Review Reports

Round 1

Reviewer 1 Report

The review article is an overview of the newest data in the treatment algorithms of gastroesophageal cancer. The main contribution of this work is a brief but detailed overview of the latest evidence-based treatment for gastric cancer.

Did not identify any significant deficiencies in the article.

The manuscript is clear, very relevant for gastric cancer treatment, and presented in a well-structured manner. The references used are current and appropriate in number. The table and figure are suitable, straightforward, easy to interpret and understand. The conclusions are consistent with the evidence and arguments presented. It is clear, comprehensive, and highly relevant to gastric cancer. This overview is very pertinent and vital for colleagues dealing with gastric cancer.

Author Response

We thank the reviewer for the highly appreciative feedback of our manuscript.

To be consistent with the terminology used in clinical trials, we have added the term “advanced” GC, where appropriate.

Please note the modified reference order in the text and table due to added citations (detailled information available via comments and the track change option included in the manuscript.)

Furthermore, we made a modifcation in table 1: the information on the study design of the Keynote-590 trial was revised: “Pembro plus FP vs. pembro” was changed correctly into “Pembro vs. placebo plus FP”.

Reviewer 2 Report

Very interesting review written by two international experts of the management of gastric cancer.

This study addresses a current topic.

The manuscript is well written and organized. English could be improved.

Figures and tables are comprehensive and clear.

The introduction explains in a clear and coherent manner the background of this study.

We suggest the following modifications:

• Introduction section: although the authors correctly included important papers in this setting, we believe some studies should be cited within the introduction ( PMID: 33916206 ; PMID: 31793342), only for a matter of consistency. We think it might be useful to introduce the topic of this interesting study. In particular, it would be interesting to add more details regarding immune-based combinations including HER2 targeted therapies.
• In addition, the authors could expand some sections, including a more personal perspective to reflect on. For example, they could answer the following questions – in order to facilitate the understanding of this complex topic to readers: What are the knowledge gaps and how do researchers tackle them? How do you see this area unfolding in the next 5 years? We think it would be extremely interesting for the readers.

However, we think the authors should be acknowledged for their work. 

We believe this article is suitable for publication in the journal although some revisions would be desired. The main strengths of this paper are that it addresses an interesting and very timely question and provides a clear answer, with some limitations.

We suggest the addition of some references for a matter of consistency. Moreover, the authors could better clarify some points. Congratulations again for this brilliant contribution.

Author Response

Point 1:

Very interesting review written by two international experts of the management of gastric cancer.

This study addresses a current topic.

The manuscript is well written and organized. English could be improved.

Figures and tables are comprehensive and clear.

The introduction explains in a clear and coherent manner the background of this study.

Response 1:

We thank the reviewer for these positive comments. We have corrected the English where appropriate.

Point 2:

We suggest the following modifications:

Introduction section: although the authors correctly included important papers in this setting, we believe some studies should be cited within the introduction ( PMID: 33916206 ; PMID: 31793342), only for a matter of consistency. We think it might be useful to introduce the topic of this interesting study. In particular, it would be interesting to add more details regarding immune-based combinations including HER2 targeted therapies.

Response 2:

Thank you for pointing this out and for providing us with the needed references for Her2-targeted therapy of gastric cancer. We agree with the reviewer’s opinion and have supplemented the introduction part with the following information:

Lines 35-79:

“An already established therapeutic approach in targeted therapy of progressive GC is the Her2-blockade in patients with Her2-positive tumors with a rate of 15-20% Her2 overexpression[4]. Here, trastuzumab has been successfully implemented as standard of care in combination with chemotherapy in the first-line setting of patients with advanced GC[5]. In the new era of immune checkpoint inhibition, combination therapies of Her2- and PD-1/PD-L1-directed therapies aim for synergistic effects. Several global phase II and III trials analyse the addition of pembrolizumab, nivolumab and ipilimumab to standard of care first-line therapy of trastuzumab plus chemotherapy in Her2-positive advanced cancer patients[6].

