Anti-HER2 Agents Explored Further in Gastric, Colorectal, and NSCLC Settings

The HER2 receptor represents a prototypical molecular abnormality that is detectable in several common solid tumors including breast, ovarian, endometrial, colon, non–small cell lung, prostate, and cervical cancer. HER2 is an established target in breast cancer, but success in other solid tumors, remains elusive. Anti-HER2 agents in breast cancer have helped inform further development of agents in other tumor types moving forward.¹ At the recent 2020 American Society of Clinical Oncology Virtual Scientific Program (2020 ASCO), key research evaluating the use of anti-HER2 agents were highlighted across multiple solid tumors, including gastric or gastroesophageal junction (GEJ) adenocarcinoma, colorectal cancer (CRC), and non–small cell lung cancer (NSCLC).

Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable linker, and a cytotoxic topoisomerase I inhibitor.

In the DESTINY-Breast01 trial (NCT03248492), which evaluated patients with HER2-positive metastatic breast cancer who had previously been treated with ado-trastuzumab emtansine (T-DM1; Kadcyla), T-DXd demonstrated strong efficacy, with an objective response rate (ORR) of 60.9% and median progression-free survival (PFS) of 16.4 months.2 These data were simultaneously published in the New England Journal of Medicine.²

Further analysis of the DESTINY-Breast01 trial was presented during 2020 ASCO. Investigators explored the association between 15 clinical predictor variables and efficacy using logistic regression models and Cox proportional hazard models. Efficacy was demonstrated in all clinical subgroups analyzed; subgroups had ORRs ranging from 46.4% to 74.5% and PFS values ranging from 12.3 to 18.1 months, similar to the results reported for the overall cohort. Variables associated with improved efficacy included hormone receptor–positive status, fewer previous treatments, pertuzumab (Perjeta) given in the first or second line, and normal renal and hepatic function.³

Additional DESTINY trials were presented during 2020 ASCO, as well as stand-alone trials with other HER2-directed therapies that are summarized herein.

Gastric Cancer Trials

Gastric cancer is proving to be an important setting for the use of anti-HER2 therapies in general and for T-DXd specifically, demonstrated by positive results from the DESTINY-Gastric01 trial (NCT03329690). Results from the primary analyses in patients with HER2-positive status were presented. HER2-positive status was determined by an immunohistochemistry (IHC) score of 3+. In cases with a borderline IHC result (score of 2+), a positive in situ hybridization (ISH) result confirming HER2 gene amplification could also indicate HER2-positive status.⁴

“Chemotherapy plus trastuzumab [Herceptin] is a standard treatment for HER2-positive gastric cancer,” Kohei Shitara, MD, staff physician in the Department of Experimental Therapeutics and Gastrointestinal Oncology, National Cancer Center Hospital East, in Kashiwa, Japan, said during a recorded presentation of the poster. “However, several phase 3 studies with other HER2- targeting agents have failed to show survival benefit. Therefore, there is still an unmet need for patients with HER2-positive gastric cancer.”

This phase 2 study enrolled 187 patients with HER2-expressing advanced gastric cancer (AGC) or GEJ adenocarcinoma at 66 sites: 48 in Japan and 18 in South Korea. Patients had progressed on 2 or more prior regimens. The primary cohort was randomized to receive 6.4 mg/kg of T-DXd every 3 weeks (n = 125) or physician’s choice of chemotherapy (n = 62; irinotecan or paclitaxel). The primary end point was ORR determined by independent central review using RECIST version 1.1, and secondary end points were overall survival (OS), duration of response, PFS, disease control rate (DCR), and safety.

Shitara said the study met its primary end point, with ORR for patients treated with T-DXd (51.3%) over patients in the physician’s choice arm (14.3%; P <.0001). Median duration of response was 11.3 months (95% CI, 5.6-not estimable) for T-DXd versus 3.9 months (95% CI, 3.0-4.9) with physician’s choice.

The investigators reported a significant improvement in median OS that favored the T-DXd arm (12.5 months) compared with 8.4 months for the physician’s choice arm (HR, 0.59; 95% CI, 0.39-0.88; P = .0097) (TABLE 1).4 Additionally, the OS P value crossed the prespecified boundary of .0202. OS rates at 6 and 12 months also favored T-DXd versus physician’s choice, at 80.3% versus 66.4% and 52.1% versus 28.9%, respectively.

