This study analyzed outcomes of systemic chemotherapy for advanced neuroendocrine carcinoma (NEC) of the digestive system. Clinical data from 258 patients with unresectable or recurrent NEC of the ...gastrointestinal tract (GI) or hepato‐biliary‐pancreatic system (HBP), who received chemotherapy, were collected from 23 Japanese institutions and analyzed retrospectively. Patients had primary sites in the esophagus (n = 85), stomach (n = 70), small bowel (n = 6), colorectum (n = 31), hepato‐biliary system (n = 31) and pancreas (n = 31). Median overall survival (OS) was 13.4 months the esophagus, 13.3 months for the stomach, 29.7 months for the small bowel, 7.6 months for the colorectum, 7.9 months for the hepato‐biliary system and 8.5 months for the pancreas. Irinotecan plus cisplatin (IP) and etoposide plus cisplatin (EP) were most commonly selected for GI‐NEC and HBP‐NEC. For patients treated with IP/EP (n = 160/46), the response rate was 50/28% and median OS was 13.0/7.3 months. Multivariate analysis among patients treated with IP or EP showed that the primary site (GI vs HBP; hazard ratio HR 0.58, 95% confidence interval CI 0.35–0.97) and baseline serum lactate dehydrogenase levels (not elevated vs elevated; HR 0.65, 95% CI 0.46–0.94) were independent prognostic factors for OS, while the efficacy of IP was slightly better than for EP (HR 0.80, 95% CI 0.48–1.33; P = 0.389). IP and EP are the most common treatment regimens for NEC of the digestive system. HBP primary sites and elevated lactate dehydrogenase levels are unfavorable prognostic factors for survival. A randomized controlled trial is required to establish the appropriate chemotherapy regimen for advanced NEC of the digestive system. This study was registered at UMIN as trial number 000005176.
Clinical data from patients with unresectable or recurrent NEC of the gastrointestinal tract (GI) or hepato‐biliary‐pancreatic system (HBP), who received chemotherapy, were collected from 23 Japanese institutions and analyzed retrospectively. This study included 258 patients. Multivariate analysis among the patients treated with IP or EP showed that the primary site (GI vs. HBP; HR 0.58, 95% CI 0.35–0.97) and baseline serum lactate dehydrogenase (LDH) levels (not elevated vs elevated; HR 0.65, 95% CI 0.46–0.94) were independent prognostic factors for OS, while the efficacy of IP was slightly better than EP (HR 0.80, 95% CI 0.48–1.33; P = 0.389).
The applicability of circulating tumor DNA (ctDNA) genotyping to inform enrollment of patients with cancer in clinical trials has not been established. We conducted a phase 2 trial to evaluate the ...efficacy of pertuzumab plus trastuzumab for metastatic colorectal cancer (mCRC), with human epidermal growth factor receptor 2 (HER2) amplification prospectively confirmed by tumor tissue or ctDNA analysis ( UMIN000027887 ). HER2 amplification was confirmed in tissue and/or ctDNA in 30 patients with mCRC. The study met the primary endpoint with a confirmed objective response rate of 30% in 27 tissue-positive patients and 28% in 25 ctDNA-positive patients, as compared to an objective response rate of 0% in a matched real-world reference population treated with standard-of-care salvage therapy. Post hoc exploratory analyses revealed that baseline ctDNA genotyping of HER2 copy number and concurrent oncogenic alterations adjusted for tumor fraction stratified patients according to efficacy with similar accuracy to tissue genotyping. Decreased ctDNA fraction 3 weeks after treatment initiation associated with therapeutic response. Pertuzumab plus trastuzumab showed similar efficacy in patients with mCRC with HER2 amplification in tissue or ctDNA, showing that ctDNA genotyping can identify patients who benefit from dual-HER2 blockade as well as monitor treatment response. These findings warrant further use of ctDNA genotyping in clinical trials for HER2-amplified mCRC, which might especially benefit patients in first-line treatment.
This phase III study compared treatment with weekly paclitaxel and biweekly irinotecan in patients with advanced gastric cancer refractory to treatment with fluoropyrimidine plus platinum.
Patients ...were randomly assigned to receive either paclitaxel (80 mg/m(2) on days 1, 8, and 15, every 4 weeks) or irinotecan (150 mg/m(2) on days 1 and 15, every 4 weeks). Primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), response rate, adverse events, and proportion of patients who received third-line chemotherapy.