As there remain Her2-positive patients who do not benefit from trastuzumab, various innovative approaches of Her2-directed therapy are under investigation including the promising antibody-drug conjugate trastuzumab-deruxtecan (T-DXd) in patients who were progressive under prior trastuzumab therapy[7]. T-DXd has already been approved by the FDA as a second Her2-directed therapy option for patients with unresectable, locally advanced or metastatic GC in 2021 and is currently under investigation as combination therapy with immune checkpoint inhibitors[8,9]. Another approach is the use of the Fc-engineered Her2-directed monoclonal antibody margetuximab. This has already shown positive effects on overall response and disease control in combination with PD-1 inhibition with pembrolizumab in a phase I/IIb clinical trial and is being further tested with retifanlimab or tebotelimab in a phase II/III trial[10,11].

The number of GC patients with progress after first- and second-line therapy grows and emphasizes the role of third- and last-line treatment options. Results of a systematic review and meta-analysis of 7 randomised controlled trials indicate a superiority in efficacy of third- and later-line therapies in advanced GC patients[12]. Although more toxicities occured in third-line treatment regimens, the overall safety profile remains manageable and encourages the use of immunotherapy in single or combination application in later therapy lines.”

We have among others included the two citations suggested by the reviewer (reference #7, #12) in the introduction section:

4. Palle, J.; Rochand, A.; Pernot, S.; Gallois, C.; Taïeb, J.; Zaanan, A. Human Epidermal Growth Factor Receptor 2 (HER2) in Advanced Gastric Cancer: Current Knowledge and Future Perspectives. Drugs 2020, 80, 401–415, doi:10.1007/s40265-020-01272-5.
5. Bang, Y.-J.; Van Cutsem, E.; Feyereislova, A.; Chung, H.C.; Shen, L.; Sawaki, A.; Lordick, F.; Ohtsu, A.; Omuro, Y.; Satoh, T.; et al. Trastuzumab in Combination with Chemotherapy versus Chemotherapy Alone for Treatment of HER2-Positive Advanced Gastric or Gastro-Oesophageal Junction Cancer (ToGA): A Phase 3, Open-Label, Randomised Controlled Trial. Lancet 2010, 376, 687–697, doi:10.1016/S0140-6736(10)61121-X.
6. Janjigian, Y.Y.; Kawazoe, A.; Yanez, P.E.; Luo, S.; Lonardi, S.; Kolesnik, O.; Barajas, O.; Bai, Y.; Shen, L.; Tang, Y.; et al. Pembrolizumab plus Trastuzumab and Chemotherapy for HER2+ Metastatic Gastric or Gastroesophageal Junction (G/GEJ) Cancer: Initial Findings of the Global Phase 3 KEYNOTE-811 Study. JCO 2021, 39, 4013–4013, doi:10.1200/JCO.2021.39.15_suppl.4013.
7. Ricci, A.D.; Rizzo, A.; Rojas Llimpe, F.L.; Di Fabio, F.; De Biase, D.; Rihawi, K. Novel HER2-Directed Treatments in Advanced Gastric Carcinoma: AnotHER Paradigm Shift? Cancers (Basel) 2021, 13, 1664, doi:10.3390/cancers13071664.
8. Shitara, K.; Iwata, H.; Takahashi, S.; Tamura, K.; Park, H.; Modi, S.; Tsurutani, J.; Kadowaki, S.; Yamaguchi, K.; Iwasa, S.; et al. Trastuzumab Deruxtecan (DS-8201a) in Patients with Advanced HER2-Positive Gastric Cancer: A Dose-Expansion, Phase 1 Study. Lancet Oncol 2019, 20, 827–836, doi:10.1016/S1470-2045(19)30088-9.
9. Janjigian, Y.Y.; Oh, D.-Y.; Rha, S.Y.; Lee, K.W.; Steeghs, N.; Chao, Y.; Di Bartolomeo, M.; Díez Garcia, M.; Haj Mohammad, N.; Stein, A.; et al. Dose-Escalation and Dose-Expansion Study of Trastuzumab Deruxtecan (T-DXd) Monotherapy and Combinations in Patients (Pts) with Advanced/Metastatic HER2+ Gastric Cancer (GC)/Gastroesophageal Junction Adenocarcinoma (GEJA): DESTINY-Gastric03. JCO 2022, 40, 295–295, doi:10.1200/JCO.2022.40.4_suppl.295.
10. Catenacci, D.V.T.; Kang, Y.-K.; Park, H.; Uronis, H.E.; Lee, K.-W.; Ng, M.C.H.; Enzinger, P.C.; Park, S.H.; Gold, P.J.; Lacy, J.; et al. Margetuximab plus Pembrolizumab in Patients with Previously Treated, HER2-Positive Gastro-Oesophageal Adenocarcinoma (CP-MGAH22-05): A Single-Arm, Phase 1b-2 Trial. Lancet Oncol 2020, 21, 1066–1076, doi:10.1016/S1470-2045(20)30326-0.
11. Catenacci, D.V.T.; Rosales, M.K.; Chung, H.C.; Yoon, H.H.; Shen, L.; Moehler, M.H.; Kang, Y.-K. Margetuximab (M) Combined with Anti-PD-1 (Retifanlimab) or Anti-PD-1/LAG-3 (Tebotelimab) +/- Chemotherapy (CTX) in First-Line Therapy of Advanced/Metastatic HER2+ Gastroesophageal Junction (GEJ) or Gastric Cancer (GC). JCO 2021, 39, TPS264–TPS264, doi:10.1200/JCO.2021.39.3_suppl.TPS264.
12. Rizzo, A.; Mollica, V.; Ricci, A.D.; Maggio, I.; Massucci, M.; Rojas Limpe, F.L.; Fabio, F.D.; Ardizzoni, A. Third- and Later-Line Treatment in Advanced or Metastatic Gastric Cancer: A Systematic Review and Meta-Analysis. Future Oncol 2020, 16, 4409–4418, doi:10.2217/fon-2019-0429.

