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Key Studies in Genitourinary, Gastrointestinal, Breast, and Lung Cancers: CCO Independent Conference Highlights of the 2021 Virtual ESMO Annual Meeting
  • CME

Eva M. Ciruelos, MD, PhD
Karim Fizazi, MD, PhD
Eric Van Cutsem, MD, PhD
person default
Vamsidhar Velcheti, MD
Released: December 15, 2021

Studies in Gastrointestinal Cancers from ESMO 2021

DESTINY-Gastric-02: Background

Eric Van Cutsem, MD, PhD:
I will now review several important trials in gastrointestinal cancer presented at ESMO 2021. I will start with studies in advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma.

DESTINY-Gastric02 is evaluating T-DXd, an antibody–drug conjugate (ADC) targeting the HER2 receptor.16 T-DXd received FDA approval in January 2021 for the treatment of locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior trastuzumab-based regimen based on data from the phase II DESTINY‑Gastric01 trial in Japanese and South Korean patients.17,18 The DESTINY‑Gastric02 trial was undertaken to evaluate T-DXd in a Western patient population and specifically in the second-line setting.

DESTINY-Gastric02: Study Design

Eric Van Cutsem, MD, PhD:
DESTINY-Gastric02 is an open-label, multicenter phase II trial that enrolled 79 American and European patients with HER2-positive unresectable metastatic gastric or GEJ adenocarcinoma. All patients had progressed on a first-line trastuzumab-containing regimen. In this study, T-DXd is administered once every 3 weeks.

Included in the DESTINY-Gastric02 trial and not included in DESTINY-Gastric01 was a tumor rebiopsy after progression on trastuzumab‑containing regimens. We wanted to ensure the tumors were still HER2-positive, as studies indicate that up to 30% of patients who progress on trastuzumab lose HER2 expression. Only patients with an immunohistochemistry (IHC) score of 3+ or an IHC 2+ with positive in situ hybridization were considered to be HER2-positive and enrolled on the trial.

The primary endpoint of this nonrandomized trial is ORR as determined by independent central review, and secondary endpoints include PFS, OS, safety, and tolerability.

DESTINY-Gastric02: Baseline Characteristics

Eric Van Cutsem, MD, PhD:
Most enrolled patients were White and male. HER2 expression was primarily IHC 3+ (86.1%), and 65.8% of the patients had GEJ cancer. Although noncardia gastric cancer was more common than GEJ cancer in the Gastric01 trial, this reflects a difference in the epidemiology of GEJ tumors, which are more common in Western patient populations than in Asian patient populations. The higher proportion of GEJ tumors is also significant because GEJ tumors are more likely to be HER2 positive.

DESTINY-Gastric02: Efficacy

Eric Van Cutsem, MD, PhD:
The primary endpoint of the trial was met with a confirmed ORR of 38% (95% CI: 27.3%-49.6%), which aligned with the ORR in the Gastric01 study. Three patients (3.8%) achieved a complete response, and the median DoR in the 30 responders was 8.1 months (95% CI: 4.1-NE). The median PFS was 5.5 months (95% CI: 4.2-7.3).

DESTINY-Gastric02: Best Percentage Change in Tumor Size

Eric Van Cutsem, MD, PhD:
Whereas only 38% of patients had an ORR, most patients had tumor regression. A few patients had disease progression at the first evaluation.

DESTINY-Gastric02: Safety

Eric Van Cutsem, MD, PhD:
The safety of T-DXd was consistent with what was observed in the Gastric01 trial and in patients treated for breast cancer (BC). The treatment-related AEs (TRAEs) oncologists fear most are pneumonitis and interstitial lung disease (ILD) and in this trial, they led to drug discontinuation in 3.8% and 2.5% of patients, respectively. This was a lower rate than has been observed in other trials. The most common TRAEs associated with dose reduction were nausea (7.6%) and decreased neutrophil count (5.1%).

DESTINY-Gastric02: Key TRAEs and Drug-Related ILD

Eric Van Cutsem, MD, PhD:
Six patients (7.6%) had drug‑related ILD with median time to onset of 80.5 days (range: 53-85) and a median duration of 38.0 days (range: 15-142). Grade ≥3 TRAEs affected 21 patients (26.6%) but the frequency of each individual grade ≥3 TRAE was <10%.

DESTINY-Gastric02: Conclusions

Eric Van Cutsem, MD, PhD:
T-DXd demonstrated single-agent activity (38% ORR with durable responses) in the second‑line treatment of patients with HER2‑positive gastric or GEJ adenocarcinoma previously treated and refractory to trastuzumab‑based treatment. The safety profile was consistent with prior reports with T-DXd. These data support the recent approval of T-DXd for patients with previously treated gastric/GEJ cancer.

