The ESDO BULLETS by the Young Group of the European Society of Digestive Oncology provide regular overviews and summaries of the latest publications in GI oncology from major journals. We cover topics which are interesting for digestive oncology specialists as well as for clinicians with multi-disciplinary background.

The bullets provide direct links to each publication. We hope you find this summary of the latest developments in digestive cancers of benefit to you in your practice and kindly ask you to share our content with your circles.

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bullets October 2023


The combination of first-line regorafenib, nivolumab, and FOLFOX shows promising activity in advanced esophagogastric adenocarcinoma.

In a single-arm, single-center phase 2 trial, patients with HER2-negative metastatic esophagogastric adenocarcinoma received 1L chemotherapy FOLFOX6 combined with nivolumab and regorafenib. The primary endpoint was 6-mo PFS in the per-protocol analysis (expected in at least 24/35 pts). The study was positive with 25 of 35 patients (71%) progression-free at 6 mo. Other findings included: 12-mo PFS of 51%, mPFS of 13.0 mo, 12-mo OS of 85%, and ORR of 76%. Serious TRAE occurred  in 26%  patients, with no treatment-related deaths observed. A randomized phase 3 clinical trial is planned.

Cytryn SL, et al. Lancet Oncol. 2023 Oct;24(10):1073-1082.



MRI is insufficient to accurately predict pCR in patients with locally advanced rectal cancer treated with TNT.

A prospective imaging substudy of NRG-GI002 (a parent phase 2 study evaluating novel radiosensitizers in rectal cancer) assessed the utility of Magnetic Resonance Tumor Regression Grade (MR-TRG) to predict pCR in patients with locally advanced rectal cancer treated with total neoadjuvant treatment (TNT). The study evaluated the data of 121 patients. MR-TRG scores were associated with pCR (p < .01) and pathologic neoadjuvant response score (p < .0001). There was a moderate agreement between MR-TRG and the pathologic response score with a kappa of 0.43. However, the PPV for pCR was only 40% (95% CI, 26 to 53), and the NPV was 84% (95% CI, 75 to 94). The authors conclude that, although MR-TRG can objectively measure regression magnitude during TNT, MRI alone is insufficient to accurately identify pCR.

Hall WA, et al. J Clin Oncol. 2023 Oct 10;41(29):4643-4651.



Pathologic lymph node regression after neoadjuvant chemotherapy is an independent predictive factor for survival in esophageal cancer.

A multicenter study from the UK aimed to evaluate how pathologic lymph node (LN) regression after neoadjuvant chemotherapy influences survival after surgery for esophageal adenocarcinoma. In total, 17930 LNs from 763 patients were examined using a three-point classification system (complete, partial and poor/no response). Of these patients, 8.1% had a complete response, 20.3% partial response, 39.7% poor/no response and 31.8% were LN negative. Mortality was reduced in patients with complete LN response (HR 0.35; 95% CI, 0.22 to 0.56), partial LN response (HR 0.72; 95% CI, 0.57 to 0.93) or negative LNs (HR 0.32; 95% CI, 0.25 to 0.42) compared with those with poor/no LN response. Primary tumor regression and LN regression were discordant in 165 patients (21.9%). Pathologic lymph node regression after neoadjuvant chemotherapy is an independent predictive factor for survival and may provide important information beyond pathologic TNM staging and primary tumor regression grading.

Moore JL, et al. J Clin Oncol. 2023 Oct 1;41(28):4522-4534.


Individual Participant Data (IPD) Network Meta-Analysis (NWA) of Neoadjuvant Chemo- or Chemoradiotherapy in Esophageal or Gastroesophageal Junction (GEJ) Carcinoma confirms overall survival benefit for both strategies over surgery alone.

The MANATEC-02 collaborative group conducted an IPD-NWA to evaluate whether neoadjuvant chemotherapy and chemoradiotherapy have a differential effect on survival for esophageal or GEJ carcinoma and, in particular, across histology, location, and sex. This NWA included 26 published randomized controlled trials, that completed accrual before the end of 2015, comparing at least two of the following strategies: upfront surgery (S), chemotherapy followed by surgery (CS), and chemoradiotherapy followed by surgery (CRS). IPD were obtained for nearly 5.000 patients. Neoadjuvant chemotherapy and chemoradiotherapy were consistently better than S alone across histology, but with some variation in the magnitude of treatment effect by sex for CRS (larger OS benefit for females) and tumor location for CS (larger OS benefit for GEJ). A strong OS difference between CS and CRS was not identified.

Faron M, et al. J Clin Oncol. 2023 Oct 1;41(28):4535-4547.



Immune checkpoint blockade does not eliminate the risk of de novo cancer in Lynch syndrome carriers but influences the types of new primary malignancies.

A retrospective analysis examined the incidence on new primary neoplasia in 172 cancer-affected patients with Lynch syndrome who had received ≥1 immune checkpoint blockade cycle, ICB (66% treated for metastatic disease). Following immunotherapy, 21 (12%) individuals developed subsequent malignancies (91% of which were dMMR). The median time to the development of new malignancy was 21 mo (interquartile range, 6-38). Among the 21 new malignances in the ICB-treated patients, 57% were skin malignancies (median to development after the 1st neoplasm: 4.5 mo), and 43% were visceral tumors (median to development after the 1st neoplasm: 43.0 mo). Additionally, premalignant polyps were found in 39% of ICB-treated patients who underwent surveillance colonoscopy. A comparison of the pre- and post-immunotherapy follow-up periods revealed that ICB did not reduce the risk overall rate of tumor development, however it altered the pattern of new cancer types: ICB reduced the incidence of visceral tumors, while it increased the incidence of skin neoplasms.

