Determinants of Survival with Combined HER2 and PD-1 Blockade in Metastatic Esophagogastric Cancer

Authors

Maron SB

Chatila W

Walch H

Chou JF

Ceglia N

Ptashkin R

Do RKG

Paroder V

Pandit-Taskar N

Lewis JS

Biachi De Castria T

Sabwa S

Socolow F

Feder L

Thomas J

Schulze I

Kim K

Elzein A

Bojilova V

Zatzman M

Bhanot U

Nagy RJ

Lee J

Simmons M

Segal M

Ku GY

Ilson DH

Capanu M

Hechtman JF

Merghoub T

Shah S

Schultz N

Solit DB

Janjigian YY

Doi

10.1158/1078-0432.CCR-22-3769

PMID: 37406106 · DOI: 10.1158/1078-0432.CCR-22-3769 · Journal: Clinical Cancer Research (2023)

TL;DR

This study reports updated clinical outcomes from a phase II trial of pembrolizumab, trastuzumab, and chemotherapy (PTC) in HER2-positive metastatic esophagogastric cancer (n = 37), alongside an independent MSK retrospective cohort (n = 226). Using 89Zr-trastuzumab PET, serial ctDNA dynamics, whole-exome sequencing, and single-cell RNA sequencing, the authors identified pretreatment intrapatient HER2 heterogeneity as a primary determinant of inferior PFS. They demonstrated that early ctDNA clearance by 9 weeks and intense 89Zr-trastuzumab PET avidity predict durable PFS, and identified a transcriptional resistance program involving MT1H, MT1E, MT2A, and MSMB.

Cohort & data

  • Phase II trial cohort: 37 patients with HER2-positive (IHC 3+ or IHC 2+/FISH+) metastatic esophageal, gastroesophageal junction, or gastric adenocarcinoma treated with pembrolizumab, trastuzumab, capecitabine, and oxaliplatin (NCT02954536) at MSK.
  • MSK retrospective cohort: 226 patients with HER2-positive EGC who received platinum-based chemotherapy with HER2-directed therapy (trastuzumab or zanidatamab) from 2010 to 2022.
  • scRNA-seq cohort: Paired pre- and on-treatment biopsies from patients receiving CAPOX with trastuzumab (n = 3) or without (n = 4) from MSK and Samsung Medical Center.
  • Cancer types: esophagogastric cancer (EGC), including esophageal (ESCA), gastroesophageal junction (GEJ), and gastric (STAD) adenocarcinoma.
  • Dataset: egc_trap_ccr_msk_2023 (available on cBioPortal).
  • Assays: targeted NGS, whole-exome sequencing, scRNA-seq, 89Zr-trastuzumab PET/CT, plasma ctDNA (Guardant Health).

Key findings

  • Updated survival (phase II, n = 37): Median PFS 13 months (95% CI: 8.5–20), median OS 27 months (95% CI: 21–44), ORR 89% (31/35 evaluable; 95% CI: 73%–97%); 6 of 37 patients had not yet progressed at median follow-up of 44 months.
  • Standard-practice PD-1 + TC cohort (n = 29): Median PFS 14.7 months (95% CI: 11.2–NR), ORR 80% (23/29; 95% CI: 60%–92%).
  • HER2 IHC uniformity predicts PFS: Patients with uniform HER2 IHC 3+ expression (n = 129/193) had longer median PFS (15 months; 95% CI: 13–20) versus heterogeneous/2+ expression (n = 64; 8.5 months; 95% CI: 6.4–13; P = 0.004). ERBB2 amplification was present in 88% (110/125) of IHC 3+ versus 36% (21/58) of 2+/heterogeneous tumors (P = 1.8e-12).
  • 89Zr-trastuzumab PET (n = 8 imaged): All 15 intensely avid lesions (SUV >= 10) decreased in size after a single dose of pembrolizumab + trastuzumab, versus only 9/32 non-intensely avid lesions (P = 2.4e-6). All 4 patients with >= 1 intensely avid lesion achieved 6-month PFS.
  • ctDNA dynamics: 12/16 (75%) patients had declining maxVAF by week 3; 9/12 (75%) of these achieved 6-month PFS versus 0/4 with rising maxVAF. Clearance of all tumor-matched ctDNA by 9 weeks was associated with longer PFS (HR 0.18; 95% CI: 0.06–0.53; P = 0.001).
  • Uniform CT response at 9 weeks: Patients with uniform CT response had decreased risk of progression (HR 0.38; 95% CI: 0.17–0.81; P = 0.01).
  • Resistance mechanisms: Upon progression, 11/21 (52%) remained HER2-positive. Resistance mechanisms included loss of HER2 expression and alterations in PIK3CA, KRAS, MET, and EGFR. One patient had concurrent MET amplification in ctDNA at progression with MET IHC positivity in escape lesions. A subclonal FGFR3-TACC3 fusion was identified by ctDNA that expanded over time.
  • Transcriptional resistance program (scRNA-seq): MT1H, MT1E, MT2A, and MSMB expression were associated with trastuzumab + chemotherapy resistance via GeneVector analysis.
  • Multivariable model (MSK cohort, n = 226): ERBB2 amplification was a positive prognostic feature for PFS. Alterations in MYC and CDKN2A/B were negative prognostic features for PFS. KRAS and CCND1 alterations were associated with inferior PFS on univariate analysis.

