ESMO update: upper gastrointestinal cancer

At the European Society for Medical Oncology (ESMO) 2022 annual meeting, several pertinent studies in the field of upper gastrointestinal cancer were presented. The most practice-changing study appeared to be the Destiny-Gastric02 study evaluating trastuzumab–deruxtecan as a second-line treatment option in patients with Her2-positive gastric and gastroesophageal junction cancer. The median overall survival was 12.1 months with a confirmed overall response rate of 41.8%. 55.7% of patients experienced grade ≥ 3 events with nausea, vomiting, and fatigue being the most frequently observed. This study led to the approval of trastuzumab–deruxtecan as second-line therapy in patients with Her2-positive gastric and gastroesophageal junction tumors who have experienced disease progression after first-line trastuzumab-containing therapy.


QOL
Quality of life TEAE Treatment-emergent adverse events TKI Tyrosine kinase inhibitors VEGFR Vascular endothelial growth factor receptor

Gastroesophageal cancer
In recent years, several clinical studies with significant implications on the standard treatment of gastroesophageal cancer have been demonstrated at scientific congresses. This trend appeared to continue for European Society for Medical Oncology (ESMO) 2022, but at a lower intensity.
The absolute highlight and practice-changing evidence of ESMO 2022 was the DESTINY-Gastric02 study (NCT04014075; Abstract 1). Initial study results were presented at ESMO 2021 and an update with longer follow-up (cut-off April 9, 2021, median followup 10.2 months) was reported at ESMO 2022.
DESTINY-Gastric02 was a phase II, single-arm study evaluating trastuzumab-deruxtecan as a second-line treatment option in Western patients with Her2-positive gastric and gastroesophageal junction cancer. As a highlight of the study design, patients should have centrally confirmed Her2 positivity (IHC3+ or IHC2+ and ISH positive as usual) in a rebiopsy specimen after progression to the trastuzumab-based regimen. After first-line treatment, patients received 6.4 mg/kg trastuzumab-deruxtecan every 3 weeks. The primary endpoint of the study was confirmed overall response according to RECIST v1.1 by an independent central review.
A total of 79 patients from the USA and the EU were able to receive the study drug. The median overall survival (OS) was 12.1 months (95% confidence interval [CI] 9.4-15.4). The confirmed overall response rate (ORR) was 41.8% (33/79; 4 complete and 29 partial responses). All patients experienced ≥ 1 treatment-emergent adverse events (TEAE); 55.7% grade ≥ 3. The most common TEAEs were nausea (67.1%), vomiting (44.3%), and fatigue (57%). The adverse event of interest was interstitial lung disease/pneumonitis in 8 patients (10.1%); 6 (7.6%) had grades 1-2 and 2 (2.5%) had grade 5. This appears to be lower than what was observed in the DESTINY-Gastric01 study, which enrolled only Asian patients [1]. Increasing physician and patient awareness of this specific adverse event could contribute to the differences observed in clinical trials. According to quality of life (QOL) assessments conducted with EQ-5D-5L and FACT-GA questionnaires, patients appeared to maintain QOL over the treatment period.
These results led to the European Medicines Agency's approval of trastuzumab-deruxtecan as second-line therapy in patients with Her2-positive gastric and gastroesophageal junction tumors who have experienced disease progression after first-line trastuzumab-containing therapy. According to this approval, rebiopsy and confirmation of Her2 status is not mandatory.
A phase III study is currently being carried out to clarify the same question (NCT04704934). DESTINY-Gastric04 is a global, randomized phase III study evaluating trastuzumab-deruxtecan versus ramucirumab + paclitaxel as second-line treatment options in patients with Her2-positive gastric and gastroesophageal junction tumors. Confirmation of Her2 status is also mandatory in this study. It remains to be seen whether the promising results of DESTINY-Gastric02 will be replicated in a randomized setting in the DESTINY-Gastric04 study.