Harrold EC, et al. Nat Med. 2023 Oct;29(10):2458-2463.



bullets September 2023


Trastuzumab combined with ramucirumab and paclitaxel showed appreciable efficacy with consistent safety profiles as 2nd line treatment for HER2-positive gastric or gastroesophageal junction(G/GEJ) cancer

In the phase II study, 50 patients with HER2-positive G/GEJ cancer were treated with trastuzumab combined with ramucirumab and paclitaxel following progression under trastuzumab-containing chemotherapy. With a median follow-up duration of 27.5 months, median PFS and OS were 7.1 months (95% CI, 4.8 to 9.4) and 13.6 months (95% CI, 9.4 to 17.7), respectively. ORR was 54 % (27 of 5) including one complete response and DCR was 96% (48 of 50). Safety profiles were consistent with previous reports.

Kim CG, et al.  J Clin Oncol. 2023 Sep 20;41(27):4394-4405.



Phase II FIRE-4.5 trial shows no superiority of 1L treatment with FOLFOXIRI-cetuximab compared to FOLFOXIRI-bevacizumab in patients with BRAF V600E mutant metastatic colorectal cancer.

In the randomized, open-label phase II trial, 109 patients with mCRC harboring the BRAF V600E mutation were randomized 2:1 to the cetuximab-FOLFOXIRI or bevacizumab-FOLFOXIRI 1L treatment arms. The primary endpoint ORR was 51% in the cetuximab-based experimental arm,  and 67% in the bevacizumab-based control arm (OR 1.93; 80%CI, 1.06-3.52; p=.92 [one sided]). Median PFS was significantly inferior (6.7 mo vs 10.7 mo; HR 1.89; p=.006) and median OS showed a trend toward shorter survival in cetuximab-treated patients (12.9 mo vs 17.1 mo; HR 1.4; p=.20). Bevacizumab-based chemotherapy remains the preferable first-line treatment of patients with BRAF V600E-mutant mCRC.

Stintzing S, et al. J Clin Oncol. 2023 Sep 1;41(25):4143-4153.



Camrelizumab plus Rivoceranib outperforms Sorafenib in patients with advanced hepatocellular carcinoma (CARES-310).

In the randomized, international phase 3 trial involving 543 patients with unresectable HCC the combination of camrelizumab (anti-PD1) + rivoceranib (mTKI) outperformed sorafenib as the first-line treatment. The results demonstrated improvements in progression-free survival and overall survival — mPFS: 5.6 mo vs 3.7 mo (HR 0.52 [95% CI 0·41–0·65], one-sided p<0.0001); mOS:  22.1 mo vs 15.2 mo  for camrelizumab + rivoceranib and sorafenib, respectively (HR 0.62 [95% CI 0.49–0.80]; one-sided p<.0001). Grade ≥3 TRAEs were observed in 81% of patients in the experimental arm (the most common being hypertension, hand-foot syndrome, elevated AST or ALT), and 52% in the control group.

Qin S, et al. Lancet. 2023 Sep 30;402(10408):1133-1146.


Stereotactic Body Radiation Therapy (SBRT) demonstrates effectiveness in the treatment of intermediate-stage hepatocellular carcinoma (the TRENDY Trial).

In a multicenter, randomized, phase 2 trial, patients with HCC eligible for transarterial chemoembolization (TACE) were randomized between TACE-DEB and stereotactic body radiation therapy (SBRT; 6 fr x 8-9Gy). The trial was closed prematurely due to slow patient enrollment, with 16 patients in the TACE-DEB group and 12 in the SBRT group. While there was no significant difference in Time to Progression (the primary end-point; median TTP 12 mo for TACE- DEB and 19 mo for SBRT; p=.15), SBRT showed better local tumor control (median LC 12 mo for TACE- DEB  and >40 mo for SBRT; p=.075). The median OS was 36.8 months for TACE-DEB and 44.1 months for SBRT (p=.36). Both treatments resulted in high response rates (>80%). Adverse events were observed in 19% of patients in the TACE-DEB group, but none in the SBRT group. The study suggests that SBRT may be effective in controlling locally advanced HCC that are not eligible for surgery.

Romero AM, et al. Int J Radiat Oncol Biol Phys. 2023 Sep 1;117(1):45-52.



bullets August 2023


Zolbetuximab + CAPOX combination provides benefit in first line treatment of CLDN18.2-positive unresectable and metastatic gastric/GE junction adenocarcinoma (the global phase 3 GLOW trial).

