2022 ESMO | DESTINY-Gastric 02 Research Update: OS reaches 12.1 months, which is expected to establish a new pattern of second-line treatment of HER2-positive advanced gastric cancer

*For medical professionals only

Tracking the latest follow-up data from the DESTINY-Gastric02 study, OS reached 12.
1 months, and the security was reliable
.

The 2022 European Society for Medical Oncology (ESMO) Congress was held from September 9 to 13 Paris time and has come to a perfect end
.

Current status and clinical dilemma of second-line treatment

       

According to GLOBOCAN data 2020, stomach cancer in China accounts for 43.
9% of new cases worldwide and 48.
6% of world deaths[2].


Moreover, the 5-year survival rate of gastric cancer in China is only 35.
9%, which is far lower than that of Japan and South Korea[3], and needs to be improved
.

The success of the ToGA phase III study established the status of trastuzumab in the treatment of HER2-positive advanced gastric cancer[4], and trastuzumab combined with chemotherapy became the first-line treatment regimen for HER2-positive advanced gastric cancer, and since then gastric cancer has entered the era of
targeted therapy.
In the nearly ten years since then, the exploration of HER2-positive advanced gastric cancer has been difficult and has mostly failed
.

In patients without trastuzumab, neither tyrosine kinase inhibitors (TKI, lapatinib) nor second-generation ADC drugs (T-DM1) improved the survival benefit of second-line therapy for HER2-positive advanced gastric cancer [5,6
].

At the same time, a meta-analysis showed that among patients who failed trastuzumab treatment, the results of phase II studies and retrospective studies at home and abroad in recent years showed that the value of trastuzumab cross-line therapy was controversial, and there was a lack of high-level evidence-based medical basis, so cross-line treatment was not supported [7].

A review of the 2022 Chinese Society of Clinical Oncology (CSCO) guidelines for the diagnosis and treatment of gastric cancer found that the second-line treatment recommendation for HER2-positive advanced gastric cancer is mainly remoxizumab plus paclitaxel or other single-agent chemotherapy, and there is no standard anti-HER2 drug [8].


In addition, the efficacy of second-line therapy varied widely, with median OS only 5.
2 to 9.
5 months and objective response rates (ORR) ranging from 9.
3% to 26.
5% [9 to 12].


Overall, second-line treatment for HER2-positive advanced gastric cancer lacks an effective treatment regimen and there is a significant unmet need
.

Breakout – T-DXd is positive for HER2

The second-line treatment of advanced gastric cancer has brought new breakthroughs

       

T-DXd, recommended in the 2022 second edition of the National Comprehensive Cancer Network (NCCN) Guidelines for Gastric Cancer and the 2022 ESMO Guidelines for the Diagnosis and Treatment of Gastric Cancer, is the only drug that promotes OS for second-line treatment of HER2-positive advanced gastric cancer to more than one year [13,14
].

Based on the impressive efficacy of the DESTINY-Gastric01 study, patients with HER2-positive advanced third-line and above gastric cancer who progressed to trastuzumab treated with T-DXd for median OS for up to 12.
5 months, significantly longer than in the chemotherapy group (8.
9 months); the ORR was 51.
3 percent, more than three times that of the chemotherapy group (14.
3 percent) [15].


And based on this, T-DXd has been approved for HER2-positive advanced gastric cancer indications (US FDA ≥ 2 lines, Japan MHLW ≥3 lines).

The DESTINY-Gastric02 study is another open-label, single-arm phase II study of T-DXd that included HER2-positive non-resectable or metastatic gastric and gastroesophageal junction adenocarcinoma (referred to as advanced gastric cancer) that progressed after first-line trastuzumab-containing monotherapy to assess the efficacy and safety of T-DXd second-line monotherapy in Western populations[1].


The main inclusion criteria include: 1) pathologically proven unresectable or metastatic advanced gastric cancer; 2) HER2-positive patients (IHC3+ or IHC2+/ISH+) validated by the central laboratory: specimen sampling progresses after first-line trastuzumab therapy; 3) ECOG PS score 0 or 1
.

The primary study endpoints were ORR as assessed by the Independent Center Review Committee (ICR), and the secondary study endpoints included progression-free survival (PFS), OS, duration of response (DoR), safety, and PRO assessed by ICR
.
Figure 1.
The DESTINY-Gastric02 study was designed[1]
The study enrolled in a total of 79 patients, more than half of the patients (63.
3%) had ECOG PS 1, 65.
8% had gastroesophageal junction cancer, 93.
7% had at least 2 metastases, and 63.
3% had liver metastases
at baseline.

Overall, enrolled patients had a poor
baseline.

