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 January 2024


Liver MRI prompts significant changes in treatment plans for colorectal liver metastases in patients scheduled for surgery on the basis of CT imaging.

In a prospective, international study involving 298 patients with CRC liver metastases scheduled for local therapy based on contrast-enhanced CT, performance of liver contrast-enhanced MRI with DWI revealed a substantial impact on treatment plans. 31% patients experienced modifications in their treatment strategies following MRI: 13% required more extensive local therapy, 4% necessitated less extensive intervention, and 11% had their curative-intent local therapy indications revoked due to excessive disease extent (9%) or benign lesions (3%). These findings highlight the critical role of liver MRI in guiding personalized treatment decisions for patients with colorectal liver metastases.

Gorgec B, et al. Lancet Oncol. 2024 Jan;25(1):137-146


The immunoscore biopsy (ISB) is validated as a biomarker to predict recurrence in patients undergoing Watch-and-wait (W&W) strategy for rectal cancer.

A multicenter international, retrospective validation cohort study of 249 W&W rectal cancer patients aimed to evaluate the utility of the ISB performed on pretreatment biopsies to predict time to recurrence (TTR) after completion of neoadjuvant treatment. Recurrence-free rates at 5 years were 91.3%, 62.5%, and 53.1% with ISB High, ISB Intermediate, and ISB Low, respectively (HR in Low vs High: 6.51 [95% CI 1.99-21.28]; log-rank P=.0004). ISB categories (High v Intermediate v Low) were significantly associated with a gradual scaling of the risk of both local regrowth and distant metastasis. In multivariate analysis, ISB was independent of patient age, sex, tumor location, cT stage, cN stage and was the strongest predictor for TTR. These findings could pave the way for prospective therapeutic trials guided by ISB to adjust monitoring and/or therapy of W&W patients.

El Sissy C, et al. J Clin Oncol. 2024 Jan 1;42(1):70-80



Tislelizumab results in better patients’ survival than 2L chemotherapy in advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-302).

In a global open-label phase III trial, 108 patients with advanced/metastatic ESCC were randomized to 2L therapy with tislelizumab (anti-PD1 Ab), or chemotherapy (paclitaxel, docetaxel or irinotecan). OS was prolonged with tislelizumab in comparison to chemotherapy: mOS  11.2 vs 6.3 mo, respectively (HR 0.55; 95% CI 0.35-0.87). While PFS was similar (mPFS 2.3 vs 2.7 mo), ORR was greater with tislelizumab (20.0% vs 11.3%). Tislelizumab had a more favorable safety profile.

Ajani J, et al. ESMO Open. 2024 Jan;9(1):102202.


Clinical features and outcomes of advanced HER2+ esophageal/GEJ cancer with brain metastasis.

Brain metastases (BRM) are uncommon in gastroesophageal cancer. In a retrospective study, among 515 patients with advanced E/GEJ cancer, HER2 overexpression was associated with increased risk of BRM (OR 2.45 [95% CI 1.10-5.46]). HER2-postive status was also associated improved PFS (HR 0.35 [95% CI 0.16-0.80]) and improved OS (HR 0.20, 95% CI 0.08-0.54) on 1L systemic therapy in patients with BRM.

Liang K, et al. ESMO Open. 2024 Jan;9(1):102199.



Use of HIPEC in patients undergoing cytoreductive surgery (CRS) for gastric cancer and synchronous peritoneal metastases does not improve OS (GASTRIPEC-I Trial).

In a randomized phase III trial, 105 gastric cancer patients with peritoneal carcinosis were randomly assigned to CRS + HIPEC (CRS + H), or CRS alone (CRS-A). In 55 patients, treatment stopped before CRS due to disease progression/death. OS was the similar in both groups (mOS 14.9 vs 14.9 mo for CRS + H and CRS-A, respectively; p = .1647). mPFS was 7.1 vs 3.5 mo, respectively (p = .047), and metastasis-free survival 10.2 vs 9.2 mo, respectively (p =.0286). No increase in AEs was observed in the CRS + H group.