Based on these data, the ongoing DESTINY‑Gastric04 trial is comparing T-DXd with ramucirumab plus paclitaxel in patients with HER2-positive gastric or GEJ cancer with progression on or after a trastuzumab-containing regimen.19 We think this targeted therapy has the potential to be better than ramucirumab plus paclitaxel based on the 38% response rate in this study, as the ORR with ramucirumab plus paclitaxel was 28% in the RAINBOW trial.20

CheckMate 649: Background

Eric Van Cutsem, MD, PhD:
The second study I will discuss is the CheckMate 649 trial for first-line treatment of HER2-negative gastric and GEJ cancers.21

Data from this study were initially presented at ESMO 2020, prior to the randomization of 2 of the 3 arms.22 In that presentation, an OS benefit was reported for first-line nivolumab plus CT vs CT alone, particularly in patients with PD-L1 CPS ≥5. These data led to the FDA approval of nivolumab in combination with fluoropyrimidine- and platinum-containing CT for advanced or metastatic gastric cancer, GEJ cancer, and esophageal adenocarcinoma in April 2021. A follow-up analysis after more than 12 months showed improvements in PFS and ORR with an acceptable safety profile.23 The third arm that was newly presented is evaluating nivolumab plus ipilimumab.

In CheckMate 648, nivolumab plus ipilimumab was superior to CT alone and similar to nivolumab plus CT in patients with squamous cell cancer of the esophagus.24 We have been looking forward to the data in gastric adenocarcinoma.

CheckMate 649: Study Design

Eric Van Cutsem, MD, PhD:
CheckMate 649 is an international, open-label, randomized phase III trial that enrolled 2031 patients with previously untreated, unresectable advanced or metastatic HER2-negative gastric, GEJ, or esophageal adenocarcinoma. Patients were stratified by PD-L1 expression, geographic region, ECOG PS, and CT received.

The current analysis presents results for the nivolumab plus doublet CT arm, the CT alone arm, and the nivolumab plus ipilimumab arm. Patients receive treatment until disease progression, unacceptable toxicity, or consent withdrawal.

The coprimary endpoints are OS and PFS in patients with PD-L1 CPS ≥5 in the nivolumab plus CT vs CT comparison. Secondary endpoints are OS and PFS in all randomized patients, response rates, and safety.

CheckMate 649: Baseline Characteristics

Eric Van Cutsem, MD, PhD:
The CT vs CT plus nivolumab groups had almost 800 patients per arm. For the new comparison of nivolumab plus ipilimumab vs CT, there were approximately 400 patients per group, as the nivolumab plus ipilimumab arm was closed prematurely.

Approximately 70% of the patients had a gastric adenocarcinoma, 16% to 20% had a GEJ tumor, and 11% to 14% had an esophageal adenocarcinoma. A PD-L1 CPS ≥5 was present in approximately 60% of the patients, and most tumors were microsatellite stable (85%-88%), with only 2% to 3% microsatellite instable (MSI).

CheckMate 649: Treatment Disposition

Eric Van Cutsem, MD, PhD:
Between 42% and 47% of the enrolled patients went on to receive subsequent treatment. The reasons for discontinuation were not strikingly different with the exception of TRAEs in patients receiving nivolumab plus ipilimumab, which resulted in 19% of discontinuations. TRAEs were responsible for only 6% to 8% of discontinuations in the other arms. The higher rate discontinuations because of TRAE with nivolumab plus ipilimumab may be due to the higher dose of ipilimumab (3 mg/kg) administered in this trial compared with previous trials.

CheckMate 649: Efficacy of Nivolumab Plus CT vs CT

Eric Van Cutsem, MD, PhD:
Patients with PD-L1 CPS ≥5 who received CT plus nivolumab had a clear improvement in median OS, at 14.4 months vs 11.1 months with CT alone (HR: 0.70, 95% CI: 0.61-0.81). There were also significant improvements with nivolumab plus CT in median PFS (HR: 0.70, 95% CI: 0.60-0.81) and ORR (60% vs 45%).

In all‑comers, the improvement with nivolumab plus CT vs CT was still there, but less notable, with the HR for both median OS and median PFS rising to 0.79.

CheckMate 649: Efficacy of Nivolumab Plus Ipilimumab vs CT

Eric Van Cutsem, MD, PhD:
These are the new efficacy data for the comparison between nivolumab plus ipilimumab and CT alone. It is disappointing that nivolumab plus ipilimumab was not better compared with CT alone. Whereas the median OS was similar between the arms in all comers, the median PFS was longer with CT alone vs nivolumab plus ipilimumab, at 7.1 months vs 2.8 months (HR: 1.66, 95% CI: 1.40-1.95). The ORR was also higher in patients who received CT vs nivolumab plus ipilimumab, at 47% vs 23%, respectively.