Cholangiocarcinoma
Ten to 15% of cholangiocarcinoma patients exhibit fibroblast growth factor receptor (FGFR) alterations in their primary tumors [2]. Here, FGFR-targeted tyrosine kinase inhibitors (TKI) yielded promising response rates in recent years, which also translated into a survival benefit leading to the approval of panFGFR inhibitors such as pemigatinib and infigratinib [3,4]. In line with these remarkable results, the phase I/II open label ReFokus study presented at ESMO 2022 introduced the highly selective, irreversible FGFR 2 inhibitor RLY-4008, which yielded an ORR of 88.2% with a favorable toxicity profile in patients with progressive disease under standard first-line therapy (Abstract 2). Randomized studies are awaited to further investigate this promising compound.
The phase III ABC-06 trial established FOLFOX as a second-line regimen after standard first-line chemotherapy with gemcitabine and cisplatin for patients with advanced biliary tract cancer [5]. Since the significant OS benefit over active symptom control alone appeared to be rather limited with 1.3 months, QOL data presented at ESMO 2022 provided some valuable extension (Abstract 3). FOLFOX in addition to active symptom control does not detrimentally impact time to deterioration of Global Health Scale and worsening of QOL seemed more pronounced in patients without chemotherapy. Therefore, FOLFOX as second-line therapy may even help to improve QOL in biliary tract cancer patients with a high symptom burden.

Pancreatic cancer
FOLFIRINOX was shown to improve progressionfree survival (PFS) as well as OS in patients with metastatic pancreatic cancer (PC) compared to gemcitabine alone and therefore represents a standard therapy regimen for fit patients together with gemcitabine and nab-paclitaxel in the first-line setting [6]. In patients with locally advanced tumors, different case series as well as meta-analyses suggested comparable results [7]. Prospective phase 3 data, however, were so far missing. The phase III study Prodige 29-UCGI 26 (Neopan) presented at the ESMO 2022 therefore compared FOLFIRINOX versus gemcitabine in PC patients with locally advanced tumors (Abstract 4). At a median follow-up of 41.1 months, PFS was shown to be significantly longer with FOLFIRINOX (9.7 versus 7.5 months, p = 0.03), which surprisingly did not translate into a significant benefit in terms of OS (15.1 versus 15.6 months, p = 0.5). In PC patients with a good performance status, however, FOLFIRINOX is clearly considered as standard of care not only in the metastatic, but also in the neoadjuvant setting.

Hepatocellular carcinoma
The phase III study IMbrave150 established the combination of the programmed death ligand 1 (PD-L1) inhibitor atezolizumab with the vascular endothelial growth factor receptor (VEGFR) inhibitor bevacizumab as standard of care in the treatment of patients with unresectable or metastatic hepatocellular carcinoma (HCC) unsuitable for locoregional therapy since PFS as well as OS were significantly prolonged compared to sorafenib [8,9]. The results of three phase III studies presented at the ESMO 2022 provide additional information about checkpoint inhibitor therapy in this setting.
LEAP-002 was a phase III randomized trial investigating the PD-1 inhibitor pembrolizumab in combination with lenvatinib versus lenvatinib alone (Abstract 5). Although a survival benefit of 2 months was observed, the preset boundary for superiority was not met and therefore this trial was negative.
The PD-1 inhibitor camrelizumab in combination with the VEGFR TKI rivoceranib was shown to yield a significantly longer PFS as well as OS as compared to the standard arm of sorafenib (Abstract 6). This benefit seemed to be maintained among all subgroups of patients. Since the majority of patients included into this study were Asian and most of the tumors virally driven, these results need to be validated in a broader spectrum of patients.
The third study investigating a PD1 inhibitor was the Rationale-301. Here, tislelizumab met its primary endpoint of non-inferiority of OS compared to sorafenib with a significantly better ORR (49% vs 18%). Therefore, tislelizumab as well as durvalumab as previously postulated by the Himalaya trial [10] presented at ASCO GI 2022 may represent another option in the first-line setting of HCC patients besides the standard combination of atezolizumab and bevacizumab.

Take-home message
The single-arm, phase II study Destiny-Gastric02 led to the approval of trastuzumab-deruxtecan as second-line therapy in patients with Her2-positive gastric and gastroesophageal junction tumors.
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