Is durvalumab is useful in adenocarcinoma of stomach without any ihc testing and WTS the rate of response with FLOT chemotherapy
I'll read the medical library skill first, then research both questions in parallel.
Quick Answer:
Durvalumab (anti-PD-L1) in gastric/gastroesophageal adenocarcinoma: its benefit is heavily tied to PD-L1 expression (CPS scoring by IHC). Without IHC testing, you cannot reliably select patients who will respond - unselected use shows modest overall benefit. FLOT (5-FU, Leucovorin, Oxaliplatin, Docetaxel) has a pathological complete response (pCR) rate of ~15-16% and an overall response rate of ~45-57% in resectable gastric adenocarcinoma.
Searching sources...
Reading File
Now I'll run all searches in parallel - library search, PubMed, and web search simultaneously.
Finding Sources
Searching PubMed
durvalumab gastric adenocarcinoma PD-L1
Searching PubMed
FLOT chemotherapy gastric adenocarcinoma response rate
Searching the Web
durvalumab gastric adenocarcinoma without PD-L1 IHC testing TOPAZ MATTERHORN 2024 2025
Excellent - this is very high quality data. Let me get more details on the MATTERHORN trial and FLOT response rates.
Reading Article
PMID: 40454643
Reading Article
PMID: 39002179
Reading Web Page
https://ascopost.com/issues/december-10-2025-supplement-conf…
Searching PubMed
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
Great clinical question. Let me give a quick answer then pull the latest evidence.
Quick Answer:
For resectable gastric adenocarcinoma, durvalumab + FLOT is now preferred and does NOT require PD-L1 IHC. For advanced/metastatic disease, nivolumab (CheckMate 649) benefits all-comers but especially CPS ≥5, so IHC guides intensity of benefit expectations. The two drugs serve different settings and aren't directly compared head-to-head.
Searching sources...
Searching PubMed
nivolumab gastric adenocarcinoma PD-L1 CPS CheckMate 649
Searching PubMed
durvalumab nivolumab comparison gastric cancer immunotherapy PD-L1
Searching the Web
nivolumab vs durvalumab gastric adenocarcinoma PD-L1 IHC CPS testing 2025 standard of care
Finding Sources
Now let me get the 5-year CheckMate 649 data and the nivolumab perioperative (ATTRACTION/KEYNOTE comparison) details.
Reading Article
PMID: 41687718
Reading Article
PMID: 38382001
Searching the Web
nivolumab perioperative resectable gastric cancer ATTRACTION-5 DANTE trial 2024 2025
I now have all the data needed for a thorough, evidence-based comparison. Here is the complete answer:
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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