CheckMate 649: Efficacy of Nivolumab Plus CT vs CT and Nivolumab Plus Ipilimumab vs CT by MSI Status

Eric Van Cutsem, MD, PhD:
Few patients had MSI‑high tumors, but those who did had a clear benefit in median OS and ORR from nivolumab plus CT and nivolumab plus ipilimumab vs CT alone with HRs of 0.38 (95% CI: 0.17-0.84) and 0.28 (95% CI: 0.08-0.92), respectively. A subset of patients with microsatellite-stable tumors also improved with combination therapy vs CT alone, but the benefit was smaller, with median OS and ORR HRs of 0.78 (95% CI: 0.70-0.88).

CheckMate 649: Safety

Eric Van Cutsem, MD, PhD:
There were no new safety signals observed with the longer follow-up. The most common grade 3/4 TRAEs in patients receiving nivolumab plus CT were neutropenia (15%), decreased neutrophil count (11%), and anemia (6%). Patients receiving nivolumab plus ipilimumab had grade 3/4 increases in lipase (7%) amylase (4%), alanine aminotransferase (4%), and aspartate aminotransferase (4%). Patients treated with nivolumab plus ipilimumab had a higher incidence of serious AEs, probably because of the higher dose of ipilimumab in this trial.

CheckMate 649: Potentially Immunologic TRAEs

Eric Van Cutsem, MD, PhD:
In the nivolumab plus ipilimumab arm, there were more endocrine, GI, hepatic, pulmonary, and skin AEs compared with nivolumab plus CT, where these immunologic AEs are less frequent.

CheckMate 649: Conclusions

Eric Van Cutsem, MD, PhD:
In this phase III study, after an additional 12 months of follow-up, nivolumab plus CT continued to show improvements in OS, PFS, and other endpoints over CT alone in patients with previously untreated advanced gastric, GEJ, and esophageal cancer. There was no significant improvement in OS with nivolumab plus ipilimumab compared with CT alone in patients with PD-L1 CPS ≥5. No new safety signals were observed.

Investigators concluded that the findings provide additional evidence supporting the use of nivolumab plus CT as a standard first-line treatment in patients with advanced gastric, GEJ, and esophageal cancer.

I think in the first‑line treatment of gastric cancer we must look at 3 things to guide treatment decisions:

  • If the tumor is HER2 positive, we should use a CT plus trastuzumab.
  • If the tumor has a PD-L1 CPS ≥5, I think this trial makes FOLFOX plus nivolumab the new SoC.
  • MSI‑high tumors benefit from checkpoint inhibitors. Although only 3% of metastatic gastric cancers are MSI-high, we check MSI‑high status in all patients, so that is important.

Claudin and FGFR are emerging biomarkers, and although data for these 2 biomarkers were not presented at ESMO, there are interesting data in phase II studies.25,26 If the phase III studies are also positive, then biomarker analysis will become even more important in the first‑line treatment of advanced gastric cancer.

In conclusion, this trial and the DESTINY-Gastric02 trials set the scene for a new SoC for patients needing first‑ and second-line treatment for advanced gastric, GEJ, and esophageal cancers.

EPOCH: Background

Eric Van Cutsem, MD, PhD:
The third study I will discuss is the EPOCH study comparing the efficacy and safety of transarterial radioembolization (TARE) with investigational yttrium‑90 (Y-90) glass microspheres plus CT vs CT alone in the second-line treatment of unresectable colorectal liver metastases.27,28

Past studies found that TARE can be active, including a randomized phase III study where Belgian patients benefited from receiving treatment in the third line with TARE.29 However, in the SIRFLOX, FOXFIRE, and FOXFIRE-Global trials of first-line treatment, CT plus TARE with resin spheres did not lead to a better outcome compared with CT alone.30

EPOCH: Study Design

Eric Van Cutsem, MD, PhD:
EPOCH was an international, open-label, randomized phase III trial of 428 patients with unresectable unilobar/bilobar metastatic colorectal carcinoma of the liver who progressed on first-line CT. Patients did not need to have liver‑limited disease, but it is clear that patients with liver‑predominant disease were targeted during enrollment.

Patients were stratified by unilobar vs bilobar disease, their first-line CT, and KRAS status to receive irinotecan or oxaliplatin‑based CT with or without targeted therapy. In the experimental arm this was with glass‑based TARE with Y-90 at a dose of 120 Gy ± 10%. Patients had follow-ups every 8 weeks until disease progression, hepatic disease progression, or death.