Rau B, et al. J Clin Oncol. 2024 Jan 10;42(2):146-156.



bullets December 2023


Addition of pembrolizumab to 1L trastuzumab + chemotherapy improves PFS in HER2+ gastric or gastro-esophageal junction adenocarcinoma (KEYNOTE-811).

In a randomized, phase III trial, 698 patients with HER2-positive gastro-esophageal adenocarcinoma were randomly assigned to receive pembrolizumab or placebo, combined with 1L chemotherapy (CAPOX or cisplatin/5-FU) + trastuzumab. Dual primary endpoints were PFS and OS. Compared with placebo, pembrolizumab significantly improved PFS: mPFS 10.0 vs 8.1 mo (HR 0.73 [95% CI 0.61-0.87]) at the third interim analysis. A subgroup analysis indicted that the improvement in PFS was pronounced if PD-L1 CPS was ≥1 (HR 0.71 [95% CI 0.59-0.86]), but was not apparent if CPS was <1 (HR 1.03 [95% CI 0.65-1.64]). OS has not meet the prespecified criteria for significance (mOS was 20.0 vs 16.8 months; HR 0.84 [95% CI 0.70-1.01]), and will continue to final analysis. TRAE of ≥G3 were observed in 58% and 51% patients, respectively.

Janjigian YY, et al. Lancet. 2023 Dec 9;402(10418):2197-2208.


Combination nivolumab with 1L chemotherapy decreases the risk of deterioration of quality of life in patients with advanced gastric/GEJ or esophageal adenocarcinoma (CheckMate 649).

In the CheckMate 649 trial, which explored the efficacy of 1L nivolumab + chemotherapy in patients with advanced GC/GEJ or esophageal adenocarcinoma, patient-reported outcomes (PROs) analysis revealed that the combination of nivolumab with chemotherapy showed a decreased risk of definitive HRQoL deterioration and a stable or better on-treatment HRQoL than chemotherapy alone. Final results showed that patient-reported symptom burden was not increased with nivolumab plus chemotherapy.

Moehler M, et al. J Clin Oncol. 2023 Dec 10;41(35):5388-5399.



The combination of lenvatinib plus pembrolizumab fails to improve survival compared to lenvatinib plus placebo in patients with advanced hepatocellular carcinoma (LEAP-002 trial).

In a global, double-blind, phase III trial, 794 patients with advanced unresectable HCC (stage BCLC-C and B) were randomized to receive 1L lenvatinib + pembrolizumab (the experimental arm) or lenvatinib + placebo (the control arm). The addition of pembrolizumab to lenvatinib failed to improve either of the primary endpoints: OS (mOS: 21.2 vs 19.9 mo, respectively; HR 0.84, 95% CI 0.71-1.00) or PFS (mPFS 8.2 vs 8.0 mo, respectively; HR 0.87, 95% CI 0.73-1.02). ORR according to RECIST 1.1 was 26% and 18%, respectively. TRAE of grade ≥3 were observed in 63% and 58% in the experimental and control arms, respectively. Combination of lenvatinib + pembrolizumab cannot be recommended as the 1L therapy of advanced HCC.

Llovet JM, et al. Lancet Oncol. 2023 Dec;24(12):1399-1410.


Tislelizumab provides non-inferior survival benefit when compared with Sorafenib in 1L advanced hepatocellular carcinoma (RATIONALE-301).

In a global, open-label, randomized phase III trial,  674 patients with histologically confirmed HCC (BCLC B or C; Child-Pugh class A status) were randomized to tislelizumab (anti-PD1 antibody) or sorafenib. Noninferiority of OS (the primary endpoint) between tiselizumab and sorafenib was tested against the non-inferiority margin of 1.08. mOS for tislelizumab was 15.9 vs 14.1 mo for sorafenib (HR = 0.85; [95.003% CI, 0.71-1.02]). The ORR was 14.3% vs 5.4%, and median DoR was 36.1 vs 11.0 mo (95% CI, 6.2-14.7), respectively. Median PFS was 2.1 vs 3.4 mo for tislelizumab vs sorafenib, respectively (HR = 1.11 [95% CI, 0.92-1.33]). Tislelizumab demonstrated a favorable safety profile. Tislelizumab was confirmed to be noninferior to sorafenib in OS.

