Medical Need
“There is an urgent need for better treatments for patients with advanced gastroesophageal cancer,” Dr Smyth stated. “The median survival for patients with HER2-positive disease is approximately 18 months with chemotherapy and trastuzumab. For 10 years, trastuzumab has been the only targeted drug that has been licensed in HER2-positive gastroesophageal cancer. In contrast, for patients with breast cancer we have had a number of drugs that demonstrated to be effective, including lapatinib and T-DM1 in the second-line, and pertuzumab in the first-line. Unfortunately, these agents failed in HER2-positive gastroesophageal cancer.
Dr Smyth explained why these therapies succeeded in breast cancer but failed in gastric cancer. “The median overall survival (OS) for HER2-positive gastric cancer is 1.5 to 2 years, with effective second-line treatment options. For HER2-positive advanced breast cancer, this is between 7 and 8 years. This survival difference illustrates that gastric cancer is in general more aggressive than breast cancer.
Furthermore, there is a benefit from HER2-directed therapy in gastric cancer, but the magnitude of the benefit is reduced due to the heterogeneity of HER2-positive gastroesophageal cancers. In addition, it became apparent in recent years that at least 1/3 of the patients with HER2-positive gastroesophageal cancer, who were treated with trastuzumab in the first-line setting, lose expression of HER2 on their tumour after disease progression. Therefore, we need biopsy to ensure they have retained HER2 expression. All in all, this illustrates a clear unmet need to develop safe and effective second-line treatment options for this population.
Comparison of T-DXd with other therapies
Dr Smyth emphasised the T-DXd advantages over other therapies investigated for the HER2-positive gastroesophageal cancer population.
Characteristics of T-DXd:
- Antibody drug conjugate (ADC) with chemotherapy payload and a trastuzumab-type antibody
- More potent payload than T-DM1
- Strong bystander effect
- Limited off-tumour toxicity
Prof. Van Cutsem added that T-DXd has already shown its potential value. "The latest data display that T-DXd, when administered in the third-line to patients of Asian origin with HER2-positive gastric or GEJ cancer, delivers an OS benefit over standard of care (12.5 months vs 8.9 months) [1]. In the second-line, T-DXd showed a confirmed overall response rate (ORR) of 38% in a Western population with HER2-positive gastric or GEJ cancer [2]. Moreover, recent results from the phase 2 DESTINY-CRC01 study demonstrated encouraging efficacy of T-DXd in HER2-positive metastatic colorectal cancer, with a safety profile that was consistent with other T-DXd trials [3].”
Updates on T-DXd presented at ASCO GI 2022
Dr Smyth elaborated on the remarks of Prof. Van Cutsem. “The first study to examine T-DXd was an Asian study called DESTINY-Gastric01. “In this trial, chemotherapy-refractory patients with HER2-positive gastroesophageal cancer, who were not re-tested for HER2-positivity, were randomised to T-DXd or chemotherapy. The primary analysis showed an ORR of approximately 50% for patients in the T-DXd arm and 14% for patients in the chemotherapy arm. At ASCO GI 2022, an update of this trial was presented, demonstrating that patients treated with T-DXd had an overall survival benefit compared with chemotherapy, independent of prior immune checkpoint inhibitor (ICI) treatment [1]. In the DESTINY-Gastric01 study, approximately 1/3 of the patients treated with T-DXd, and 1/4 of the patients treated with chemotherapy, received prior ICIs (nivolumab, pembrolizumab, or avelumab). Patients in the T-DXd arm who received prior ICI treatment had an ORR of 65.9% compared with 42.7% for those without prior treatment. For patients in the chemotherapy arm, the ORR was 25.0% for patients treated with prior ICIs and 10% for patients who were not treated with prior ICIs. The corresponding median OS times were 16.6 months and 10.3 months for patients in the T-DX-d arm, with and without prior ICIs, respectively, and 8.6 and 8.4 months for patients in the chemotherapy arm. Furthermore, the long-term follow-up data showed that T-DXd was well tolerated and that the incidence of pneumonitis or interstitial lung disease (ILD) an identified T-DXd-related AE, was not higher among patients who previously had been treated with immune checkpoint inhibitors. These are important findings, since the majority of patients will be receiving immune checkpoint inhibitors in the first-line setting.” Dr Smyth added that the incidence of pneumonitis among patients treated with T-DXd has decreased since the initial development of this agent. “With pre-emptive, regular screening, high awareness of ILD, and protocols in place for the treatment of this complication, the number of patients presenting with ILD decreased. Moreover, if we detect ILD, we can treat it effectively.” Prof. Van Cutsem agreed that ILD is a manageable AE in most cases and explained that the overall discontinuation rate of patients treated with T-DXd is low: “In the Western population in the DESTINY-Gastric02 study (n=79), we observed pneumonitis or ILD in about 8% of the patients. Only 1 patient experienced a grade 5 event, the other cases were grade 1 or grade 2 events. Across all trials that have been performed on this agent, including breast cancer and lung cancer studies, the incidence of ILD is approximately 10%. Besides this serious adverse event, the most common adverse events of T-DXd were fatigue and nausea. These events were manageable and did generally not result in discontinuations. In conclusion, the DESTINY-Gastric01 and DESTINY-Gastric02 trials showed that T-DXd is an emerging option for second-line or third-line therapy in patients with HER2-positive gastric or GEJ cancer.”