Forty-eight percent of patients in the T-DXd arm received poststudy treatment, with 31.2% receiving a PD-1/PD-L1 inhibitor, versus 74.2% of patients in the physician’s choice arm, with 45.2% receiving a PD-1/PD-L1 inhibitor.

“Interestingly, more patients were on treatment at the time of data cutoff in the T-DXd arm than in the physician’s choice arm [22.4% vs 4.8%],” Shitara said.

Median PFS was 5.6 months (95% CI, 4.3-6.9) with T-DXd versus 3.5 months (95% CI, 2.0-4.3) with physician’s choice (HR, 0.47; 95% CI, 0.31- 0.71; P = .0003). In subgroup analyses, ORRs also favored T-DXd and were consistent within each treatment arm across subgroups.

Regarding safety, the most common grade 3 or greater treatment-emergent adverse effects (TEAEs) were decreased neutrophil count, observed in 51.2% of patients who received T-DXd and 24.2% of patients who received physician’s choice, followed by anemia (37.6% vs 22.6%), decreased white blood cell count (20.8% vs 11.3%), and decreased appetite (16.8% vs 12.9%). Among patients in the T-DXd arm, 9.6% developed interstitial lung disease (ILD)/pneumonitis, with a median time to onset of 84.5 days (range, 36-638 days). Most cases were grade 1 or 2 in severity, although there were 2 patients with grade 3 and 1 patient with grade 4.

“In summary, T-DXd demonstrated statistically significant and clinically meaningful improvements in objective response rate and overall survival compared with the standard chemotherapy in patients with HER2-positive gastric cancer, with separation [of the Kaplan-Meier curves] and [with] intestinal lung disease as notable toxicity,” Shitara said. “Based on these findings, T-DXd may be an effective treatment option for patients with advanced HER2-positive gastric/GEJ adenocarcinoma who have progressed after trastuzumab.”

Combination Therapies

Further research in the gastric setting is examining combination therapies. The following phase 1 and 2 trials often combine anti-HER2 agents with immunotherapies.

Significant tumor shrinkage was observed in the phase 1b/2 PANTHERA trial (NCT02901301) of the triplet combination of pembrolizumab (Keytruda), trastuzumab, and chemotherapy as first-line therapy for HER2-positive AGC.⁵

Investigators from Yonsei Cancer Center of Yonsei University College of Medicine in Seoul, South Korea, reported tumor shrinkage of 95.3%, a median depth of response of 54.6%, and an ORR of 76.7% (TABLE 2).5 Further analysis revealed that the ORR consisted of 16.3% complete responses (CRs) and 60.5% partial responses (PRs), and the DCR was 97.7%. Median PFS was 8.6 months (95% CI, 7.2-22.0), and median OS was 18.4 months (95% CI, 17.9-not available).

Results of the open-label, phase 1b Ni-HIGH study to determine the safety and tolerability of adding an anti–PD-1 antibody to trastuzumab in patients with HER2-positive AGC were also presented at 2020 ASCO. The trial consisted of a safety portion and an expansion portion.⁶ Eligible patients had histopathologically confirmed HER2-positive AGC and measurable lesions.

In the safety portion, patients were randomized to receive nivolumab (Opdivo; 360 mg), trastuzumab (course 1, 8 mg/kg; course ≥2, 6 mg/kg), and oxaliplatin (130 mg/m2) once every 3 weeks plus either S-1 (a prodrug of 5-fluorouracil at 40 mg/m2 twice per day) or capecitabine (1000 mg/m2 twice per day) for 14 days of every 3-week cycle until disease progression or unacceptable toxicity.

Both the S-1– and capecitabine-containing regimens were shown to be well tolerated. The investigators reported that this ongoing study demonstrates favorable efficacy for these combinations.

Another trial evaluated pembrolizumab with trastuzumab, fluoropyrimidine, and platinum chemotherapy in HER2-positive metastatic esophagogastric cancer using plasma and tumor-based biomarker analysis.⁷

The objectives were to evaluate circulating tumor DNA (ctDNA) as a possible early predictor of therapeutic response and resistance and to identify genomic mutations leading to resistance. Tumor biopsies and serial blood samples were collected from patients. To be eligible for this first-line regimen, patients had to have a diagnosis of stage IV, HER2-positive metastatic esophagogastric cancer.