Data from the first analysis, reported at the 2021 ESMO Annual Meeting,[16] showed a median follow-up of 5.
9 months as of April 9, 2021, a confirmed ORR of 38%, a median DoR of 8.
1 months, a disease control rate (DCR) of 81%, and a median PFS of 5.
5 months
.
Figure 2.
DESTINY-Gastric02 findings[1]
The updated study data at ESMO 2022 show that as of August 2021, the median follow-up time was 10.
2 months, and the ICR-confirmed ORR was 41.
8%, of which 5.
1% of patients achieved complete response (CR), 36.
7% achieved partial response (PR), and 39.
2% achieved disease stability (SD
。
The confirmed DCR was 81.
0%, the median DoR was 8.
1 months, and the median response time (TTR) was 1.
4 months
.

The median OS was 12.
1 months and the median PFS was 5.
6 months[1].

Figure 3.
OS and PFS benefit[1]
In terms of safety, the median duration of treatment was 4.
3 months
.

The incidence of drug-related TEAEs at any grade was 94.
9%, and the incidence of ≥-grade 3 drug-related TEAEs was 30.
4%.


The most common TEAEs were nausea 67.
1%, vomiting 44.
3% and fatigue 41.
8%.


The incidence of drug-related interstitial lung disease/pneumonia (ILD) was 10.
1% (8/79), of which 6 (7.
6%) patients were grade 1-2 and 2 (2.
5%) were grade 5, and ILD was controllable
in most patients.

The median duration of determined drug-associated ILD was 80.
5 days and the median duration was 36 days, all of which were broadly consistent
with the results of the initial analysis.

Indicates that T-DXd-2-positive advanced gastric cancer continues to benefit in Western populations with extended follow-up time[1].

Figure 4.
Safety data[1]
PRO is one of the forms of clinical outcomes that is patient-centered, emphasizing the patient's experience, perspective, and needs, with patients directly reporting their feelings about their disease and corresponding treatment during treatment, which is a very important complement to existing clinical trials [17].


PRO data from the DESTINY-Gastric02 study were also presented at the ESMO conference, demonstrating the clinical benefits
of T-DXd from a patient perspective.

As of April 9, 2021, there were no significant changes in health-related quality of life (HRQoL) between T-DXd treatment and cycle 7 compared with baseline, as assessed on EQ-5D and FACT-Ga.
(Gastric Cancer Treatment Function Assessment Scale)[1].


This shows that with the prolongation of follow-up time, T-DXd treatment can maintain the quality
of life of patients with HER2-positive advanced gastric cancer.
Figure 5.

The FATE Gastric02 study not only supplemented data from Western populations in terms of subject distribution (DESTINY-Gastric01 only included Asian populations); The results of the initial analysis have confirmed that T-DXd has significant efficacy and safety in the second-line treatment of HER2-positive advanced gastric cancer.
The data updated by the ESMO conference shows that after T-DXd second-line treatment, the ORR of HER2-positive advanced gastric cancer patients is as high as 41.
8%, and the OS breakthrough is 1 year, which is the highest record in the current second-line treatment plan for HER2-positive gastric cancer; And HRQoL is maintained
during treatment.

Further reveals the broad prospects of
T-DXd second-line treatment of HER2-positive advanced gastric cancer.

Summary and outlook – positive for HER2

The future pattern of second-line treatment of advanced gastric cancer

       

China has the largest population of gastric cancer patients in the world, and the overall survival rate is worrying
.

According to the 2022 CSCO guidelines for the diagnosis and treatment of gastric cancer, there is a lack of effective post-line therapy in patients with HER2-positive advanced gastric cancer after the failure of first-line therapy using a combination regimen based on trastuzumab
.

Based on the excellent performance of the DESTINY-Gastric01 study, the 2022 NCCN and ESMO guidelines recommend T-DXd for the second-line and subsequent treatment
of HER2-positive advanced gastric cancer.

The DESTINY-Gastric02 study updated at ESMO Conference shows that T-DXd has achieved a double breakthrough in the second-line treatment of HER2-positive advanced gastric cancer, and is the first HER2-positive second-line treatment drug for advanced gastric cancer with OS breakthrough of 1 year, and the patient's HRQoL has been maintained
throughout the treatment process.

Provide evidence-based medical evidence
that T-DXd has become the standard for second-line treatment of HER2-positive advanced gastric cancer.
In an ongoing global, multicenter, randomized, open-label, stage III DESTINY-Gastric04 clinical study, head-to-head comparison of the differences between T-DXd monotherapy and remoxizumab + paclitaxel in HER2-positive advanced gastric cancer treated with trastuzumab [18] will further consolidate the second-line treatment status
of T-DXd in HER2-positive advanced gastric cancer.