DESTINY-Gastric03 study: promising preliminary results at ASCO 2022
“Next, we need to assess whether we can safely combine T-DXd with other drugs,” continued Dr Smyth. “The DESTINY-Gastric03 was designed to investigated this. This is a multi-arm study, combining T-DXd with a number of different standard of care chemotherapies, and immune checkpoint inhibitors in patients with gastric cancer, including fluoropyrimidines, oxaliplatin, durvalumab, and pembrolizumab. Preliminary data regarding T-DXd plus fluoropyrimidines regimens was presented at ASCO GI 2022 [4]. The recommended phase 2 dose of fluorouracil (5-FU) was found to be 600mg/m2, twice daily, which will be administered next to T-DXd. Furthermore, results from the capecitabine plus T-DXd arm showed that the preferred phase 2 dose of capecitabine was 1000mg/m2, orally, twice daily. The preliminary safety results displayed that anaemia (33%), decreased neutrophil count (33%), nausea (13%) and stomatitis (13%) were the most common grade 3 or higher adverse events in the 5-FU arm. Correspondingly, the most common grade 3 or higher toxicities in the capecitabine arm were decreased neutrophil count (40%), anaemia (30%), and nausea (20%). In addition, the preliminary response rates were promising. The efficacy in the 5-FU arm was approximately 50% in 6 patients. In the capecitabine arm, 3 out of 7 patients displayed a confirmed response. These are certainly acceptable levels of efficacy. However, the results are preliminary, and do not have results on progression-free survival or overall survival yet.”
Next steps for T-DXd
Several trials will further investigate the potential of T-DXd in patients with gastric cancer, according to Dr Smyth. “DESTINY-Gastric04 is a global randomised trial evaluating T-DXd versus standard of care in the second-line setting, which is ramucirumab + paclitaxel. Notably, in this trial, patients will require demonstration of retained HER2-positivity status after first-line treatment. Therefore, as the DESTINY-Gastric02 study, this trial will select the patients who will most likely benefit from T-DXd treatment. Moreover, the DESTINY-Gastric03 trial will assess T-DXd in the first-line. At this moment there are several options: T-DXd plus 5-FU; T-DXd plus 5-FU and an immune checkpoint inhibitor; or T-DXd plus 5-FU plus oxaliplatin and an immune checkpoint inhibitor. More results are necessary to determine the future direction.”
Prof. Van Cutsem added that the DESTINY-Gastric01 and DESTINY-Gastric02 studies were performed with patients showing disease progression on first-line trastuzumab plus chemotherapy. “The trials did not include patients who progressed on the novel FDA-approved first-line therapy of chemotherapy plus trastuzumab plus pembrolizumab. Although this does not change the results of these trials, since T-DXd was investigated as a second-line agent, T-DXd probably needs to be delivered in a combination regimen, as we perceived the remarkable 75% ORR in the first-line for patients treated with chemotherapy, trastuzumab, and pembrolizumab. The DESTINY-Gastric03 trial will provide new insights on T-DXd in the first-line. Furthermore, other trials are currently being designed to target patients with operable disease in the neoadjuvant and adjuvant setting.”
- Yamaguchi K, et al. Abstract 242, ASCO GI 2022, 20-22 January.
- Van Cutsem E, et al. Late-breaking abstract 55, ESMO 2021, 16-21 September.
- Siena S, et al. The Lancet Oncology. 2021; 22(6):779-789.
- Janjigian Y, et al. Abstract 295, ASCO GI 2022, 20-22 January.
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