Of 223 patients, 219 were eligible for analysis. Median OS was 9.5 months in 108 patients allocated to the paclitaxel group and 8.4 months in 111 patients allocated to the irinotecan group (hazard ratio HR, 1.13; 95% CI, 0.86 to 1.49; P = .38). Median PFS was 3.6 months in the paclitaxel group and 2.3 months in the irinotecan group (HR, 1.14; 95% CI, 0.88 to 1.49; P = .33). Response rate was 20.9% in the paclitaxel group and 13.6% in the irinotecan group (P = .24). Common grade 3 to 4 adverse events were neutropenia (paclitaxel group, 28.7%; irinotecan group, 39.1%), anemia (21.3%; 30.0%), and anorexia (7.4%; 17.3%). Treatment-related deaths occurred in two patients (1.8%) in the irinotecan group. Third-line chemotherapy was administered in 97 patients (89.8%) after paclitaxel treatment and in 80 patients (72.1%) after irinotecan treatment (P = .001).
No statistically significant difference was observed between paclitaxel and irinotecan for OS. Both are reasonable second-line treatment options for advanced gastric cancer.
Cancer treatment with epidermal growth factor receptor inhibitors (EGFRIs) often induces severe xerotic dermatitis. Various irritants facilitate development of dermatitis in xerotic skin. As zinc ...deficiency plays a role in the development of irritant dermatitis, we measured serum zinc levels in 25 patients with xerotic dermatitis due to treatment with EGFRIs. Of these patients, nine were treated with EGFR tyrosine kinase inhibitors and 16 were treated with anti‐EGFR antibody alone or in combination with other anticancer agents. Serum zinc levels of all patients were lower than the normal range of >80 μg/dL, with a mean ± SD serum zinc level of 56.4 ± 11.7 μg/dL. These were correlated with serum magnesium levels in patients. As the serum magnesium level is known to be reduced by the inhibition of EGFR, a similar mechanism may also be involved in decreasing the serum zinc level. Among 21 patients treated with zinc supplementation for more than 2 months, xerotic dermatitis markedly improved, with an increase of serum zinc levels in 16 patients. The other five patients exhibited no significant improvement in their skin condition, and insufficient and unstable increase in serum zinc levels. In conclusion, zinc supplementation may be beneficial in supportive care for patients with EGFRI‐induced xerotic dermatitis.
OncoBEAM
RAS CRC kit using BEAMing technology is a circulating tumour DNA (ctDNA) test for detecting plasma RAS mutational status in metastatic colorectal cancer (mCRC). We conducted a multicentre, ...prospective study to investigate the concordance of the RAS mutational status between plasma ctDNA and tumour tissue DNA.
mCRC patients without prior anti-EGFR antibodies or regorafenib treatment were enroled. Plasma- and tissue-based RAS mutational status were determined by BEAMing, respectively.
A total of 280 patients from eight institutions were eligible. The overall agreement between plasma- and tissue-based analyses was 86.4%, with a positive percent agreement of 82.1% and negative percent agreement of 90.4%. From logistic regression analysis, lung metastasis alone indicated the most significant factor associated with discordance. The agreement between plasma- and tissue-based analyses was 64.5% in patients with lung metastasis alone (n = 31) indicating lower amount of ctDNA. Among the cases with lung metastasis alone, all plasma- and tissue-based analyses were perfectly concordant in cases with ≥20 mm of maximum lesion diameter or ≥10 lesions.
The clinical validity of OncoBEAM
RAS CRC kit was confirmed. Careful attention should be paid for mCRC patients with lung metastases alone having fewer metastases or smaller diameter lesions.
This multicenter phase II study first investigated the efficacy and safety of nanoparticle albumin‐bound paclitaxel (nab‐paclitaxel) when given every 3 weeks to patients with unresectable or ...recurrent gastric cancer who had received a prior round of fluoropyrimidine‐containing chemotherapy. Patients with unresectable or recurrent gastric cancer who experienced progression despite fluoropyrimidine‐containing treatment were studied. Nab‐paclitaxel was given i.v. at 260 mg/m2 on day 1 of each 21‐day cycle without anti‐allergic premedication until disease progression or study discontinuation. The primary endpoint was the overall response rate. The secondary endpoints were the disease control rate, progression‐free survival, overall survival, and safety. From April 2008 to July 2010, 56 patients were enrolled, 55 patients received the study treatment, and 54 patients were evaluable for responses. According to an independent review committee, the overall response rate was 27.8% (15/54; 95% confidence interval CI, 16.5–41.6) and the disease control rate was 59.3% (32/54; 95% CI, 45.0–72.4). One patient had a complete response. The median progression‐free survival and overall survival were 2.9 months (95% CI, 2.4–3.6) and 9.2 months (95% CI, 6.9–11.4), respectively. The most common grade 3/4 toxicities were neutropenia (49.1%), leucopenia (20.0%), lymphopenia (10.9%), and peripheral sensory neuropathy (23.6%). There were no treatment‐related deaths. Nab‐paclitaxel, given every 3 weeks, showed promising activity against previously treated unresectable or recurrent gastric cancers, with well‐tolerated toxicities. (Trial registration, ClinicalTrials.gov: NCT00661167).