Zolbetuximab, a monoclonal antibody that targets CLDN18.2, plus capecitabine and oxaliplatin (CAPOX) as first-line treatment for CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma, met both primary and key secondary endpoints. 507 patients were randomized 1:1 to zolbetuximab + CAPOX or placebo + CAPOX. Results showed statistically and clinically significant improvement in mPFS (8.21 mo vs. 6.80; HR = 0.687; 95% CI, 0.544–0.866; P = 0.0007) and mOS (14.39 mo vs. 12.16 mo; HR = 0.771; 95% CI, 0.615–0.965; P = 0.0118). These results further support the survival benefits observed in the recent phase 3 SPOTLIGHT trial were zobetuximab was combined with a mFOLFOX backbone in the same treatment setting.

Shah MA, et al. Nat Med. 2023 Aug;29(8):2133-2141.



Risk-adapted neoadjuvant chemoradiotherapy in rectal cancer (OCUM study).

In the multicenter study, patients with rectal cancer (cT2–4, any cN, cM0) were classified according to minimal distance between the tumor, suspicious lymph nodes or tumor deposits, and mesorectal fascia on pelvic MRI. Patients with distance > 1 mm underwent upfront total mesorectal excision TME (low-risk group); those with distance ≤ 1 mm and/or cT4 and cT3 tumors in the lower rectal third received neoadjuvant chemoradiotherapy (nCRT) followed by TME (high-risk group). 530 patients underwent upfront TME and 354 patients received nCRT followed by TME. Results indicated 5-year locoregional recurrence (LR) rates of 4.1% (95% CI, 2.7 to 5.5) for patients treated per protocol, 2.9% (95% CI, 1.3 to 4.5) after up-front surgery, and 5.7% (95% CI, 3.2 to 8.2) after nCRT followed by surgery. The 5-year rate of distant metastases was 15.9% (95% CI, 12.6 to 19.2) and 30.5% (95% CI, 25.4 to 35.6), respectively. In a subgroup analysis of 570 patients with lower and middle rectal third cII and cIII tumors, the 5-year LR rate was 3.8% (95% CI, 1.4 to 6.2) after up-front surgery. In 271 high-risk patients, the 5-year rate of LR was 5.9% (95% CI, 3.0 to 8.8) and of metastases 34.5% (95% CI, 28.6 to 40.4). The findings support avoidance of nCRT in low-risk patients and suggest that in high-risk patients, neoadjuvant therapy should be intensified to improve prognosis.

Ruppert R, et al. J Clin Oncol. 2023 Aug 20;41(24):4025-4034.


The combination of Durvalumab-Tremelimumab with mFOLFOX6 in 1L RAS-mutant mCRC is tolerable and shows promising clinical activity (MEDITREME trial).

A phase Ib/II included 48 patients with RAS-mutant microsatellite stable mCRC, treated in 1L with mFOLFOX6 + durvalumab (750 mg q2w) + tremelimumab (75 mg q4w). Patients with stable or responding tumors after 3 months of combination therapy, continued on maintenance durvalumab (750 mg q2w) for a maximum of 1 year. This study reached its primary objective, with 3-month PFS of 90.7%, 6-mo PFS of 60% and mPFS of 8.2 months. ORR was 63%. Higher tumor mutational burden and lower genomic instability were seen in responders. Transcriptomic analysis underlined that high immune signature and low epithelial–mesenchymal transition were associated with better outcome.

Thibaudin M, et al. Nat Med. 2023 Aug;29(8):2087-2098.


Identification of molecular signature predictive of ICI benefit in MSI-H mCRC.

A translational study retrospectively evaluated genomic (DNA) and transcriptional (RNA) markers for predicting response to immunotherapy (anti-PD1 ± anti-CTLA4) in 116 patients with MSI-H mCRC. Tumor mutation burden, MSIsensor score, or specific cellular contingents within the tumor bulk did not predict ICI resistance. In contrast, PFS by immune RECIST (iPFS) was negatively influenced by multiplex MSI signature involving mutations in 19 microsatellites (HR = 3.63, 95% CI 1.65-7.99), and fibrotic, non-epithelial transforming growth factor beta (TGFB)-related RNA markers (HR = 1.75; 95% CI 1.03-2.98).

Ratovomanana T, et al. Ann Oncol. 2023 Aug;34(8):703-713.


Association of alcohol intake with the risk of early-onset colorectal cancer.

In this Korean trial, the risk of early-onset CRC and the association between average daily alcohol consumption were investigated among over 5 million individuals aged between 20-49 years. 8314 cases of early-onset CRC were identified. Moderate (10 to <30 g/d for men, 10 to <20 g/d for women) and heavy (≥30 g/d for men, ≥20 g/d for women) drinkers showed an increased risk of early-onset CRC compared with light drinkers (aHR, 1.09 [95% CI, 1.02 to 1.16] and aHR, 1.20 [95% CI, 1.11 to 1.29], respectively). Subgroup analysis by tumor location showed positive dose-response significance for early-onset distal colon and rectal cancers, but not for proximal colon cancer.

Jin EH, et al. J Clin Oncol. 2023 Aug 1;41(22):3816-3825.



Erdafitinib demonstrates clinical activity across a range of GI cancers harboring FGFR alterations (RAGNAR study).

