In this commentary, Aditya Bardia, MD, MPH; Yelena Y. Janjigian, MD; and Sandip P. Patel, MD, provide key updates about diagnostic testing and antibody–drug conjugates (ADCs) directed toward HER2, HER3, and TROP2 transmembrane proteins in breast, gastrointestinal, and lung cancers. These key learning points were discussed during a recent live Clinical Care Options satellite symposium held during the American Association for Cancer Research annual conference.
ADCs represent a relatively new class of targeted chemotherapeutic agents for patients with cancer. ADCs comprise a monoclonal antibody that is tethered to a cytotoxic agent (also known as a “payload”) by a chemical linker that is stable in the circulation but releases the cytotoxic agent in the target cell. This therapeutic modality enables targeted delivery of highly potent cytotoxic payloads to tumor cells while minimizing toxicity to normal tissue.
Aditya Bardia, MD, MPH:
ADCs in Breast Cancer
- HER2-directed ADCs, ado-trastuzumab emtansine (T-DM1) and fam-trastuzumab deruxtecan (T-DXd), have each received FDA approval for HER2-positive metastatic breast cancer (MBC). T-DM1 is approved for patients with HER2-positive MBC after previous taxane and trastuzumab therapy, separately or in combination, or for patients who have disease recurrence within 6 months of completing adjuvant therapy. T-DM1 is also approved for adjuvant therapy in patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment. T-DXd is approved for patients with HER2-positive MBC who have received previous HER2-based therapy in the metastatic setting or as neoadjuvant or adjuvant therapy, with disease progression within 6 months of completing therapy.
- In the pivotal phase III DESTINY-Breast03 trial comparing T-DXd vs T-DM1 in patients with HER2-positive MBC who were previously treated with trastuzumab plus a taxane, progression-free survival (PFS) was improved with T-DXd (median PFS: not reached vs 6.8 months with T-DM1; HR: 0.28; 95% CI: 0.22-0.37; P = 7.8 x 10-22). This 72% reduction in the risk of progression or death with T-DXd vs T‑DM1 was impressive, and T‑DXd is considered the new standard second‑line treatment in this setting. Another HER2 ADC, trastuzumab duocarmazine, improved PFS vs chemotherapy in in the phase III TULIP trial of patients with previously treated HER2-positive MBC.
- Sacituzumab govitecan (SG) is a TROP2-directed ADC with SN-38, an irinotecan-based molecule, as the cytotoxic payload. SG is approved by the FDA for unresectable, locally advanced or metastatic triple-negative breast cancer (TNBC) who have received ≥2 previous systemic therapies, with at least 1 for MBC. In the ASCENT trial, SG demonstrated improved median PFS compared with single-agent chemotherapy (5.6 vs 1.7 months; HR: 0.41; 95% CI: 0.32-0.52; P <.001).
- Data are awaited for the phase III TROPiCS-02 trial of SG in hormone receptor–positive breast cancer after previous standard therapies, and encouraging data also have been presented from a phase II trial of another TROP2-targeting ADC, datopotamab deruxtecan, in patients with TNBC.
- In a phase I window-of-opportunity study, the HER3-targeted ADC patritumab deruxtecan has shown promising efficacy for patients with treatment-naive, hormone receptor–positive, HER2-negative early breast cancer, regardless of baseline HER3 expression.
- With many ADCs available in breast cancer, mechanisms of resistance will need to be considered for both the antibody and cytotoxic agent portions of the agents when sequencing therapy with ADCs.
Biomarker and Polymorphism Testing in Breast Cancer
- Initial definitions of HER2 positivity developed during the trastuzumab era may not apply to HER2-directed ADCs. Data suggest that T-DXd may be effective not only in HER2‑positive tumors (IHC 3+) but also in tumors that have low levels of HER2 expression (IHC1+ or 2+).
- Although high TROP-2 levels did correlate somewhat with better responses in the ASCENT trial, the response rates were higher with SB vs standard chemotherapy regardless of TROP-2 expression levels. Thus, there is no utility in evaluating TROP2 expression for clinical decision-making in metastatic TNBC.
- In terms of pharmacogenomics, individuals with UGT1A1 polymorphisms may have a higher incidence of certain adverse events like febrile neutropenia with SG due to differences in metabolism of SN-38. Routine testing for UGT1A1 polymorphisms is not currently recommended; but if a patient experiences severe adverse events, including neutropenia, SG dose can be reduced.
Yelena Y. Janjigian, MD:
Recommendations for HER2 Biomarker Testing in GI Cancers
- Individuals with advanced gastric or gastroesophageal (GEJ) cancer should be tested for HER2 overexpression and retested upon progression. Expression can be tested via immunohistochemistry, fluorescence in situ hybridization (FISH), or next-generation sequencing (NGS). A result of IHC3+ by immunohistochemistry is considered HER2 positive. If IHC2+, reflex FISH testing should be performed; if positive, the tumor is considered HER2+. HER2 amplification by NGS may be a more robust biomarker of response for gastric or GEJ cancer.
- Individuals with colorectal cancer (CRC) should be tested for HER2 overexpression at diagnosis of metastatic disease. If the tumor has a known RAS/BRAF mutation, HER2 testing is not necessary as these are mutually exclusive.