This multicenter phase II study first investigated the efficacy and safety of nanoparticle albumin‐bound paclitaxel (nab‐paclitaxel) when given every 3 weeks to patients with unresectable or recurrent gastric cancer who had received a prior round of fluoropyrimidine‐containing chemotherapy. This regimen showed promising activity, with well‐tolerated toxicities.
This randomized phase II trial compared panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) with bevacizumab plus FOLFIRI as second‐line chemotherapy for wild‐type (WT) KRAS exon 2 ...metastatic colorectal cancer (mCRC) and to explore the values of oncogenes in circulating tumor DNA (ctDNA) and serum proteins as predictive biomarkers. Patients with WT KRAS exon 2 mCRC refractory to first‐line chemotherapy containing oxaliplatin and bevacizumab were randomly assigned to panitumumab plus FOLFIRI or bevacizumab plus FOLFIRI. Of 121 randomly assigned patients, 117 were eligible. Median overall survival (OS) for panitumumab plus FOLFIRI and bevacizumab plus FOLFIRI were 16.2 and 13.4 months hazard ratio (HR), 1.16; 95% CI, 0.76–1.77, respectively. Progression‐free survival (PFS) was also similar (HR, 1.14; 95% CI, 0.78–1.66). KRAS, NRAS, and BRAF status using ctDNA was successfully examined in 109 patients, and mutations were identified in 19 patients (17.4%). Panitumumab plus FOLFIRI showed favorable survival compared with bevacizumab plus FOLFIRI in WT patients and unfavorable survival in those with mutations (P for interaction = 0.026 in OS and 0.054 in PFS). OS with bevacizumab plus FOLFIRI was better than panitumumab plus FOLFIRI in patients with high serum vascular endothelial growth factor‐A (VEGF‐A) levels and worse in those with low levels (P for interaction = 0.016). Second‐line FOLFIRI plus panitumumab and FOLFIRI plus bevacizumab showed a similar efficacy in patients with WT KRAS exon 2 mCRC. RAS and BRAF mutation in ctDNA could be a negative predictive marker for panitumumab.
Second‐line FOLFIRI plus panitumumab and FOLFIRI plus bevacizumab showed a similar efficacy in patients with WT KRAS exon 2 mCRC. RAS and BRAF mutation in ctDNA could be a negative predictive marker for panitumumab.
Background
This study was conducted to investigate whether human epidermal growth factor receptor 2 (HER2) status, epidermal growth factor receptor (EGFR) status, and c-MET status are independent ...prognostic factors for advanced gastric cancer patients who received standard chemotherapy.
Method
Unresectable or recurrent gastric or gastroesophageal junction cancer patients with histologically confirmed adenocarcinoma treated with S-1 plus cisplatin as first-line chemotherapy were eligible. Formalin-fixed paraffin-embedded tumor samples were examined for HER2, EGFR, and c-MET status using immunohistochemistry (IHC). Additionally, gene amplification was examined using fluorescent in situ hybridization (FISH) for HER2. Positivity was defined as an IHC score of 3+ or an IHC score of 2+/FISH positive for HER2, and an IHC score of 2+ or 3+ for both EGFR and c-MET.
Results
Of the 293 patients from nine institutions, 43 (15 %) were HER2 positive, 79 (27 %) were EGFR positive, and 120 (41 %) were c-MET positive. Ten patients (3 %) showed positive co-expression of HER2, EGFR, and c-MET. After a median follow-up time of 58.4 months with 280 deaths, there was no significant difference in overall survival (OS) in terms of HER2 and EGFR status. However, there was a significant difference in OS between c-MET-positive and c-MET-negative patients median, 11.9 months vs 14.2 months; hazard ratio, 1.31 (95 % confidence interval, 1.03–1.67); log-rank
P
= 0.024. Multivariate analysis also showed that c-MET positivity was still a prognostic factor for OS hazard ratio, 1.30 (95 % confidence interval, 1.02–1.67);
P
= 0.037.