In phase II, single-arm, basket trial, erdafitinib (pan-FGFR TKI) demonstrated clinical benefit in tumors harboring predefined FGFR1–4 alterations (mutations or fusions). The trial included previously treated patients with no alternative standard therapy available who were diagnosed with advanced pancreatic cancer (n = 18, ORR = 56%, DCR = 94%, mPFS 7.0 mo, mOS 19.7 mo), cholangiocarcinoma (n = 31, ORR = 52%, DCR = 97%, mPFS 8.3 mo, mOS 14.7 mo), gastric cancer (n = 8, ORR = 13%, DCR = 63%, mPFS 2.4 mo, mOS 3.6 mo), and esophageal cancer (n = 8, ORR = 13%, DCR = 38%, mPFS 1.4 mo, mOS 7.0 mo). The most common ≥G3 TRAE were stomatitis (12%), hand-foot syndrome (6%), and hyperphosphatemia (5%).

Pant S, et al. Lancet Oncol. 2023 Aug;24(8):925-935.




bullets July 2023


Zanidatamab in gemcitabine-refractory HER2-amplified advanced biliary tract cancer (HERIZON-BTC-01).

In a single-arm phase 2b study, zanidatamab (a bispecific Ab targeting two distinct HER2 epitopes) was assessed in patients with HER2-amplified, unresectable, locally advanced, or metastatic biliary tract cancer who had experienced disease progression on gemcitabine-based therapy. Among 80 patients with HER2 2+ or 3+ expression in IHC, zanidatamab resulted ORR of 41%, mPFS of 5.5 mo, and a 9-mo OS rate of 69.9%.

Harding JJ, et al. Lancet Oncol. 2023 Jul;24(7):772-782.



Trastuzumab deruxtecan in HER2-positive advanced gastric or gastroesophageal junction cancer pretreated with trastuzumab-containing regimens (DESTINY-Gastric02).

In a single-arm phase 2 study conducted in Western countries, trastuzumab deruxtecan was evaluated in the 2L+ setting in 79 patients with HER2-positive advanced gastric or gastroesophageal junction cancer who had previously been treated with a trastuzumab-containing regimen. In an updated analysis, trastuzumab deruxtecan demonstrated ORR of 42% (including CR in 5% pts), mPFS of 5.6 mo, and mOS of 12.1 mo.

Van Cutsem E, at al. Lancet Oncol. 2023 Jul;24(7):744-756.



Neoadjuvant FOLFOX is noninferior to CRT in treatment of locally advanced rectal cancer (PROSPECT).

PROSPECT was a multicenter randomized noninferiority trial of neoadjuvant FOLFOX6 versus combined chemo- and radiation therapy, which enrolled adults with locally advanced rectal cancer (cT2N+, cT3N0, or cT3N+), who were candidates for sphincter-sparing surgery. 1128 patients started treatment, of those 585 were assigned to the FOLFOX group (6 cycles) and 543 to the chemoradiotherapy group (CRT: 50,4 Gy with 5-FU or capecitabine). Adjuvant chemotherapy was optional in each arm. Patients with suboptimal responses to FOLFOX (<20% tumor regression) selectively received preoperative CRT (used in 9% participants in the FOLFOX arm). At a median follow-up of 58 mo, FOLFOX was noninferior to CRT for DFS (HR = 0.92, 90.2% CI, 0.74-1.14, p=0.005 for noninferiority). 5-year DFS was 80.8% in the FOLFOX and 78.6% in the chemoradiotherapy group. No significant differences in OS were found.

Schrag D, et al. N Engl J Med 2023; 389:322-334.

Patient-Reported Outcomes (PROs) during and after treatment for locally advanced rectal cancer in the PROSPECT Trial (Alliance N1048)

Within the PROSPECT trial, patients were asked to provide patient-reported outcomes (PROs), which included 14 symptoms from the PRO-CTCAE at baseline, during neoadjuvant therapy and at 12 months after surgery. In total, 940 patients contributed PRO-CTCAE data. During neoadjuvant treatment, significantly lower rates of diarrhea and better overall bowel function were reported in the FOLFOX cohort, while anxiety, appetite loss, constipation, depression, fatigue, neuropathy, and vomiting were lower with 5-FU CRT (p<0.05). At 12 months post-surgery, patients assigned to FOLFOX reported significantly lower rates of fatigue and neuropathy and better sexual function compared to 5-FU CRT (p<0.05). In conclusion, for patients with locally advanced rectal cancer choosing between neoadjuvant FOLFOX and 5-FU CRT, the distinctive PRO profiles inform treatment selection and shared decision making.

Basch E, at al. J Clin Oncol. 2023 Jul 20;41(21):3724-3734.


Fruquintinib improves survival in patients with heavily pretreated metastatic colorectal cancer (FRESCO-2).

In an international randomized phase 3 study, fruquintinib (an oral inhibitor of VEGFRs 1-3) was compared to a placebo in 691 patients with metastatic colorectal cancer who had previously received all standard approved therapies, including trifluridine-tipiracil and/or regorafenib. Fruquintinib demonstrated improvements in OS (mOS = 7.4 vs 4.8 mo, respectively; HR= 0.66, 95% CI 0.55-0.80) and PFS (mPFS = 3.7 vs 1.8 mo, respectively; HR = 0.32, 95% CI 0.27-0.39) compared to the placebo. Grade ≥3 adverse events occurred in 63% of patients who received fruquintinib (mainly hypertension, asthenia, and hand-foot syndrome), while the rate was 50% for those on placebo.