Genes & alterations

  • ERBB2 – Amplification and overexpression define the treatment-eligible population; ERBB2 amplification was a positive prognostic factor for PFS in multivariable analysis. Loss of HER2 expression was a major resistance mechanism (48% of progressing patients lost HER2 positivity) PMID:37406106.
  • KRAS – Oncogenic alterations associated with inferior PFS on univariate analysis and identified as a resistance mechanism in escape lesions PMID:37406106.
  • MYC – Oncogenic alterations associated with inferior PFS on multivariable analysis PMID:37406106.
  • CDKN2A / CDKN2B – Alterations associated with inferior PFS on multivariable analysis PMID:37406106.
  • PIK3CA – Alterations identified as resistance mechanisms in escape lesions PMID:37406106.
  • PIK3CD – PIK3CD S367L variant demonstrated increased AKT phosphorylation, suggesting functional relevance as a resistance mechanism PMID:37406106.
  • MET – Co-amplification detected in ctDNA at progression; MET IHC expression confirmed in escape lesions PMID:37406106.
  • EGFR – Amplification identified as a resistance mechanism PMID:37406106.
  • TP53 – Highly correlated with ERBB2 amplification status; nearly all HER2-expressing EGC patients harbor TP53 mutations PMID:37406106.
  • FGFR3 / TACC3 – Subclonal FGFR3-TACC3 fusion identified at single-cell level and by serial ctDNA; expanded on-treatment, implicating it as a resistance driver PMID:37406106.
  • CCND1 – Alterations associated with inferior PFS on univariate analysis PMID:37406106.
  • MT1H, MT1E, MT2A – Metallothionein isoforms associated with trastuzumab + chemotherapy resistance by scRNA-seq; may serve as future therapeutic targets PMID:37406106.
  • MSMB – Microseminoprotein-beta expression associated with trastuzumab resistance; linked to hypoxia-driven MAPK pathway activation PMID:37406106.

Clinical implications

  • Biomarker-guided therapy selection: Uniform HER2 IHC 3+ expression, plasma ERBB2 amplification, and intense 89Zr-trastuzumab PET avidity (SUV >= 10) predict durable benefit from pembrolizumab + trastuzumab + chemotherapy and could be used to stratify patients.
  • ctDNA as early response biomarker: Declining ctDNA maxVAF at 3 weeks and complete ctDNA clearance by 9 weeks predict >= 6-month PFS and could inform early therapy escalation or de-escalation, potentially reducing need for frequent cross-sectional imaging.
  • Resistance surveillance: Serial ctDNA monitoring can detect emerging resistance mechanisms (MET amplification, KRAS alterations, loss of ERBB2) before radiographic progression, enabling proactive therapy changes.
  • Combination therapy rationale: The observation that some patients with progressive lesions after induction responded to the addition of chemotherapy highlights the value of combination approaches in overcoming heterogeneity-driven resistance.

Limitations & open questions

  • Phase II trial was a single-arm, single-institution study (n = 37) without a randomized comparator, limiting causal inference about the contribution of pembrolizumab.
  • 89Zr-trastuzumab PET was performed in only 8 patients, making these imaging-based conclusions exploratory.
  • The scRNA-seq resistance program (MT1H, MT1E, MT2A, MSMB) was identified from a small sample and requires orthogonal preclinical validation.
  • The multivariable analysis of the MSK cohort did not demonstrate a significant PFS difference with versus without concurrent PD-1 blockade, despite positive signals in multiple phase II/III trials.
  • PANTHERA reported that pretreatment RTK/RAS pathway alterations were associated with improved PFS, conflicting with this study’s findings; the authors attribute this to differences in how oncogenic alterations were defined (61% vs. 28% of patients).
  • Site-matched pre- and post-treatment biopsies were not available for escape lesions, limiting mechanistic characterization of resistance.
  • Only 49% of plasma NGS alterations at progression could be tumor-matched, suggesting significant clonal hematopoiesis or off-target site contributions.

Citations from this paper used in the wiki

  • “Median PFS was 13 [95% CI: 8.5-20] months, median OS was 27 (95% CI: 21-44) months, and 31 of 35 evaluable patients (89%; 95% CI: 73%-97%) achieved a RECIST response.” PMID:37406106
  • “Patients with uniformly high pretreatment tumor HER2 overexpression [IHC 3+; n = 129/193 (67%)] had longer median PFS [15 (95% CI: 13-20) vs. 8.5 (95% CI: 6.4-13) months]” PMID:37406106
  • “All 15 intensely 89Zr-trastuzumab avid lesions decreased in size by CT after a single dose of pembrolizumab and trastuzumab, whereas only 9 of 32 non-intensely avid lesions (8%) showed reduction (P = 2.4e-6)” PMID:37406106
  • “the 17 in whom all [ctDNA alterations] were cleared by 9 weeks exhibited longer PFS than in the 6 patients who did not (HR 0.18; 95% CI, 0.06-0.53)” PMID:37406106
  • “MT1H, MT1E, MT2A, and MSMB expression were associated with CAPOX+trastuzumab resistance” PMID:37406106
  • “ERBB2 amplification as a positive prognostic feature, and alterations in MYC, CDKN2A/B as negative prognostic features for PFS” PMID:37406106

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