The co-primary endpoints were PFS and hepatic PFS. Secondary endpoints were OS, ORR, and DCR.

EPOCH: Baseline Characteristics

Eric Van Cutsem, MD, PhD:
Approximately one third of the patients in each arm had their primary tumor in situ and between 63.8% to 69.8% had a left‑sided tumor. Extrahepatic lesions excluding the primary in situ tumor affected between 44.6% to 52.6% of the patients, although the majority of the tumor burden was within the liver.

EPOCH: Treatment Characteristics

Eric Van Cutsem, MD, PhD:
Most patients in each arm received second‑line irinotecan‑based CT. The number of patients receiving a biologic agent was also similar between the arms, with 40.9% of the patients in the Y-90 arm and 43.7% of patients in the CT arm receiving aflibercept plus ramucirumab, bevacizumab, cetuximab, or panitumumab.

EPOCH: PFS (Coprimary Endpoint)

Eric Van Cutsem, MD, PhD:
The coprimary PFS endpoint was met with a median PFS of 7.2 months with CT alone vs 8 months with Y-90 plus CT (HR: 0.69; 95% CI: 0.54-0.88; P = .0013). The separation of the curves was maintained over follow-up and the benefit was across prespecified subgroups: KRAS mutation, sidedness of the tumor, tumor burden, number of metastases, and addition of biologic agent.

EPOCH: Hepatic PFS (Coprimary Endpoint)

Eric Van Cutsem, MD, PhD:
The other coprimary endpoint was hepatic PFS. Adding locoregional therapy to CT for liver metastases was clearly better than CT alone, with a median hepatic PFS of 9.1 months with Y-90 plus CT vs 7.2 months with CT alone (HR: 0.59; 95% CI: 0.46-0.77; P <.0001). There was also a clear separation of the curves with a consistent benefit across the different subgroups.

EPOCH: Overall Survival

Eric Van Cutsem, MD, PhD:
The OS data were disappointing, as there was no survival difference between CT alone and Y-90 plus CT. The curves completely overlap, and the median OS was 14.0 months in the Y-90 plus CT arm vs 14.4 months in the CT alone arm (HR: 1.07; 95% CI: 0.86-1.32; P = .7229).

EPOCH: Response and DCR

Eric Van Cutsem, MD, PhD:
The ORR was higher in the Y-90 plus CT group, at 34.0% vs 21.1% in the CT alone group, with a difference of 12.8% (95% CI: 4.0-21.4; P = .0019). The DCR was 79.5% vs 72.8% in favor of the Y-90 plus CT arm, with a difference of 6.8% (95% CI: -1.6-15.1; P = .0626).

EPOCH: Safety

Eric Van Cutsem, MD, PhD:
As expected, there were more AEs with the combination of Y-90 and CT. Grade ≥3 treatment-emergent AEs (TEAEs) were 68.4% in the combined modality arm and 49.3% in the CT arm, but their impact was mild if you look at the type of AEs, which were primarily neutropenia, fatigue, and anemia. Moreover, there were no treatment‑related deaths within 30 days of Y‑90 infusion.

EPOCH: Conclusions

Eric Van Cutsem, MD, PhD:
EPOCH was an important trial and the first positive phase III trial of Y-90 TARE with CT in the second-line setting for patients with colorectal liver metastases demonstrating significant delay in disease progression.

Looking at the coprimary endpoints of PFS and PFS in the liver, both were met. However, it was disappointing that there was no OS difference. I think before adaptation into guidelines, we need more data for this strategy since OS is extremely relevant in these patients. However, it is still promising that we can see a significant difference in PFS with the combination of Y-90 plus CT.

KRYSTAL-1 Trial of Adagrasib ± Cetuximab in KRAS G12C-Mutated mCRC

Eric Van Cutsem, MD, PhD:
Conceptually, another important trial presented at ESMO 2021 is the phase I/II KRYSTAL-1 trial evaluating adagrasib vs adagrasib plus cetuximab in patients with KRAS G12C-mutated colorectal cancer.31 The combination of adagrasib and cetuximab targets the KRAS pathway at 2 levels, similar to what we do in BRAF‑mutant tumors using BRAF inhibitors in combination with EGFR antibodies.

In the 45 evaluable patients who received adagrasib alone, ORR was 22%. ORR was 43% in the 28 evaluable patients who received the combination of adagrasib and cetuximab. DCR was 87% with adagrasib alone vs 100% in patients receiving combination therapy. Conceptually, these data show that there is activity with the combination of EGFR antibody plus KRAS inhibition. A randomized phase III trial is now being launched for this combination in patients with the KRAS G12C mutation.

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