Point 3:

In addition, the authors could expand some sections, including a more personal perspective to reflect on. For example, they could answer the following questions – in order to facilitate the understanding of this complex topic to readers: What are the knowledge gaps and how do researchers tackle them? How do you see this area unfolding in the next 5 years? We think it would be extremely interesting for the readers.

Response 3:

We thank the reviewers for this comment and agree with expanding sections of the manuscript. We have supplemented the following sections with additional references and provided a more personal perspective for the readers to think about. Recent results from ASCO GI 2022 have also been included.

6. Combination of Immune Checkpoint Inhibition and Her2-Targeted Therapy:

Lines 387-410:

“However, one future challenge remains to identify and address trastuzumab resistant patients with loss of Her2 expression. Several studies have analysed changes in Her2 status after progression of first-line Her2-directed therapy to clarify the lack of survival advantage in the second-line setting of anti-Her2 therapy in Her2-positive advanced GC patients: a multicenter observational study reevaluated the Her2 status in patients with advanced or recurrent GC refractory to trastuzumab in order to identify possible biomarkers for loss of response to Her2-targeted first-line therapy with trastuzumab[42]. The Her2 status from biopsy samples of patients showing resistance to trastuzumab was evaluated before and after development of trastuzumab resistance. Loss of Her2 expression was detected in 60.6% of patients with refractory disease after first-line trastuzumab (20/33). Immunohistochemical Her2 overexpression was clearly decreased after trastuzumab treatment. These data indicate that Her2 status should be re-evaluated especially in Her2-positive patients who progressed after trastuzumab first-line therapy. The lack of effect of Her2-directed agents is further analysed using margetuximab in combination with pembrolizumab in 60 Her2-positive advanced EGA patients in second-line setting post trastuzumab progression and the results recently presented at ASCO GI 2022. By ctDNA-analysis, 61% ERBB2 amplification was detected and predicted response to combination therapy of margetuximab plus pembrolizumab (24% vs. 0% (p = 0.0655), especially in PD-L1 positive patients. In the subgroup of ctDNA- and PD-L1 positive GC patients, ORR was 57% and DCR was 86%[43]. Further research is needed to filter responders from non-responders to Her2-directed therapy after trastuzumab progression and to clarify the role of re-evaluation of the Her2 status (ERBB2 amplification) beyond progression as possible predictive biomarker for response to Her2-targeted therapy regimes in second-line post trastuzumab settings.”

