated the efficacy of trastuzumab plus lapatinib in patients with KRAS wild-type, chemotherapy-refractory HER2-positive mCRC. Longterm data from the HERACLES trial showed that one patient achieved a sustained complete response, 25% of patients achieved a partial response, and 41% achieved stable disease. Overall, the response rate was 28%, the median PFS was 4.7 months, and the median OS was 10.0 months. The study investigators concluded that the combination of lapatinib and trastuzumab should be used as a treatment standard for this patient population.²⁵

Following HERACLES, the HERACLES-B trial (NCT03225937) examined the effectiveness of the combination of pertuzumab (Perjeta) and ado-trastuzumab emtansine (T-DM1; Kadcyla) in mCRC. Participants in the HERACLES-B trial had histologically confirmed wild-type RAS/BRAF and HER2-positive mCRC refractory to standard treatments. The ORR of 9.7%, among the 48.0% of patients with 4 or more lines of previous treatments, was below the end point for success in the trial. However, 77.4% of patients achieved disease control, and the median PFS was comparable with other anti-HER2 regimens. Moreover, the combination of pertuzumab and T-DM1 exhibited an excellent safety profile.²⁶

Data from the My Pathway trial (NCT02091141) showed that among 57 patients with HER2-amplified mCRC, dual HER2-targeting monoclonal antibody therapy with trastuzumab plus pertuzumab led to an objective response in 18 patients.²⁷ The most common all-grade TEAEs were diarrhea, fatigue, and nausea.²⁷ The investigators found that the combination treatment was effective against a broad spectrum of KRAS wild-type HER2-amplified/overexpressed tumors but had limited efficacy against KRAS-mutant tumors.²⁸

The TRIUMPH study (UMIN000027887) evaluated the pertuzumab-plus-trastuzumab combination therapy in patients with RAS wild-type, HER2-positive mCRC prospectively confirmed by tumor tissue or circulating tumor DNA (ctDNA) analysis.²⁹ The primary end point was attained with a confirmed ORR of 30% in 27 patients who were tissue positive (95% CI, 14%-50%) and 28% in 25 patients who were ctDNA positive (95% CI, 12%-49%) compared with 0% in a matched real-world reference group given standard-of-care salvage treatment (95% CI, 0%-25%). The investigators asserted that ctDNA genotyping might identify patients who benefit from dual HER2 inhibition and track therapeutic response.²⁹

Another trial that examined the efficacy of dual HER2-targeted therapy with pertuzumab and trastuzumab in mCRC was the TAPUR trial (NCT02693535).³⁰ Participants had previously treated mCRC with HER2 amplification and/or HER2/3 mutation. Of these, 74% were HER2 amplified with or without HER2/3 mutation, and 26% had only HER2/3 mutation. In the HER2-amplified group, the CR was 54%, and the ORR was 25%. Moreover, the median PFS was 17.2 weeks, and median OS was 60.0 weeks. Patients with HER2/3 mutations and KRAS or BRAF mutations had no response to therapy. No new safety signals were detected.³⁰

Lastly, the efficacy and safety of fam-trastuzumab deruxtecan-nxki [Enhertu], a combination of trastuzumab and the topoisomerase I inhibitor deruxtecan, were studied in patients with HER2-expressing mCRC. This therapeutic, classified as an antibody-drug conjugate, was approved for adults with HER2-positive unresectable or metastatic treatment-refractory breast cancer and for adults with HER2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma.³¹

In the open-label phase 2 DESTINY-CRC01 trial (NCT03384940), trastuzumab deruxtecan was evaluated in patients with HER2-amplified mCRC who had received 2 or more prior therapies.³² Participants received 6.4 mg/kg of intravenous trastuzumab deruxtecan every 3 weeţs. After a median follow-up of 27.1 weeks, 45.3% of patients with HER2-positive tumors had a confirmed objective response.³² Longer-term safety and efficacy data presented at the 2022 American Society of Clinical Oncology Gastrointestinal Cancers Symposium showed a median duration of response (DOR) of 7.0 months, a median PFS of 6.9 months, and a median OS of 15.5 months.³³

The subsequent phase 2 global DESTINY-CRC02 trial (NCT04744831) is assessing trastuzumab deruxtecan at dosages of 5.4 mg/kg and 6.4 mg/kg in patients with HER2-overexpressing, RAS wild-type or mutant mCRC. The primary end point is confirmed ORR, and secondary end points include DOR, DCR, clinical benefit ratio, investigator-assessed ORR, PFS, OS, pharmacokinetics, patient-reported outcomes, and safety.³⁴

Antibody-drug conjugates differ from existing HER2-targeting medications, according to Bekaii-Saab. ܹ"I think about [antibody-drug conjugates] more as chemotherapy agents,ܺ"he said. ܹ"They mostly care about the presence of the receptor; they donܼt care as much about the activity of the receptor.ܺ" In effect, these medications deliver their chemotherapeutic payload directly to HER2-positive tumor cells, but they may also target neighboring cells with little or no HER2 activity.³⁵

Consequently, as per DESTINY-CRC02, chemotherapy-related toxicities, such as fatigue, nausea, vomiting, neutropenia, and thrombocytopenia, were expected. Furthermore, grade 3 or greater TEAEs occurred in at least 65.1% of participants, the most common being hematologic and gastrointestinal. Adverse effects leading to treatment discontinuation occurred in 15.1% of patients, and 9.3% of patients developed interstitial lung disease.³⁴

Present Outlook and Future Directions

Even before the FDA approved tucatinib and trastuzumab on January 19, 2023, as second-line treatment for patients with RAS wild-type, HER2-positive mCRC, some anti-HER2 therapies were already being utilized in clinical practice for mCRC. “Our national guidelines list 3 anti-HER2 regimens as options for patients with HER-positive RAS wild-type disease,ܺ Strickler said. ܹThis includes the lapatinib-trastuzumab combination, the trastuzumab-pertuzumab combination, and then the trastuzumab deruxtecan antibody-drug conjugate.ܺ

Nonetheless, there are obstacles to broader usage. ܹ"With HER2 therapy in CRC, although we see ơuite a few responses—for instance, with tucatinib and trastuzumab, we’ve seen some of the best responses in CRC—but itܼs still 40% of the patients and many progress with time,ܺ" Bekaii-Saab noted. “So [a] major challenge to understand [is] what are those drivers of resistance that may lead to the cancer progressing early or not responding to treatment.ܺ

Still, the anticipation of trial results, such as those from MOUNTAINEER-03 and DESTINY-CRC02, and the development of novel therapeutics are exciting prospects for the future of this therapy. ܹ

"Thereܼs ơuite a bit of worţ܍and thereܼs more going on that we’re hoping will keep us moving forward with this target,ܺ Bekaii-Saab said.

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