Is durvalumab is useful in adenocarcinoma of stomach without any ihc testing and WTS the rate of response with FLOT chemotherapy
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durvalumab gastric adenocarcinoma PD-L1
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FLOT chemotherapy gastric adenocarcinoma response rate
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durvalumab gastric adenocarcinoma without PD-L1 IHC testing TOPAZ MATTERHORN 2024 2025
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durvalumab FLOT MATTERHORN response rate PD-L1 overall survival event-free survival
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FLOT perioperative gastric cancer pathological complete response Al-Batran
I now have very comprehensive, current data. Let me compile the full answer.
Durvalumab in Gastric Adenocarcinoma: Does It Require IHC Testing?
The Short Answer: No - IHC testing is NOT required for the perioperative setting (as of 2025)
This is a significant paradigm shift driven by the landmark MATTERHORN trial (NEJM 2025, PMID: 40454643).
1. MATTERHORN Trial - The Pivotal Evidence
The phase III MATTERHORN trial randomized 948 patients (1:1) with resectable Stage II-IVA gastric or gastroesophageal junction (GEJ) adenocarcinoma to:
- Durvalumab 1500 mg every 4 weeks + FLOT (4 cycles: 2 neoadjuvant + 2 adjuvant) → then durvalumab monotherapy for 10 additional cycles
- Placebo + FLOT (same schedule)
Key Results
| Endpoint | Durvalumab + FLOT | Placebo + FLOT | HR / RR |
|---|---|---|---|
| 2-year Event-Free Survival | 67.4% | 58.5% | HR 0.71 (95% CI 0.58-0.86); P<0.001 |
| 2-year Overall Survival | 75.7% | 70.4% | HR 0.67 (from month 12 onward); P=0.03 |
| Pathological Complete Response (pCR) | 19.2% | 7.2% | RR 2.69 (95% CI 1.86-3.90) |
Critical Point: PD-L1 Status Is NOT Required
- The final OS analysis presented at ESMO 2025 confirmed that benefit was seen regardless of PD-L1 expression status
- Experts at ASCO 2025 described durvalumab + FLOT as "the right therapy for everyone" with resectable gastric cancer
- This is fundamentally different from the advanced/metastatic setting (e.g., nivolumab in CheckMate 649, pembrolizumab in KEYNOTE-590), where CPS ≥ 5 or CPS ≥ 10 thresholds were used to select patients
FDA Approval (November 25, 2025)
The FDA approved durvalumab (Imfinzi) + FLOT as neoadjuvant and adjuvant treatment for adults with resectable GC/GEJC - without requiring PD-L1 IHC as a prerequisite for use.
Important Subgroup Caveat
Discussants at ESMO cautioned that female patients, node-negative disease, and diffuse-type histology showed numerically smaller benefit - though confidence intervals were wide and numbers small. IHC testing (PD-L1 CPS) may still be informative for shared decision-making in these subgroups.
2. Durvalumab in Advanced/Metastatic Gastric Adenocarcinoma (Non-Resectable)
For the non-perioperative (advanced/metastatic) setting, the picture is different:
- PLATFORM trial (ESMO Open 2024, PMID: 39002179): Maintenance durvalumab after first-line chemo in HER2-negative advanced OG adenocarcinoma showed no significant PFS benefit overall (HR 0.84, P=0.13), but exploratory analysis found a favorable OS trend in CPS ≥5 patients (HR 0.63) vs CPS <5 (HR 0.93)
- DURIGAST trial (JAMA Oncol 2024, PMID: 38573643): FOLFIRI + durvalumab ± tremelimumab in 2nd-line did not demonstrate a survival benefit in unselected patients
Conclusion for advanced disease: Without IHC testing, durvalumab does not reliably benefit unselected patients in the advanced setting. PD-L1 CPS and TME characterization remain important for patient selection here.
3. FLOT Response Rates
FLOT (5-Fluorouracil + Leucovorin + Oxaliplatin + Docetaxel) is the perioperative backbone for resectable gastric/GEJ adenocarcinoma. Data from the landmark FLOT4-AIO trial (Al-Batran et al., Lancet Oncol 2016; Lancet 2019) and MATTERHORN's placebo arm:
| Response Parameter | FLOT (Monotherapy arm) | Source |
|---|---|---|
| Pathological Complete Response (pCR, ypT0N0) | ~16% | FLOT4-AIO Ph2 |
| pCR in MATTERHORN placebo arm | 7.2% | MATTERHORN 2025 |
| Major Pathologic Response (< 10% residual tumor) | ~37% | FLOT4-AIO |
| R0 resection rate | ~85% | FLOT4-AIO |
| Clinical/radiological ORR | ~45-57% | Multiple trials |
| 5-year Overall Survival | 45% | FLOT4 phase 3 |
| Median OS (vs ECF/ECX) | 50 months vs 35 months | FLOT4 phase 3 |
Note on MATTERHORN's 7.2% pCR in the FLOT placebo arm: This is lower than FLOT4-AIO's ~16%. This likely reflects the stricter pathological assessment methodology (ypT0N0 definition) used in MATTERHORN and differences in patient populations.