Dasari A, at al. Lancet. 2023 Jul 1;402(10395):41-53.


Choice of 1L treatment in patients with initially unresectable CRC with liver metastases (CAIRO5).

In a phase 3 study, 530 patients with initially unresectable colorectal cancer liver metastases were randomized to receive different systemic treatments based on the primary tumor location and RAS/BRAF mutational status. For right-sided or RAS/BRAF V600E-mutated tumors, FOLFOXIRI + bevacizumab demonstrated superiority over FOLFOX or FOLFIRI + bevacizumab in terms of PFS (mPFS 10.6 vs 9.0 mo, respectively; HR = 0.76, 95% CI 0.60-0.98), ORR (54% vs 33%; p = 0.0004), and complete local treatment rate. In left-sided and RAS/BRAF V600E wild-type tumors, similar PFS were achieved with either bevacizumab or panitumumab, both in combination with FOLFOX or FOLFIRI (mPFS 10.8 vs 10.4 months, respectively; HR = 1.11, 95% CI 0.84-1.48). The addition of panitumumab resulted in a higher ORR compared to bevacizumab (80% vs. 53%; p < 0.0001), although the complete local treatment rate did not differ. OS data are pending.

Bond MJG, et al. Lancet Oncol. 2023 Jul;24(7):757-771.


Anti–EGFR rechallenge combined with trifluridine-tipiracil improves PFS in refractory RAS wild-type mCRC.

In an Italian phase II trial, 62 patients with refractory RAS-wt mCRC who had achieved a response to 1L chemotherapy plus an anti-EGFR antibody were randomized in a 1:1 ratio to receive trifluridine-tipiracil ± panitumumab as part of their late-line therapy. The addition of panitumumab to FTD/TPI improved PFS compared to FTD/TPI alone (mPFS 4.0 vs 2.5 mo; HR = 0.48; 95% CI, 0.28-0.82). Pretreatment plasma RAS/BRAF wild-type ctDNA was associated with a clinical benefit from panitumumab. Among patients whose tumors were wild-type for KRAS, NRAS, BRAF V600E, EGFR, ERBB2, MAP2K1, and PIK3CA (comprising 65% of the participants), mPFS of 6.4 mo was achieved with trifluridine-tipiracil + panitumumab.

Napolitano S, et al. JAMA Oncol. 2023 Jul 1;9(7):966-970.

bullets June 2023


Pembrolizumab in combination with gemcitabine and cisplatin provides survival benefit in 1L treatment of advanced biliary tract cancer (KEYNOTE-966)

KEYNOTE-966 was a global, randomized, double-blind phase 3 trial conducted in patients with previously untreated, unresectable, locally advanced or metastatic biliary tract cancer (BTC). Participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine and cisplatin. 1564 patients were screened for eligibility, 1069 of whom were randomly assigned. The study met its primary endpoint on median OS: 12.7 mo (95% CI, 11.5–13.6) vs 10.9 mo (9.9–11.6) with HR = 0.83 (95% CI, 0.72–0.95; one-sided p = .0034).

Kelly RK, et al. Lancet. 2023 Jun 3;401(10391):1853-1865.



Adjuvant oxaliplatin does not improve survival in older patients with CRC

In a pooled analysis of 8 randomized trials comparing adjuvant oxaliplatin-containing vs fluoropyrimidine-based adjuvant CTx in high-risk patients with stage II–III colorectal cancer, the use oxaliplatin did not improve OS (HR = 1.02; 95% CI, 0.82-1.27) or DFS (HR = 0.87; 95% CI, 0.76-1.00) in elderly patients (70 y.o). Improvements were seen in non-elderly patients with HRs = 0.74 (95% CI, 0.64-0.84) for OS and = 0.74 (95%, CI 0.69-0.79) for DFS.

Dottorini L, et al. J Clin Oncol. 2023 Jun 20;41(18):3300-3303.


Consensus molecular subtypes (CMS) impact outcomes in RAS wild-type metastatic CRC treated with 1L maintenance 5-FU and folinic acid with or without panitumumab

In retrospective analysis of phase II PanaMa trial, consensus molecular subtypes (CMS) influenced outcomes (ORR, PFS, OS) in patients with RAS wild-type mCRC treated with maintenance 5-FU and folinic acid ± panitumumab after mFOLFOX6 + panitumumab. Better outcomes were observed for CMS2 (canonical subtype) and CMS4 (mesenchymal), while CMS1 (MSI immune) and CMS3 (metabolic) subtypes were associated with less favorable PFS & OS. Addition of panitumumab to the 5-FU maintenance in CMS2/4 improved PFS (CMS2: HR = 0.58, 95% CI, 0.36-0.95, p = .03; CMS4: HR = 0.63, 95% CI, 0.38-1.03, p = .07) and OS (CMS4: HR = 0.54; 95% CI, 0.30-0.96, p = 0.04), but produced no benefits in survival in CMS1/3.

Stahler A, et al. J Clin Oncol. 2023 Jun 1;41(16):2975-2987.