42. Saeki, H.; Oki, E.; Kashiwada, T.; Arigami, T.; Makiyama, A.; Iwatsuki, M.; Narita, Y.; Satake, H.; Matsuda, Y.; Sonoda, H.; et al. Re-Evaluation of HER2 Status in Patients with HER2-Positive Advanced or Recurrent Gastric Cancer Refractory to Trastuzumab (KSCC1604). Eur J Cancer 2018, 105, 41–49, doi:10.1016/j.ejca.2018.09.024.
43. Catenacci, D.V.T.; Park, H.; Uronis, H.E.; Kang, Y.-K.; Lacy, J.; Enzinger, P.C.; Park, S.H.; Lee, K.W.; Ng, M.C.H.; Gold, P.J.; et al. Margetuximab (M) plus Pembrolizumab (P) in ERBB2-Amplified PD-L1+ Gastroesophageal Adenocarcinoma (GEA) Post Trastuzumab (T). JCO 2018, 36, 4030–4030, doi:10.1200/JCO.2018.36.15_suppl.4030.

 

7. Molecular biomarkers in advanced gastric cancer , 7.1 PD-L1 CPS:

Lines 444-470:

“Nonetheless, there remain some unanswered questions on how to handle the PD-L1 CPS score as a reliable tool to differentiate between responders and non-responders to immunecheckpoint inhibitor therapy of GC in the future.

The question of a reliable cut-off value of the PD-L1 CPS score as a consistent marker to predict benefit from immunecheckpoint inhibition needs to be clarified. As mentioned above, recent phase II and III trials indicate a survival benefit of immunecheckpoint therapy especially in patients with high CPS-scores (CPS ≥ 5). The assumed lack of benefit of the subgroup of patients with low CPS scores (CPS ≤ 5, ≤ 1) was investigated in randomised phase III trials (CHECKMATE-649, KEYNOTE-062 and KEYNOTE-590) that compared the addition of immune checkpoint inhibitors with chemotherapy using a Kaplan-Meier subtraction approach. The comparison analysis confirmed, that the patients with low PD-L1 CPS scores (subgroups of CPS 1-9 and CPS 1-4) investigated in these trials did not show significant benefit from the addition of immunecheckpoint inhibitors compared with standard chemotherapy in advanced EGC[46]. We personally recommend to further classify the subgroup of PD-L1 CPS low patients by specific analyses and to reflect the rational use of immune checkpoint inhibitors in patients with low CPS scores.

The magnitude and consitency of PD-L1 as a predictive marker is the object of investigation of a current systematic review and meta-analysis of 14 phase III trials in advanced EGC. The primary results were presented at ASCO GI 2022 and identified PD-L1 CPS as the second strongest predictive biomarker for survival benefit from immune checkpoint inhibition compared to standard-of-care after MSI[47]. This study also confirms further findings of gender differences in response to immunecheckpoint therapy as already demonstrated for example in KEYNOTE-590 with lower benefit from pembrolizumab plus chemotherapy vs. placebo for women compared to men (HR = 0.89 (0.59-1.35) vs. HR = 0.70 (0.58-0.84), 95% CI)[22]. We strongly support the clarification of the sex-specific differences in response to immunotherapy in future immune checkpont inhbitior trials and to work out the possible role of sex as a predictive marker for immune checkpoint inhibitors.”

 

46. Zhao, J.J.; Yap, D.W.T.; Chan, Y.H.; Tan, B.K.J.; Teo, C.B.; Syn, N.L.; Smyth, E.C.; Soon, Y.Y.; Sundar, R. Low Programmed Death-Ligand 1–Expressing Subgroup Outcomes of First-Line Immune Checkpoint Inhibitors in Gastric or Esophageal Adenocarcinoma. JCO 2022, 40, 392–402, doi:10.1200/JCO.21.01862.
47. Yoon, H.H.; Jin, Z.; Kour, O.; Shitara, K.; Gibson, M.K.; Prokop, L.; Kang, Y.-K.; Shi, Q.; Ajani, J.A. Association of Magnitude and Consistency of PD-L1 Expression and Other Variables Associated with Benefit from Immune Checkpoint Inhibition (ICI): Systematic Review and Meta-Analysis of 14 Phase 3 Trials in Advanced Gastroesophageal Cancer (GEC). JCO 2022, 40, 344–344, doi:10.1200/JCO.2022.40.4_suppl.344.