FLOT + Durvalumab pCR rate: 19.2% (nearly 3x the placebo arm's 7.2% in the same trial)
Summary
| Question | Answer |
|---|---|
| Does durvalumab require IHC testing for use in resectable gastric adenocarcinoma? | No - FDA-approved (Nov 2025) based on MATTERHORN; benefit is PD-L1-independent |
| Does durvalumab require IHC in advanced/metastatic disease? | Yes - benefit is largely confined to CPS ≥5 patients; unselected use not supported |
| FLOT pCR rate (chemo alone) | ~7-16% (7.2% in MATTERHORN, 16% in FLOT4-AIO) |
| FLOT + Durvalumab pCR rate | 19.2% |
| FLOT overall response rate (clinical) | ~45-57% |
The MATTERHORN data represent a meaningful advance: perioperative durvalumab + FLOT is now regarded by many as the new standard of care for resectable gastric/GEJ adenocarcinoma, without requiring upfront PD-L1 IHC selection.
Key references:
- Janjigian YY et al., NEJM 2025 [PMID: 40454643] - MATTERHORN trial
- Fong C et al., ESMO Open 2024 [PMID: 39002179] - PLATFORM trial (maintenance, advanced disease)
- Al-Batran SE et al., Lancet Oncol 2016 [PMID: 27776843] - FLOT4-AIO phase 2/3
- FDA approval notice, November 25, 2025
Is ihc testing best for pdl 1 and using novilumab or using directly durvalumab is best for stomach adenocarcinoma
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nivolumab gastric adenocarcinoma PD-L1 CPS CheckMate 649
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nivolumab vs durvalumab gastric adenocarcinoma PD-L1 IHC CPS testing 2025 standard of care
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nivolumab perioperative resectable gastric cancer ATTRACTION-5 DANTE trial 2024 2025
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IHC PD-L1 Testing, Nivolumab vs Durvalumab in Gastric Adenocarcinoma: A Head-to-Head Comparison
The answer depends critically on disease stage (resectable vs. advanced/metastatic) and the clinical context. These two drugs operate in different settings and are not interchangeable.
Setting 1: RESECTABLE Gastric Adenocarcinoma (Perioperative Intention)
Durvalumab + FLOT: No IHC testing required - use for everyone
The phase III MATTERHORN trial (NEJM 2025, PMID: 40454643) is the gold standard here:
| Outcome | Durvalumab + FLOT | FLOT alone | Significance |
|---|---|---|---|
| 2-yr Event-Free Survival | 67.4% | 58.5% | HR 0.71, P<0.001 |
| Final OS (ESMO 2025) | Not reached | Not reached | HR 0.78, P=0.021 |
| pCR (ypT0N0) | 19.2% | 7.2% | RR 2.69 |
Key point on PD-L1 IHC: The benefit was confirmed to be independent of PD-L1 expression at ESMO 2025 final OS analysis. The FDA approved durvalumab + FLOT on November 25, 2025, without any PD-L1 IHC requirement. Experts at ASCO 2025 described it as "the right therapy for everyone."
What about nivolumab in resectable gastric cancer?
Nivolumab has been tested in two perioperative/adjuvant gastric cancer trials with disappointing results:
- ATTRACTION-5 (Lancet Gastroenterol Hepatol 2024): Adjuvant nivolumab + chemotherapy after D2 gastrectomy in stage III gastric cancer - did NOT improve relapse-free survival (HR 0.90, non-significant). The post-surgical immunosuppressive microenvironment likely limits efficacy.
- KEYNOTE-585 (pembrolizumab, the closest analog): Also failed to show significant event-free survival benefit with perioperative pembrolizumab + chemotherapy, suggesting the FLOT backbone is key to the efficacy seen with durvalumab in MATTERHORN.
Verdict for resectable disease: Durvalumab + FLOT is the clear winner and the new global standard of care. IHC is not needed. Nivolumab is NOT approved or recommended for perioperative resectable gastric cancer.