Qin S, et al. JAMA Oncol. 2023 Dec; 9(12): 1651–1659.


Artificial intelligence-based pathology may predict response to atezolizumab - bevacizumab in patients with hepatocellular carcinoma (HCC).

Atezolizumab–bevacizumab response signature (ARBS) defined using molecular biology profiling techniques was previously shown to predict PFS in patients with advanced HCC treated with atezolizumab–bevacizumab. In the current multicenter retrospective study, AI-based pathology reporting system was developed to predict ABRS (ABRS-P) directly from digital histological slides. ARBS-P was then tested as a  predictive marker for PFS in patients treated with atezolizumab–bevacizumab. Study of samples from 840 patients illustrated a moderate correlation between the ABRS (molecular) parameter and the ABRS-P (AI-based pathology) score: r=0.62 (mean p<.0001) in the training series, and r=0.60 (p<.0001) and r=0.53 (p<.0001) in two validation series. In 122 patients treated with atezolizumab + bevacizumab, those with ABRS-P-high tumors (n=74) showed significantly longer mPFS (12 mo [95% CI 7–not reached]) than those with ABRS-P-low tumors (n=48; mPFS 7 mo [95% CO 4–9]; p = .014).

Zeng Q, et al. Lancet Oncol. 2023 Dec;24(12):1411-1422.



Combination of tucatinib and trastuzumab in patients with previously treated HER2–positive metastatic biliary tract cancer (mBTC) appears effective and safe (SGNTUC-019 basket study).

In a global open-label phase II basket trial, 30 patients with mBTC with HER2 overexpression and/or amplification were treated on a 21-day cycle with tucatinib (an oral selective HER2 inhibitor) plus trastuzumab. Patients had received a median of 1 prior treatment line in the advanced setting and were naïve to HER2-targeting agents. Confirmed ORR per investigator assessment was 46.7% (90% CI, 30.8 to 63.0), with a DCR of 76.7% (90% CI, 60.6 to 88.5) and PFS of 6.0 mo (90% CI, 5.5 to 6.9). Treatment was well tolerated.

Nakamura Y, et al. J Clin Oncol. 2023 Dec 20;41(36):5569-5578.



Avasopasem, a selective dismutase mimetic, demonstrates promising activity in patients with pancreatic adenocarcinoma treated with stereotactic body radiotherapy.

In a phase Ib/II trial, avasopasem (an agent used to protect normal cells from, and sensitize cancer cells to radiation) was tested in 42 patients treated with SBRT with localized pancreatic adenocarcinoma. The primary objective was to identify the optimal dose of SBRT with avasopasem or placebo as determined by the late-onset EffTox method (it determines an optimal dose of radiotherapy considering both efficacy and toxicity). Late-onset EffTox responses were observed in 89% and 100% patients treated at 50 and 55 Gy in the avasopasem group, respectively, while the responses were described in 50% and 75% of the patient in the control group at 50 and 55 Gy, respectively. Combination of avasopasem and SBRT in locally advanced pancreatic cancer will be validated in a larger phase II trial.

Taniguchi CM, et al. Lancet Oncol. 2023 Dec;24(12):1387-1398.



Combination of sotorasib plus panitumumab resulted in a longer progression-free survival than standard treatment in patients with chemorefractory colorectal cancer harboring a KRAS G12C mutation (CodeBreaK 300).