- HER2 overexpression is an emerging target in other GI tumors, such as biliary cancer.
- GI tumors are chromosomally unstable. HER2 is never the sole driver, and resistance occurs. When possible, obtain a biopsy at each progression.
Integration of Immunotherapies and ADC in GI Cancers
- Trastuzumab is currently approved by the FDA in combination with cisplatin and either capecitabine or 5-fluorouracil for treatment of patients with HER2-overexpressing metastatic gastric or GEJ cancer who have not received previous therapy for metastatic disease.
- Pembrolizumab was approved by the FDA in combination with trastuzumab, platinum-, and fluoropyrimidine-based chemotherapy for locally advanced, or metastatic HER2-positive gastric or GEJ cancers based on findings from the KEYNOTE-811 trial (overall response rate [ORR]: 74.4%).
- T-DXd was approved by the FDA for use in second or later lines of therapy in patients with locally advanced or metastatic HER2-positive gastric or GEJ cancers who have received prior trastuzumab-based therapy based on results from the DESTINY-Gastric01 (ORR: 43%) and DESTINY-Gastric02 (ORR: 38%) trials.
- In CRC, T-DXd or trastuzumab plus pertuzumab or lapatinib may be considered in certain settings for patients with HER2-amplified tumors and wild type RAS/BRAF only.
- The DESTINY-CRC01 trial of T-DXd in HER2-expressing metastatic CRC resulted in an ORR of 45.3%.
- Studies of TROP2-targeting agents are underway in GI cancers, including preliminary data from the phase I/II IMMU-132-01 basket trial.
Sandip P. Patel, MD:
Recommendations for HER2-Focused Biomarker Testing in NSCLC
- At least one half of patients with nonsquamous non-small-cell lung cancer (NSCLC) have a targetable mutation, including HER2 mutations.
- In NSCLC, current trials use HER2 mutations (optimally identified by NGS) as a biomarker instead of HER2 overexpression/amplification identified by IHC or FISH. HER2 mutations must be identified using NGS tissue or liquid biopsy DNA panel.
- HER3 overexpression occurs in NSCLC primary tumors and metastatic disease. HER3 expression level is associated with poor prognosis and treatment resistance in NSCLC. Current trials of HER3-targeted agents in NSCLC focus on patients with EGFR mutations who have progression after EGFR TKI.
Studies of HER2, TROP2, and HER3 ADC in NSCLC
- No HER2-, TROP2-, or HER3-targeted agents are approved by the FDA for patients with NSCLC; however, guidelines recommend the HER2-targeted ADCs T-DM1 and T-DXd as emerging options for patients with oncogenic HER2 mutations.
- T-DM1 demonstrated activity in advanced HER2-mutant NSCLC in a single-arm phase II basket trial (ORR: 44%) and T-DXd demonstrated activity in the HER2-mutated NSCLC cohort in the DESTINY-Lung01 study (ORR: 55%) and less so in the HER2-overexpressing cohort (ORR: 24.5%). Based on the findings from the DESTINY-Lung01 trial, T-DXd was granted breakthrough therapy designation by the FDA for HER2-mutant NSCLC with progression on or after platinum-based chemotherapy.
- The phase I/II IMMU-132-01 basket trial with the TROP2-targeted ADC SG demonstrated activity in NSCLC (ORR: 17%). The phase I TROPION-PanTumor01 trial with datopotamab deruxtecan showed promising response rates for heavily pretreated advanced NSCLC (ORR: 24%), including patients with treated brain metastases.
- The phase I trial of patritumab deruxtecan, a novel HER3-targeted ADC, demonstrated activity in patients with EGFR-mutant NSCLC following progression on EGFR TKI (ORR: 39%), including some patients with stable brain metastases. Response rate did not correlate with HER3 expression in this trial.
- Interstitial lung disease (ILD) appears to be the main emergent toxicity with this drug class in the NSCLC population. Early diagnosis and intervention of ILD is key for patients receiving ADC, and patients should be closely monitored for ILD symptoms such as shortness of breath, cough, and fever. Other etiologies causing these symptoms, such as infection, should be ruled out. For confirmed ILD, treatment is holding the ADC and initiating steroid treatment.
ADCs have radically changed the treatment landscape for breast cancer and are rapidly affecting therapeutic choices in other diseases as well. Understanding which biomarkers need to be assessed in each tumor type and how best to perform that assessment is key to incorporating these novel therapies into clinical practice. Whereas HER2 mutation testing is relatively straightforward with NGS, evaluating HER2 overexpression is continuing to evolve. Assessing HER2 expression or mutations as appropriate for the tumor type is recommended for breast, lung, and GI tumors. As with HER2, overexpression of HER3 and HER3 mutations are both attractive targets. Efficacy with the HER3 ADC patritumab deruxtecan does not correlate with HER3 overexpression, thus HER3 biomarker testing is not indicated at this time. Similarly, current TROP2 ADCs show efficacy regardless of the level of TROP2 expression so testing for TROP2 in advance of treatment with TROP2-targeted ADCs is not warranted. There are numerous ongoing trials with agents targeting HER2, HER3, or TROP2. As we learn more about these treatment options, we will be able to integrate these novel agents into the treatment landscape for various solid tumors.
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