Plasmatic BRAF-V600E allele fraction is a prognostic factor in metastatic colorectal cancer treated with BRAF combinatorial treatments

In multicenter study, the prognostic and predictive role of the plasmatic BRAF allele fraction (AF) were evaluated for the combination of a BRAF inhibitor + anti-EGFR ± MEK inhibitor. In total, 47 patients were included in the discovery cohort & 29 patients in the validation cohort. In the discovery cohort, median PFS and OS were 4.4 and 10.1 months, respectively. Patients with high BRAF AF (≥2%, n = 23) showed worse PFS (HR 2.97, 95% CI 1.55-5.69; p = 0.001) and worse OS (HR 3.28, 95% CI 1.58-6.81; p = 0.001) than low-BRAF AF patients (<2%, n = 24). An exploratory analysis of predictive value revealed that high-BRAF AF patients (n = 35) benefited more from triplet therapy than low-BRAF AF patients (n = 41; PFS and OS interaction tests, p < 0.01).

Ros J, et al. Ann Oncol. 2023 Jun;34(6):543-552.


Early detection of molecular residual disease and risk stratification for stage I to III colorectal cancer via circulating tumor DNA methylation

In longitudinal cohort study of 299 patients with stage I to III colorectal cancer (CRC), circulating tumor DNA status was evaluated with 6 DNA methylation markers. At postoperative month 1, ctDNA-positive patients were 17.5 times more likely to relapse than were ctDNA-negative patients (HR, 17.5; 95% CI 8.9-34.4; p<.001). After adjuvant chemotherapy, ctDNA-positive patients had a significantly shorter recurrence-free survival when compared to the ctDNA-negative patients (HR, 13.8; 95% CI, 5.9-32.1; p<.001). Longitudinal ctDNA analysis after the post-definitive treatment showed that ctDNA-positive patients had poorer recurrence-free survival than ctDNA-negative patients (HR, 20.6; 95% CI, 9.5-44.9; p<.001). Post-definitive treatment analysis detected CRC recurrence earlier than radiologically confirmed recurrence, with a median lead time of 3.3 months (IQR, 0.5-6.5 months).

Mo S, et al. JAMA Oncol. 2023 Jun 1;9(6):770-778.



bullets May 2023


  • Addition of Liposomal Irinotecan (nal-IRI) to Fluorouracil and Leucovorin improves PFS
    in patients with previously treated Metastatic Biliary Tract Cancer (NIFTY trial)

In Asian open-label phase IIb trial, addition of nal-IRI to FU/LV (LV5FU2) significantly improved PFS in patients with previously treated advanced BTC (central review mPFS: 4.2 mo for nal-IRI + FU/LV vs 1.2 mo for FU/LV alone; HR 0.61, 95% CI 0.44-0.86, p=0.004).

Hyung J, et al. JAMA Oncol 2023;9(5), 692-699



  • Dabrafenib + trametinib in diverse BRAF V600E-mutated advanced cancers (ROAR trial)

In a phase 2 basket trial, dabrafenib (BRAFi) + trametinib (MEKi) demonstrated tumor-agnostic activity in previously treated BRAF V600E-mutated advanced cancers. The trial enrolled 43 patients with biliary tract cancers (investigator-assessed ORR 53% [all PR], mPFS 9.0 mo, mOS 13.5 mo) and 3 persons with small intestine adenocarcinoma (ORR 67%, mPFS 9.5 mo, mOS 21.8 mo).

Subbiah V, et al. Nat Med 2023, 29, 1103–1112.




  • Addition of Bevacizumab to Trifluridine-Tipiracil (FTD/TPI) improves of PFS and OS in refractory Metastatic Colorectal Cancer (SUNLIGHT trial)

In phase III randomized trial, 492 patients with mCRC after 1 or 2L of palliative treatment received FTD/TPI + bevacizumab or FTD/TPI alone (1:1 ratio). The addition of anti-VEGF-A prolonged PFS (mPFS: 5.6 vs 2.4 mo; HR 0.44; 95% CI 0.36-0.54, p<0.001), and OS (mOS: 10.9 vs 7.5 mo; HR 0.61; 95% CI 0.49-0.77, p < 0.001). No new safety signals were identified.

Prager GW, et al. N Engl J Med 2023; 388:1657-1667.


  • Dual HER2 targeted regimen Tucatinib + Trastuzumab shows clinically relevant antitumor activity in refractory HER2+/RAS WT unresectable or metastatic colorectal cancer (MOUNTAINEER)

In a global open label, phase 2 study enrolled 117 patients with chemo-refractory HER2+/RAS WT unresectable or metastatic CRC. In 84 patients treated with Tucatinib (oral HER2 targeted TKI) + Trastuzumab (iv anti-HER2 mAb) combo the confirmed ORR per blinded independent central review was 38.1% (95% CI 27.7-49.3), of which 3 patients achieved a complete response.

Strickler JH, et al. Lancet Oncol. 2023 May;24(5):496-508.



  • Encorafenib + Binimetinib + Cetuximab demonstrates encouraging efficacy in 1L treatment of BRAF V600E-mutant Metastatic Colorectal Cancer (ANCHOR CRC trial)

In phase II single-arm trial, patients with BRAF V600E mutant mCRC were treated in 1L with encorafenib (BRAFi) + binimetinib (MEKi) + cetuximab (anti-EGFR Ab). Triplet therapy had a manageable safety profile and resulted in ORR of 47.4% (all PR), mPFS 5.8 mo, and mOS 18.3 mo.