In a multicenter, randomized, phase 3 trial, 160 patients with chemorefractory metastatic CRC harboring KRAS G12C mutation received sotorasib (960 mg or 240 mg once daily) combined with panitumumab, or the investigator’s choice of trifludine-tipiracil or regorafenib (standard care). All patients received prior treatment with fluoropyrimidine, oxaliplatin and irinotecan. The median PFS was 5.6, 3.9 and 2.2 mo in the 960-mg sotorasib-panitumumab, 240-mg sotorasib-panitumumab, and standard-care groups, respectively (HR 0.49 [95% CI, 0.30-0.80; P = 0.006] for the 960 mg sotorasib-pani vs the control group; HR 0.58 [95% CI, 0.36-0.93; P = 0.03] for the 240 mg sotorasib-pani vs the control group). ORR was 26.4%, 5.7%, and 0% in the 960-mg sotorasib-panitumumab, 240-mg sotorasib-panitumumab, and standard-care groups, respectively. The OS analysis is immature. Skin-related toxic effects and hypomagnesemia were the most common adverse events observed with sotorasib + panitumumab.

Fakih MG, et al. N Engl J Med. 2023 Dec 7;389(23):2125-2139.


Real-world data suggest that the efficacy of trifluridine/tipiracil (FTD/TPI), when combined with bevacizumab, is independent of the RAS mutational status in metastatic CRC.

Data from 123 patients from five Austrian cancer centers were retrospectively collected.  Eligible patients had previously received FTD/TPI + bevacizumab (any treatment line) and had available info on their molecular profile. Median OS was similar in the RAS wild-type [9.63 mo (95% CI 8.055-13.775)] and the RAS-mutant cohorts [8.78 mo (95% CI 8.055-11.014)], which was confirmed in a multivariable model adjusting for potential confounders; HR 1.05 (95% CI 0.618-1.785; p = .857). OS was 8.88 mo (95% CI 7.332-12.92) in patients with KRAS G12 mutation, compared to 9.47 mo (95% CI 8.088-11.375) in patients with RAS WT/non-KRAS G12 disease [HR: 0.822 (95% CI 0.527-1.282; p = .387)]. This suggests that the addition of bevacizumab to FTD/TPI may overcome the resistance to FTD/TPI monotherapy that was described in KRAS G12-mutant mCRC in past reports.

Doleschal B, et al. ESMO Open. 2023 Nov 15;8(6):102064.


Both Panitumumab +  Fluorouracil/Leucovorin and Panitumumab + FOLFOX are effective and safe 1L treatment options in Elderly Patients With RAS and BRAF wild-type Metastatic Colorectal Cancer (PANDA Trial).

An open-label, randomized phase II non-comparative study explored the safety and efficacy of panitumumab added to mFOLFOX (arm A) or  LV-FU (arm B) as 1L treatment for patients aged ≥70 y.o. with unresectable RAS/BRAF wild-type mCRC. The primary endpoint was PFS, assuming a null hypothesis of mPFS at ≤6 mo. The study met its primary endpoint in both arms. mPFS was 9.6 and 9.0 mo for arm A and B, respectively (p < .001 in each arm). A post-hoc evidence indicated ORR of 69% and 52%, respectively, while mOS was 23.5 and 22.0 mo, respectively. As expected, 5-FU + LV + PAN was associated with a better safety profile. The overall rate of ≥G3 chemotherapy-related AE was 60% and 37%, respectively. Both mFOLFOX and 5-FU/LV + PAN are reasonable options as initial therapy of elderly patients with RAS/BRAF wild-type mCRC.

Lonardi S, et al. J Clin Oncol. 2023 Dec 1;41(34):5263-5273.


A novel multimodal ctDNA-based blood test shows a promising accuracy in the detection of CRC.

A multimodal ctDNA-based blood test that integrates genomics, epigenomics and fragmentomics, plus proteomic profiling (in a refined version) was evaluated as a potential CRC screening method. The study tested two groups of individuals: people with a positive fecal immunochemical test (FIT) test, and patients diagnosed with CRC (623 persons in total). Sensitivity and specificity of the assay to detect CRC was 93% and 90%, respectively. The sensitivity of CRC detection was 84%, 94% and 96% for stage I, II and III CRC, respectively. Sensitivity to detect advanced premalignant lesions was 23% with a refined version of the test (integrating proteomics).

Bessa X, et al. Ann Oncol. 2023 Dec;34(12):1187-1193.


Majority of older patients experience good QoL and stay independent after colorectal cancer surgery (GOSAFE study).