From the current research progress, ADC drugs, TKI, and bispecific antibodies represented by T-DXd are actively explored
in the second-line treatment of HER2-positive advanced gastric cancer.

In the future, with the release of these new drug research data, it is believed that more new treatment options can be brought to patients with HER2-positive advanced gastric cancer, prolonging survival time and improving quality of
life.


Expert profile

Professor Guo Weijian

• Ph.

  
  

• Director of the Department of Gastrointestinal Oncology, Affiliated Cancer Hospital of Fudan University

• Director of the Chinese Society of Clinical Oncology (CSCO).

  
  

• Member of the Standing Committee of Pancreatic Cancer Committee of Chinese Society of Clinical Oncology

• Member of the Standing Committee of the Precision Treatment Committee of the Chinese Anti-Cancer Association

• Member of the Gastric Cancer Committee of the Chinese Anti-Cancer Association

• Member of the Gastric Cancer Committee of the Chinese Society of Clinical Oncology

• Chairman of the Special Committee of Cancer Rehabilitation and Palliative Care of Shanghai Anti-Cancer Association

• Vice Chairman of the Special Committee on Molecular Targeting and Immunotherapy for Gastric Cancer of Shanghai Anti-Cancer Association

• Member of the Standing Committee of the Bowel Cancer Committee of Shanghai Anti-Cancer Association and Deputy Head of the Metastasis Group

• He has undertaken a number of major special projects for the National Natural Science Foundation of China and the Ministry of Science and Technology for the creation of new drugs, and has won the second prize of the Ministry of Education's Science and Technology Progress Award

References:

[1] Updated analysis of DESTINY-Gastric02:A phase II single-arm trial of trastuzumab deruxtecan(T-DXd)in western patients(Pts)with HER2-positive(HER2+)unresectable/metastatic gastric/ gastroesophageal junction(GEJ)cancer who progressed on or after trastuzumab-containing regimen.

[2] Sung H,Ferlay J,Siegel RL,et al.

[3] Allemani C,Matsuda T,Di Carlo V,et al.

[4] Bang YJ,Van Cutsem E,Feyereislova A,et al.

[5] Satoh T,Xu RH,Chung HC,et al.

[6] Thuss-Patience PC,Shah MA,Ohtsu A,et al.

[7] Palle J,Rochand A,Pernot S,Gallois C,Taïeb J,Zaanan A.

[8] Guidelines Working Committee of Chinese Society of Clinical Oncology.

[9] Li Q,Jiang H,Li H,et al.
Efficacy of trastuzumab beyond progression in HER2 positive advanced gastric cancer:a multicenter prospective observational cohort study.
Oncotarget.
2016 Aug 2; 7(31):50656-50665.

[10] Hironaka S,Ueda S,Yasui H,et al.
Randomized,open-label,phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum:WJOG 4007 trial.
J Clin Oncol.
2013 Dec 10; 31(35):4438-44.

[11] RAINBOW-Asia:A randomized,multicenter,double-blind,phase 3 study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of advanced gastric or gastroesophageal junction(GEJ)adenocarcinoma following disease progression on first-line chemotherapy with platinum and fluoropyrimidine.
2021 ASCO GI.
Abstract 199.

[12] Kang JH,Lee SI,Lim DH,et al.
Salvage chemotherapy for pretreated gastric cancer:a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone.
J Clin Oncol.
2012 May 1; 30(13):1513-8.

[13] NCCN Gastric Cancer.
2022 V2.

[14] Lordick F,Carneiro F,Cascinu S,et al.
Gastric cancer:ESMO Clinical Practice Guideline for diagnosis,treatment and follow-up.
Ann Oncol.
2022 Jul 29:S0923-7534(22)01851-8.

[15] Shitara K,Bang YJ,Iwasa S,et al;DESTINY-Gastric01 Investigators.
Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer.
N Engl J Med.
2020 Jun 18; 382(25):2419-2430.

[16] Primary Analysis of a Phase 2 Single-Arm Trial of Trastuzumab Deruxtecan(T-DXd)in Western Patients With HER2-Positive(HER2+)Unresectable or Metastatic Gastric or Gastroesophageal Junction(GEJ)Cancer Who Progressed on or After a Trastuzumab-containing Regimen.
2021 ESMO.
Abstract LBA55.

[17] The Drug Review Center of the State Food and Drug Administration, "Guidelines for the Application of Patient-Reported Outcomes in Clinical Research of Drugs (Trial)" _msthash="296951" _msttexthash="1721135">[18]https://clinicaltrials.
gov/ct2/show/NCT04704934

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