Van Cutsem E, et al. J Clin Oncol 2023, 41:14, 2628-2637.




  • Tislelizumab + chemotherapy shows OS benefit over placebo + chemotherapy in 1st line advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-306)

In a global, randomized, placebo-controlled phase III trial the combination of chemo + Tislelizumab (anti-PD-1) provided superior OS (mOS: 17.2 vs 10.6 mo; HR 0.66; 95% CI 0.54-0.80; p<0.0001). Benefit was observed across all prespecified patient subgroups, including PD-L1 expression and investigator-chosen chemo regimen.

Xu J, et al. Lancet Oncol. 2023 May;24(5):483-495.




Zolbetuximab significantly prolongs PFS & OS compared to placebo, when combined with mFOLFOX6 in Claudine 18.2 positive/HER2 negative 1st line locally advanced or metastatic gastric & GE Junction adenocarcinoma treatment (SPOTLIGHT)

In a global, randomized, placebo-controlled phase III trial the combination of mFOLFOX6 + Zolbetuximab (first-in-class CLDN18.2 targeted mAb) proved superior in terms of PFS (mPFS: 10.61 vs 8.67 mo) and OS (mOS: 18.23 vs 15.54 mo) when compared to mFOLFOX6 + placebo. The HR for disease progression or death was 0.75 (95% CI 0.60-0.94; p=0.0066). CLDN 18.2 is a tight junction protein specifically expressed in 40% of HER2 negative adenocarcinomas in the upper GI tract.

Shitara K, et al. Lancet. 2023 May 20;401(10389):1655-1668.




Paraaortic lymph node (PALN) metastasis do not negatively impact survival of patients with resectable pancreatic head adenocarcinoma

In a retrospective German study, among 148 patients who underwent upfront resection for PDAC, 125 (85%) received paraaortic lymphadenectomy. In this group, PALN metastases did not negatively impact OS (mOS 18.9 for PALN(+) vs 19.0 mo for PALN(-); HR 1.3; 95% CI 0.7-2.6, p=0.392), or DFS (mOS 14.0 for PALN(+) vs 10.7 mo for PALN(-); HR 1.7; 95% CI 0.9-3.2, p=0.076). The authors conclude that the presence of PALN metastases is not a contraindication for resection of pancreatic head cancer.

Petrova E, et al. Eur J Surg Oncol, vol 49(5): 996-1000.



bullets April 2023


In Chinese single-arm phase II trial, definitive chemoradiotherapy (50,4 Gy with 5 weekly cycles of cisplatin + paclitaxel) combined with toripalimab (anti PD-1, concurrent with CRTx and continued up to 1 y) demonstrated encouraging activity in locally advanced unresectable ESCC (1-y OS: 78.4%, 1-y PFS: 54.5%).

Zhu Y, et al. Lancet Oncol., Volume 24, Issue 4, 371 – 382



  • Zolbetuximab plus mFOLFOX6 improves survival in patients with CLDN18.2-positive, HER2-negative unresectable/metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT)

In randomized phase III trial, the addition of zolbetuximab (anti-CLDN18.2 antibody) to 1L mFOLFOX6 chemotherapy improved PFS and OS in patients with CLDN18.2-positive, HER2-negative unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma – mPFS: 10.61 vs 8.67 mo,  HR = 0.75, 95% CI 0.60–0.94; p=.0066; mOS: 18.23 vs 15.54 mo, HR = 0.75, 95% CI 0.60–0.94; p=.0053.

Shita K, et al. Lancet (2023)



In retrospective analysis of phase II PanaMa trial, consensus molecular subtypes (CMS) influenced outcomes (ORR, PFS, OS) in patients with RAS wild-type mCRC treated with 5-FU and folinic acid with or without panitumumab after mFOLFOX6 + panitumumab induction. More favorable outcomes were observed for CMS2 (canonical) and CMS4 (mesenchymal) subtypes, while CMS1 (MSI immune) and CMS3 (metabolic) subtypes were associated with less favorable PFS and OS. The addition of panitumumab to the maintenance chemotherapy improved PFS in CMS2 and OS in CMS4, but produced no benefits in CMS1/3.

Stahler A, et al. J Clin Oncol. (2023)

  • Neoadjuvant pembrolizumab in localized microsatellite instability high/deficient mismatch repair solid tumors

 In a single-arm phase II trial, neoadjuvant pembrolizumab was administered to dMMR/MSI-H cancer patients (27 with CRC and 8 with non-colorectal cancers) up to 6 months before surgery, with an option to continue for 12 months after surgery. The trial produced high rates of ORR (82%) and pathological CR (65% in resected cases). 17 patients were managed without surgery, with 2 cases of PD.

Ludford K, et al. J Clin Oncol. 2023 41:12, 2181-2190



  • Adjuvant nab-paclitaxel + gemcitabine does not improve disease-free survival as compared to gemcitabine alone in pancreatic adenocarcinoma (APACT phase III trial)

 In resected pancreatic ductal adenocarcinoma adjuvant nab-paclitaxel + gemcitabine did not improve independently assessed disease-free survival (iDFS) as compared to gemcitabine alone (the primary end-point – median iDFS: 19.4 vs 18.8 mo, HR = 0.88; 95% CI, 0.729 to 1.063; P = .18). Mature OS favored nab-paclitaxel + gemcitabine versus gemcitabine (mOS: 41.8 vs 37.7 mo; HR = 0.80; 95% CI, 0.678 to 0.947; P = .0091).