A prospective international study evaluated risk factors for failing to achieve a good quality of life (QoL) and functional recovery in patients >70 years undergoing elective surgery for CRC. Complete data were available for 625 patients (435 colon and 190 rectal cancer), median age 79.0 y. At 3-6 months, 68.9-70.3% patients experienced equal/better QoL (72.8-72.9% colon, 60.1-63.9% rectal cancer). With regards to QoL, preoperative Flemish Triage Risk Screening Tool (fTRST) ≥2 and postoperative complications are associated with decreased QoL after colectomy, whereas a Charlson Age Comorbidity Index ≥7, ECOG ≥2, severe complications, fTRST ≥2 and palliative surgery are risk factors for not achieving functional recovery.

Montroni I, et al. J Clin Oncol. 2023 Dec 1;41(34):5247-5262.




bullets November 2023


Pembrolizumab + chemotherapy exhibits a significant improvement in overall survival in HER2-negative advanced gastric (KEYNOTE-859).

In a global multicenter randomized double-blind phase III trial, 1579 participants were randomly assigned to receive pembrolizumab + chemotherapy (n=790) or placebo + chemotherapy (n=789). The investigator’s choice of chemotherapy was CAPOX in 86% and Cisplatin-Fluorouracil in 14% of cases. mOS was longer in the pembrolizumab group in the ITT population (12.9 vs 11.5 mo; HR 0.78 [95% CI 0.70–0.87]; p<.0001), in participants with PD-L1 CPS of ≥1 (13.0 vs 11.4 mo; HR 0.74 [95% CI 0.65–0.84]; p<.0001), and in participants with PD-L CPS of ≥10 (15.7 vs 11.8 mo; 0.65 [95% CI 0.53–0.79]; p<.0001). Toxicity was manageable and no new safety signals were identified.

Rha SY, et al. Lancet Oncol. 2023 Nov;24(11):1181-1195.



KRAS and BRAF V600E mutations associate with different prognostic values in MSS and MSI stage III colon cancer (ACCENT/IDEA analysis).

In a pooled analysis of 7 trials evaluating the duration of adjuvant chemotherapy in resected stage III colon cancer, the prognostic impact of MMR status, and KRAS (codon 12 & 13) and BRAF V600E mutations was tested. In MSS tumors, KRAS and BRAF V600E mutations, as compared to KRAS/BRAF wild-type status, negatively impacted time-to-recurrence (TTR; HR 1.58 and 1.31, respectively, both p<.001; 5-y DFS 66%, 62% and 73%, respectively). The presence of KRAS and BRAF mutations was also detrimental for OS (HR 1.35 & 2.06, respectively; p<.0001 for both) and survival after recurrence (HR 1.25 & 2.87, respectively; p<.0001 for both). In MSI tumors, no influence of KRAS or BRAF mutations on TTR was seen (HR 0.99 & 0.98; 5-y DFS 76%, 76% and 75% in KRAS mut, BRAF V600E mutant, and KRAS/BRAF wild-type groups, respectively); however, BRAF V600E mutation had a negative effect on OS (HR 1.36, p=.042), and KRAS and BRAF mutations worsened survival after recurrence (HR 1.52, p=.07, and HR 1.99, p<.001)."

Taieb J, et al. Ann Oncol. 2023 Nov;34(11):1025-1034.



In esophageal cancer, prolonged time to surgery after neoadjuvant CRT does not improve histological complete response, but may lead to worse patients’ survival (NeoRes II).

The multi-centered trial aimed to assess whether standard (4-6 weeks) or prolonged (10-12 weeks) time to surgery (TTS) in patients with esophageal cancer after neoadjuvant CRT was associated with a better histological response. In total, 249 patients with esophageal cancer were randomized: 125 to standard and 124 to prolonged TTS. The primary endpoint, the rate of complete histological response (pCR) in patients with adenocarcinoma, was not significantly different between the standard (21%) and prolonged (26%) TTS cohorts (p=.429). Similarly, pCR rate in patients with resected squamous cell cancers was comparable in both treatment arms (55% vs 46% in the standard and prolonged TTS cohorts, respectively; p=.545) Tumor regression, resection margins and number of resected lymph nodes did not differ either. However, a trend of worse survival was found after prolonged TTS (HR 1.35; 95% CI 0.94-1.95, p=.107), suggesting caution in routinely delaying surgery for >6 weeks after neoadjuvant CRT.