Tumor-matched ctDNA was detected at baseline in 84% of patients. Median PFS was longer in patients who cleared ctDNA at 9 weeks (12.3 months; 95% CI, 7.44-not available) than in those who did not (3.9 months; 95% CI, 2.01-not available). Activating KRAS or PIK3CA alterations were found in 10 patients upon progression.

Loss of HER2 overexpression/amplification was noted in 44% of patients with postprogression samples, as determined by IHC or fluorescence ISH. The reappearance of ctDNA preceded radiographic progression in 56% of patients with serial ctDNA. The investigators concluded that reappearance of ctDNA may serve as an early predictor of progression.

DESTINY-CRC01

The open-label, phase 2 DESTINY-CRC01 study (NCT03384940) evaluated T-DXd in patients with HER2-expressing, unresectable, and/or metastatic CRC. Eligible patients had progressed on 2 or more lines of therapy and had wild-type RAS and BRAF genes.

“Importantly, patients who received prior anti-HER2 therapies were allowed to enroll, [whereas] patients with a history of or suspected interstitial lung disease were excluded,” lead investigator Salvatore Siena, MD, a professor of medical oncology at Università degli Studi di Milano in Italy, said during a recorded presentation of the data.⁸

Three cohorts were evaluated. Cohort A comprised 53 patients with HER2-positive tumors, defined as IHC 3+ or IHC 2+/ISH positive. Siena said that futility monitoring was conducted after at least 20 patients in cohort A had undergone 12 weeks of follow-up to inform the opening of cohorts B and C, which both had low HER2 expression. Cohort B comprised 7 patients whose tumors were HER2 IHC 2+ and ISH negative. Cohort C contained 18 patients who had HER2 IHC 1+ tumors.

The primary end point was confirmed ORR by independent central review in cohort A. In the overall study population, the median age was 58.5 years. The median sum of target lesions was 8.4 cm in cohort A and 8.8 cm for all patients. The primary tumor site was the left intestine in almost 90% of patients, both in cohort A (88.7%) and in the overall study population (89.7%). About 80% of patients had microsatellite-stable tumors; the remainder had unknown status.

Regarding previous treatments, 100% of patients in cohort A had received either panitumumab (Vectibix) or cetuximab (Erbitux), which are both anti-EGFR antibodies. About 30% of patients in cohort A had received anti-HER2 agents, such as pertuzumab, trastuzumab, T-DM1, lapatinib (Tykerb), or tucatinib (Tukysa).

The ORR in cohort A was 45.3% (24 of 53 patients) and consisted of 1 CR and 23 PRs. An additional 20 patients in cohort A had stable disease, resulting in a DCR of 83%.

“Interestingly, median duration of response was not reached,” Siena said. “There were no confirmed responses in cohorts B and C.”

The median treatment duration was 4.8 months (range, 1-11) in cohort A and 3.5 months (range, 1-11) in all patients.

Drug-related TEAEs of grade 3 or higher occurred in 50.9% of patients in cohort A and 48.7% of all patients. Serious drug-related TEAEs were reported in 22.6% of patients in cohort A and 17.9% of all patients. There were 2 deaths related to the study drug, including 1 death of pneumonitis and 1 caused by ILD; both occurred in cohort A.

“[ILD] was an adverse effect of special interest,” Siena said. “Among 78 patients treated with T-DXd, ILD occurred in 5 patients, with a median time to onset of 80 days, ranging from 22 to 132 days.” He added that ILD is an important risk that requires careful monitoring and proper intervention.

DESTINY-Lung01

Interim results of DESTINY-Lung01 (NCT03505710) revealed a high response rate that was durable in 42 patients with HER2- mutated NSCLC who were treated with T-DXd.9 Findings were presented in a prerecording by Egbert Smit, MD, PhD, professor of pulmonary medicine (pulmonary oncology) at the Netherlands Cancer Institute and in the Department of Pulmonary Diseases of Vrije Universiteit Medical Centre in Amsterdam, the Netherlands.

Eligible patients had unresectable, metastatic NSCLC that was relapsed or refractory to standard treatments. The primary end point was confirmed ORR by independent central review.

Cohort 1 enrolled patients with HER2-expressing tumors, defined as IHC 2+ or 3+. Cohort 2 consisted of patients whose tumors harbored an activating HER2 mutation. All patients were treated with T-DXd (6.4 mg/kg) every 3 weeks. The authors presented results for cohort 2 in this report.