Tempero MA, et al. J Clin Oncol. 2023 41:11, 2007-2019



In randomized Chinese phase III trial, the use of adjuvant Hepatic Arterial Infusion Chemotherapy (HAIC; 1 or 2 cycles of FOLFOX) improved disease-free survival after radical resection of HCC with microvascular invasion) – median DFS: 20.3 mo for HAIC vs 10.0 mo for routine follow-up; HR = 0.59; 95% CI, 0.43 to 0.81; P = .001). No significant difference in OS was detected.

Li S-H et al. J Clin Oncol. 2023 41:10, 1898-1908



In randomized phase III, the addition of pembrolizumab to 1L chemotherapy (cisplatin for up to 8 cycles and gemcitabine with no maximum duration) modestly improved OS in patients with advanced biliary tract cancer (mOS: 12.7 mo vs 10.9 mo, HR = 0.83; 95% CI 0.72–0.95; P = .0034). No significant differences in ORR or PFS were observed.

Kelly RK, et. al. Lancet 2023 (online)



bullets March 2023


  • 1st line pembrolizumab + chemotherapy in advanced gastric/esophagogastric junction adenocarcinoma (KEYNOTE-859)

Pembrolizumab added to fluoropyrimidine- and platinum-containing chemotherapy (PF or CAPOX) improved ORR, PFS and OS in patients with advanced HER2-negative gastric/esophagogastric junction adenocarcinoma (mOS: 12.9 mo with pembro + chemo vs 11.5 mo with placebo + chemo, HR = 0.78, 95% CI 0.70-0.87; P < 0.0001). Results were consistent across PD-L1 expression subgroups.

Rha SY, et al. Annals of Oncology, Volume 34, Issue 3, 319 - 320


  • PD-1 antibody plus chemotherapy in patients with advanced ESCC with low PD-L1 expression.

Meta-analysis of randomized phase III trials indicated superiority of PD-1 antibody plus chemotherapy to chemotherapy alone in terms of OS and ORR in patients with advanced esophageal squamous cell carcinoma with low PD-L1 expression.

Wu XH, et al. J Clin Oncol. 2023 41:9, 1735-1746



  • Germline mutations in homologous-recombination genes influence the risk of gastric cancer in patients infected with H. pylori

Results of a large Japanese study indicate that germline pathogenic variants in homologous recombination genes (BRCA1, BRCA2, PALB2, ATM) significantly increase the risk of gastric cancer, but only in carriers that were infected with Helicobacter pylori.

Usui Y, et al. N Engl J Med 2023; 388:1181-1190



  • Patients with KRAS G12-mutant mCRC do not derive benefit from treatment with trifluridine/tipiracil.

In large retrospective analysis of real world data and results of phase III RECOURSE trial, OS was not prolonged with treatment with trifluridine/tipiracil versus placebo in patients with KRAS G12-mutant metastatic colorectal cancers (HR = 0.97; 95% CI 0.73–1.20; P = 0.85). In contrast, FTD/TPI was highly effective in KRAS G13-mutant CRC. The predictive influence of KRAS mutational status was confirmed in vitro.

Van de Haar J, et. al. Nature Medicine, volume 29, 605–614 (2023).


  • Preoperative Chemotherapy improves outcomes in operable Colon Cancer (FOxTROT).

In FOxTROT randomized phase III trial 6 weeks of preoperative oxaliplatin-fluoropyrimidine chemotherapy for operable colon cancer (cT3-4, N0-2, M0) produced histopathologic down-staging, improved resectability, and reduced the 2-year recurrence rate (16.9% preoperative chemotherapy vs 21.5% control; HR = 0.72 [95% CI, 0.54 to 0.98]; P = .037). Preoperative panitumumab did not enhance the benefit. The advantage of preoperative chemotherapy was not seen in dMMR cancers.

Morton D, et al. J Clin Oncol. 2023 41:8, 1541-1552



In randomized, phase II trial comparing temozolomide versus capecitabine/temozolomide in patients with advanced pancreatic NETs (G1-G2), capecitabine + temozolomide significantly improved progression-free survival. No change in OS was detected.

Kunz PL, et al. J Clin Oncol. 2023 41:7, 1359-1369


  • 2nd line FOLFIRI + bevacizumab vs FOLFIRI in advanced NEC (PRODIGE 41-BEVANEC)

In phase 2 randomized trial the addition of bevacizumab to FOLFIRI in 2nd line treatment of advanced neuroendocrine carcinomas (gastroenteropancreatic or of unknown primary origin) did not improve 6-month overall survival.

Walter D, et al. Lancet Oncol. 2023 Mar;24(3):297-306



  • 2nd line pembrolizumab in Asian patients with advanced HCC (KEYNOTE-394)

In randomized, phase III trial treatment with pembrolizumab improves ORR, PFS and OS vs placebo in Asian patients with advanced hepatocellular carcinoma who progressed or did not tolerate sorafenib.

Qin S, et al. J Clin Oncol. 2023 41:7, 1434-1443




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