22. Sun, J.-M.; Shen, L.; Shah, M.A.; Enzinger, P.; Adenis, A.; Doi, T.; Kojima, T.; Metges, J.-P.; Li, Z.; Kim, S.-B.; et al. Pembrolizumab plus Chemotherapy versus Chemotherapy Alone for First-Line Treatment of Advanced Oesophageal Cancer (KEYNOTE-590): A Randomised, Placebo-Controlled, Phase 3 Study. The Lancet 2021, 398, 759–771, doi:10.1016/S0140-6736(21)01234-4.

 

7. Molecular biomarkers in advanced gastric cancer, 7.2 MSI:

Lines 490-509 :

“Further studies are needed to clarify, whether patients with high levels of microsatellite instability or deficient mismatch repair (dMMR) in particular qualify for single / combination immunotherapy. There are subgroup analyses indicating no survival benefit for patients with MSI-high EGC treated with chemotherapy in the perioperative setting compared with surgery (meta-analysis of MAGIC, CLASSIC, ARTIST, ITACA-S trial)[51] As presented at ESMO 2021, results of the DANTE-trial shows benefit for MSI-high patients treated with a combination of immune checkpoint inhibitors and chemotherapy: with rates of pathological complete response or subtotal regression (TRG1a/b) being 80% (8/10) after FLOT plus atezolizumab vs. 59% (7/12) after FLOT monotherapy[52]. Furthermore, the role of neoadjuvant nivolumab plus ipilmumab and adjuvant nivolumab with localized MSI-high/dMMR EGC was investigated in the GERCOR NEONIPIGA phase II trial with the primary endpoint of pathological complete response rate (pCRR). First results presented at ASCO GI 2022 showed neoadjuvant immune checkpoint inhibition as feasible therapy option. The pCRR was 59% (17/29 patients) and 94% of patints were free of events after 12 months of follow up[53]. These results raise the question whether immunotherapy postpone or even replace surgery in patients with MSI-high / dMMR tumors. We recommend that testing the MSI status of EGC patients should be routinely performed at the time of diagnosis prior to treatment . With larger future studies, we might really implement immunotherapy in perioperative settings, especially for patients with MSI-high / dMMR tumors.”

52. Al-Batran, S.-E.; Lorenzen, S.; Homann, N.; Thuss-Patience, P.C.; Schenk, M.; Lindig, U.; Kretzschmar, A.; Heuer, V.; Goekkurt, E.; Haag, G.M.; et al. 1429P Pathological Regression in Patients with Microsatellite Instability (MSI) Receiving Perioperative Atezolizumab in Combination with FLOT vs. FLOT Alone for Resectable Esophagogastric Adenocarcinoma: Results from the DANTE Trial of the German Gastric Group at the AIO and SAKK. Annals of Oncology 2021, 32, S1069, doi:10.1016/j.annonc.2021.08.1538.
53. Andre, T.; Tougeron, D.; Piessen, G.; De La Fouchardiere, C.; Louvet, C.; Adenis, A.; Jary, M.; Tournigand, C.; Aparicio, T.; Desrame, J.; et al. Neoadjuvant Nivolumab plus Ipilimumab and Adjuvant Nivolumab in Patients (Pts) with Localized Microsatellite Instability-High (MSI)/Mismatch Repair Deficient (DMMR) Oeso-Gastric Adenocarcinoma (OGA): The GERCOR NEONIPIGA Phase II Study. JCO 2022, 40, 244–244, doi:10.1200/JCO.2022.40.4_suppl.244.

Conclusion

Lines 535-539:

In the progress of immunotherapy in adenocarcinomas of the stomach / gastroesophageal junction, it remains necessary to further identify and subdivide subgroups and sex-specific differences of patients who particularly seem to benefit from response to immunotherapy by possible predictive biomarkers (PD-L1 CPS, MSI, EBV) within the next years.

Point 4:

However, we think the authors should be acknowledged for their work.

We believe this article is suitable for publication in the journal although some revisions would be desired. The main strengths of this paper are that it addresses an interesting and very timely question and provides a clear answer, with some limitations.

We suggest the addition of some references for a matter of consistency. Moreover, the authors could better clarify some points. Congratulations again for this brilliant contribution.

Response 4:

We once again thank the reviewer for this positive feedback.

 

Round 2

Reviewer 2 Report

Acceptance.