The median age of patients at baseline was 63.0 years, and the majority (64.3%) were women. ECOG performance status was 0 (23.8%) or 1 (76.2%). Central nervous system metastases were present in 45.2%. Median prior lines of treatment was 2 and included platinum-based therapy (90.5%), a PD-1/PD-L1 inhibitor (54.8%), and docetaxel (19.0%).

The investigators reported that 45.2% of patients in cohort 2 remained on treatment at the data cutoff in November 2019. The other 54.8% discontinued treatment, with the primary reasons being progressive disease (21.4%) and adverse events (AEs; 21.4%).

The confirmed ORR by independent review was 61.9% (95% CI, 45.6%-76.4%). One patient (2.4%) had a CR, 59% had PRs, and 28.6% had stable disease as their best outcome.

Median PFS was 14.0 months (95% CI, 6.4- 14.0), and median OS was not reached (95% CI, 11.8-not evaluable).

The safety profile in the cohort with HER2- mutated NSCLC was generally consistent with what was previously reported, said Smit. Low-grade gastrointestinal and hematological AEs were most commonly observed. TEAEs that occurred in more than 15% of patients were mainly nausea, alopecia, anemia, decreased appetite, decreased neutrophil count, and vomiting. The majority of the TEAEs were either grade 1 or 2.

“Of note, the median duration of exposure of patients to the study drug was 7.8 months,” Smit said. The most common TEAEs associated with dose reduction were fatigue and nausea. The most common TEAEs associated with dose interruption were decreased neutrophil count and lung infection. Five patients with TEAEs died, but investigators noted that none of the deaths were considered to be related to the treatment.

“In this analysis, there were 5 patients [who] experienced grade 2 interstitial lung disease, but there were no patients [who] had interstitial lung disease of higher grades,” said Smit.

“However, ILD remains an important identified risk for patients treated with T-DXd and requires careful monitoring and management,” Smit said. “The study was expanded with an additional 50 patients to better characterize the risk-benefit ratio of T-DXd in patients with HER2-mutated non–small cell lung cancer,” Smit concluded.

_{R E F E R E N C E S}

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_{3. Modi S, Andre F, Krop IE. Trastuzumab deruxtecan for HER2-positive metastatic breast cancer: DESTINY-Breast01 subgroup analysis. J Clin Oncol. 38: 2020 (suppl 15):1036. doi:10.1200/JCO.2020.38.15_suppl.1036}

_{4. Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab deruxtecan (T-DXd; DS- 8201) in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: a randomized, phase II, multicenter, open-label study (DESTINY-Gastric01). J Clin Oncol. 2020;38: (suppl 15): 4513. doi:10.1200/JCO.2020.38.15_suppl.4513}

_{5. Rha SY, Lee CK, Kim HS, et al. Targeting HER2 in combination with anti-PD-1 and chemotherapy confers a significant tumor shrinkage of gastric cancer: A multi-institutional phase Ib/II trial of first-line triplet regimen (pembrolizumab, trastuzumab, chemotherapy) for HER2-positive advanced gastric cancer (AGC). J Clin Oncol. 2020;38(suppl 15):3081. doi:10.1200/ JCO.2020.38.15_suppl.3081}

_{6. Takahari D, Shoji H, Minashi K, et al. A phase Ib study of nivolumab plus trastuzumab with S-1/capecitabine plus oxaliplatin for HER2-positive advanced gastric cancer (Ni-HIGH study): safety evaluation. J Clin Oncol. 2020;38(suppl 15):4525. doi:10.1200/JCO.2020.38.15_suppl.4525}

_{7. Maron SB, Chatila WK, Millang BM, et al. Pembrolizumab with trastuzumab and chemotherapy (PTC) in HER2-positive metastatic esophagogastric cancer (mEG): plasma and tumor-based biomarker analysis. J Clin Oncol 38;2020(suppl 15):4559. doi:10.1200/JCO.2020.38.15_suppl.4559}

_{8. Siena S, Di Bartolomeo M, Raghav KPS, et al. A phase II, multicenter, open-label study of trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): DESTINY-CRC01. J Clin Oncol. 2020;38(suppl 15):4000. doi:10.1200/ JCO.2020.38.15_suppl.4000}

_{9. Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung01. J Clin Oncol. 2020;38(suppl 15):9504. doi:10.1200/JCO.2020.38.15_suppl.9504}