Nillson K, et al. Ann Oncol. 2023 Nov;34(11):1015-1024.



Adjuvant atezolizumab plus bevacizumab improves recurrence free survival versus active surveillance in patients with high-risk hepatocellular carcinoma (IMBRAVE-050).

In a randomized phase III trial, 668 patients with high-risk surgically resected or ablated hepatocellular carcinoma were randomly assigned to either atezolizumab (1200 mg) plus bevacizumab (15 mg/kg) for 17 cycles, or to active surveillance. High-risk features included: tumor size >5 cm, tumor number >3, vascular invasion (micro- or macrovascular) and poor tumor differentiation (G3-4). At the prespecified interim analysis, recurrence-free survival (the primary end-point) was improved in the adjuvant arm  compared with active surveillance (median RFS not achieved in either arm; HR = 0.72 [95% CI 0.53–0.98], p=.012). Both atezolizumab and bevacizumab were discontinued because of adverse events in 9% of patients who received atezolizumab plus bevacizumab. Longer follow-up for both recurrence-free and overall survival is needed to assess the benefit–risk profile more fully.

Qin S, et al. Lancet. 2023 Nov 18;402(10415):1835-1847.



Nimotuzumab, an anti-EGFR antibody, plus gemcitabine improves outcomes in KRAS wild-type locally advanced or metastatic pancreatic cancer.

A Chinese randomized phase III trial evaluated the efficacy of the addition of nimotuzumab (anti-EGFR Ab) to first-line gemcitabine in patients with KRAS wild-type locally advanced or metastatic pancreatic cancer. 82 individuals with KRAS wild-type tumors were eligible. Nimotuzumab + gemcitabine, as compared to gemcitabine monotherapy, resulted in numerically superior OS, the primary end-point (mOS 10.9 vs 8.5 mo; HR 0.66 [95% CI, 0.42 to 1.05]; p=.08 ). Since the proportional hazards assumption was violated due to the separation of survival curves only after 6 mo, the authors used the restricted mean survival time (RMST) model to calculate the survival differences. The experimental arm resulted in a superior RMST (18.05 vs 11.4 mo in the experimental group and control groups, respectively, ratio = 0.62, [95% CI 0.40-0.97]; p=.036). While the experimental arm produced superior PFS (mPFS: 4.2 vs 3.6 mo; HR  0.60 [95% CI 0.37-0.99]), ORR and DCR rates were similar in both arms (7% vs 10%, and 68% vs 63% in the investigational and control arms, respectively).

Qin S, et al. J Clin Oncol. 2023 Nov 20;41(33):5163-5173.


In a large pan-cancer cohort, pancreatic acinar cell carcinoma (PACC) was identified as the cancer type with the highest prevalence of BRCA2 germline pathogenic variants and genomic features of HRD.

Somatic and germline analyses were performed in 28,780 patients with cancer, 49 of whom were diagnosed with PACC. Eighteen of 49 (36.7%) PACCs harbored germline pathogenic variants in homologous recombination (HR) and DNA damage response (DDR) genes, including BRCA1 (n = 1), BRCA2 (n = 12), PALB2 (n = 2), ATM (n = 2), and CHEK2 (n = 1). BRCA2 germline pathogenic variants (11 of 31, 35%) were significantly more frequent in pure PACCs than in pancreatic adenocarcinoma, high-grade serous ovarian carcinoma, prostate cancer, and breast cancer. Genomic features of HR deficiency (HRD) were detected in 7 of 12 PACCs tested with WGS. These data suggest that PACC should be considered as part of the spectrum of BRCA-related malignancies.

Mandelker D, et al. J Clin Oncol. 2023 Nov 20;41(33):5151-5162.




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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