Conclusions
The study suggested that c-MET-positive status had poor prognostic value. These data could be used as the basis for future clinical trials for targeting agents for advanced gastric cancer patients.
ObjectivesWe assessed the safety, tolerability, pharmacokinetics, preliminary antitumour activity and pharmacodynamics of danvatirsen, an antisense oligonucleotide targeting signal transducer and ...activator of transcription 3 (STAT3), monotherapy and danvatirsen plus durvalumab, an antiprogrammed cell death ligand 1 monoclonal antibody, in patients with advanced solid malignancies.DesignPhase 1, open-label study with two cohorts.SettingTwo centres in Japan.ParticipantsJapanese individuals aged ≥20 years, with histologically confirmed solid malignancies, except for hepatocellular carcinoma, refractory to standard therapy.InterventionsIn cohort 1, patients received danvatirsen monotherapy; in cohort 2, patients received danvatirsen plus durvalumab combination therapy.Primary and secondary outcome measuresThe primary endpoint was safety and tolerability based on adverse events (AEs). Secondary endpoints were pharmacokinetics, immunogenicity, antitumour activity and pharmacodynamics.ResultsEleven patients were assigned to treatment and included in the analysis. Danvatirsen dose reductions were only required in cohort 2 for hepatic function abnormal (alanine aminotransferase (ALT)/ aspartate aminotransferase (AST)/gamma-glutamyl transferase (γGT) increased), neutrophil count decreased and platelet count decreased. One patient experienced grade 3 ALT/AST increased and new appearance of eosinophilia as a dose-limiting toxicity. AEs were reported in 90.9% (10/11) patients. Commonly reported AEs causally related to the danvatirsen were platelet count decreased (60% (3/5)) and ALT/AST/γGT increased (50% (3/6)) in cohorts 1 and 2, respectively; none was causally related to durvalumab. One serious AE occurred in cohort 1 (pancreatitis; unrelated to study treatment). One case of ALT/AST/γGT increased occurred in cohort 2, leading to discontinuation. No AEs led to death. Danvatirsen did not accumulate in plasma after multiple dosing. In cohort 2, three patients had disease control at 12 weeks and one had unconfirmed partial response. STAT3 expression tended to decrease regardless of monotherapy or combination therapy.ConclusionsDanvatirsen was well tolerated by Japanese patients with advanced solid tumours as monotherapy and combined with durvalumab. No new safety signals arose.Trial registration numberNCT03394144; ClinicalTrials.gov.
Background
Oral fluoropyrimidine plus cisplatin is often not tolerated by patients with severe peritoneal metastases of gastric cancer. Combination of 5-fluorouracil (5-FU),
l
-leucovorin (
l
-LV), ...and paclitaxel (FLTAX) has promising activity for such patients. We conducted a phase II/III study comparing FLTAX with 5-FU/
l
-LV.
Methods
Eligibility criteria included: unresectable or recurrent gastric adenocarcinoma; 20–75 years; performance status (PS) 0–2; peritoneal metastases + ; massive ascites and/or inadequate oral intake; no prior chemotherapy. Patients were randomly assigned to receive 5-FU/
l
-LV or FLTAX. The primary endpoint of phase III was overall survival: UMIN000010949.
Results
We enrolled 101 patients. Early deaths occurred in patients with PS 2 having massive ascites and inadequate oral intake simultaneously; the protocol was amended to exclude such patients. Median survival times were 6.1 and 7.3 months for the 5-FU/
l
-LV and the FLTAX arms, respectively (HR 0.792; 80% CI 0.596–1.053; one-sided
p
= 0.1445). FLTAX arm had longer progression-free survival (PFS) 1.9 vs 5.4 months (HR 0.64; 95% CI, 0.43–0.96;
p
= 0.029). Grade 3/4 adverse events such as leucopenia and anorexia were more frequently observed in the 5-FU/
l
-LV arm. In the 5-FU/
l
-LV arm, two deaths were treatment-related. In the 5-FU/
l
-LV and FLTAX arms, 12 and 3 deaths occurred within 30 days after the last protocol treatment, respectively.
Conclusions
Chemotherapy was indicated for patients with severe peritoneal metastases excluding patients with PS 2 having massive ascites and inadequate oral intake simultaneously. FLTAX did not confer a significant survival benefit but may be preferred because of longer PFS and acceptable toxicity.
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