Setting 2: ADVANCED / METASTATIC Gastric Adenocarcinoma (First-line, HER2-negative)
Nivolumab + chemotherapy: IHC testing IS required for optimal decision-making
The phase III CheckMate 649 trial is the benchmark here (PMID: 41687718 - 5-year follow-up, Ann Oncol 2026):
| CPS Subgroup | OS Benefit | PFS Benefit |
|---|---|---|
| CPS ≥ 5 (primary endpoint) | HR 0.71, 5-yr OS: 16% vs 6% | HR 0.71 |
| CPS ≥ 1 | Significant, maintained | Significant |
| CPS < 5 | HR 0.94 - no meaningful benefit | Minimal/none |
| CPS < 1 | HR 0.92 - no benefit | No benefit |
- ORR: 58% (nivolumab + chemo) vs 46% (chemo alone) in CPS ≥5
- Median duration of response: 8.5 months vs 6.9 months
IHC Testing Guidance for Nivolumab in Advanced Disease:
| CPS Score | Clinical Decision |
|---|---|
| CPS ≥ 5 | Strong indication - add nivolumab to FOLFOX/CAPOX |
| CPS 1-4 | Modest/uncertain benefit - shared decision-making; many oncologists still use it |
| CPS < 1 (0) | No benefit - chemotherapy alone recommended |
| MSI-H/dMMR | Strong immunotherapy benefit regardless of CPS |
The recommended IHC assay for nivolumab is Dako PD-L1 IHC 28-8 pharmDx, measuring CPS (not just tumor proportion score/TPS).
Durvalumab in Advanced Disease: NOT recommended without IHC, and weaker evidence overall
- PLATFORM trial (ESMO Open 2024, PMID: 39002179): Maintenance durvalumab after first-line chemo showed no PFS benefit overall (HR 0.84, P=0.13)
- Exploratory benefit only in CPS ≥5 and immune-rich TME patients (HR 0.63 for OS)
- DURIGAST trial (JAMA Oncol 2024): Second-line FOLFIRI + durvalumab - no survival benefit in unselected patients
- Durvalumab is NOT FDA-approved for advanced/metastatic gastric cancer
Head-to-Head Comparison Summary
| Factor | Durvalumab (Imfinzi) | Nivolumab (Opdivo) |
|---|---|---|
| Mechanism | Anti-PD-L1 (blocks ligand) | Anti-PD-1 (blocks receptor) |
| Best setting | Resectable, perioperative | Advanced/metastatic, 1st line |
| IHC required? | No (perioperative) | Yes (CPS ≥5 is primary endpoint) |
| FDA approval (gastric) | Nov 2025 - resectable GC/GEJC | Yes - advanced/metastatic HER2-negative |
| Key trial | MATTERHORN (NEJM 2025) | CheckMate 649 (Lancet 2021, Ann Oncol 2026) |
| pCR rate with chemo | 19.2% (vs 7.2% FLOT alone) | Not tested perioperatively |
| 5-yr OS (advanced, CPS≥5) | Not applicable | 16% vs 6% (chemo) |
| Failed in setting | Advanced/metastatic (PLATFORM, DURIGAST) | Perioperative resectable (ATTRACTION-5) |
Practical Recommendation
For a patient with gastric adenocarcinoma:
-
If resectable (Stage II-IVA) - Use durvalumab + FLOT perioperatively. No IHC needed. This is the new global standard (FDA approved Nov 2025).
-
If advanced/metastatic, HER2-negative - Perform PD-L1 IHC (CPS using 28-8 assay):
- CPS ≥5: Nivolumab + FOLFOX/CAPOX (FDA approved, robust 5-year data)
- CPS <1: Chemotherapy alone (nivolumab adds nothing)
- Also test for MSI-H/dMMR and CLDN18.2 as they further guide immunotherapy decisions
-
IHC testing is always worth doing even in the resectable setting - it provides prognostic information and guides decision-making if surgery is not feasible or disease becomes metastatic.
Key References:
- Janjigian YY et al., NEJM 2025 [PMID: 40454643] - MATTERHORN (durvalumab + FLOT)
- Janjigian YY et al., Ann Oncol 2026 [PMID: 41687718] - CheckMate 649 5-year results (nivolumab)
- Kang YK et al., Lancet Gastroenterol Hepatol 2024 - ATTRACTION-5 (nivolumab adjuvant, negative)
- Fong C et al., ESMO Open 2024 [PMID: 39002179] - PLATFORM (durvalumab maintenance, negative)
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