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Neoadjuvant therapy produces almost complete response in dMMR colon cancer

29th September 2022

Neoadjuvant therapy before surgery in patients with DNA mismatch repair deficient (dMMR) colon cancer gave rise to a huge pathologic response

Neoadjuvant therapy (NAT) prior to surgery in patients with DNA mismatch repair deficient (dMMR) colon cancer gave rise to a major pathologic response of 95% according to the findings by Dutch researchers presented at the recent European Society of Medical Oncology Congress.

The World Health Organisation estimated that in 20202, there were 1.93 million cases of colorectal cancers and which gave rise to 916 000 deaths. Moreover, defective DNA mismatch repair (dMMR) occurs in approximately 15% of sporadic colorectal cancers and evidence indicates that patients with dMMR colon cancers do not benefit from treatment with adjuvant 5-fluorouracil chemotherapy. In the Nivolumab, Ipilimumab and COX2-inhibition in Early Stage Colon Cancer: an Unbiased Approach for Signals of Sensitivity (NICHE) trial, patients with stage 1-3 adenocarcinoma of the colon and with no signs of distant metastases, were treated with short-term immunotherapy (nivolumab and ipilimumab) and COX2-inhibitors prior to surgical resection of the tumour. The results showed that a pathological response was observed in 20/20 dMMR tumours, with 19 major pathological responses (i.e., ≤10% residual viable tumour, RVT) and 12 pathological complete responses.

Based on these findings, researchers instigated NICHE-2 in which patients with non-metastatic dMMR colon cancer received NAT with 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab in the first cycle, then only nivolumab in the second cycle 2 weeks later, followed by surgery within 6 weeks of enrolling on the trial. They set the primary end points as 3-year disease-free survival (DFS) and safety with secondary end points including major pathological response (MPR) and complete response. For the purposes of the study, a pathologic response (PR) was defined as ≤ 50% residual viable tumour (RVT) and MPR as ≤ 10% RVT.

Neoadjuvant therapy treatment outcomes

A total of 112 patients with a median age of 60 years (58% female) were enrolled. For 107 patients included in the efficacy analysis, baseline radiologic assessment revealed 89% to be at stage III, 77% high-risk stage III and 64% T4 tumours. The median time between the first dose of neoadjuvant therapy and surgery was 5 weeks.

A pathologic response was observed in 106/107 (99%) patients with 95% achieving a MPR and a complete response was observed in 67% of patients with 4% achieving a partial response. After a median follow-up of 13 months none of the patients had disease recurrence. 

Grade 3-4 immune-related adverse events were observed in 3% of patients and only 3 experienced delay in surgery, meeting the safety primary endpoint.

The authors concluded by stating that ‘the first survival data suggest a strong potential for neoadjuvant immunotherapy to become standard of care and allow further exploration of organ-sparing approaches.’

Citation
Chalabi M et al. Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: The NICHE-2 study LBA7

Adjuvant pembrolizumab increases event-free survival in triple negative breast cancer

18th February 2022

Adjuvant pembrolizumab in addition to chemotherapy has been found to improve event-free survival in triple negative breast cancer patients

Adjuvant pembrolizumab added to chemotherapy post surgery significantly improves event-free survival compared to chemotherapy alone. This was the conclusion of a study by researchers from the Centre of Experimental Cancer Medicine, Barts Cancer Institute, London, UK.

Triple negative breast cancer constitutes 10-15% of female breast cancers and is a more aggressive cancer with more frequent recurrence and worse survival compared with the non-triple negative form. Clinical trial data has revealed improved disease-free survival with postoperative chemotherapy in patients with either triple-negative or HER2-positive breast cancer who had residual disease after neoadjuvant chemotherapy. Whether the addition of pembrolizumab to neoadjuvant chemotherapy would increase the proportion of patients with early triple-negative breast cancer who had a pathological complete response after surgery was unclear until publication in 2020, of the KEYNOTE-522 trial. The trial concluded that the percentage of patients with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy.

For the present study, the authors have reported on an updated analysis of the KEYNOTE-522 trial and in particular, event-free survival as well as additional efficacy and updated safety information. Participants were adults with confirmed triple negative breast cancer or those with newly diagnosed and previously untreated non-metastatic disease with primary tumour and regional lymph node involvement. During the adjuvant phase, patients with previously untreated stage II or III triple negative breast cancer, were randomised 2:1 to receive either pembrolizumab (the pembrolizumab–chemotherapy group) or placebo (the placebo–chemotherapy group), administered once every 3 weeks. After surgery, patients received either pembrolizumab or placebo and chemotherapy every 3 weeks for up to nine cycles. The primary endpoint was pathological complete response and event-free survival.

Adjuvant Pembrolizumab and event-free survival

A total of 1174 patients were randomly assigned to either arm and during follow-up, 123 (15.7%) patients assigned to the pembrolizumab arm had an event or died compared to 93 (23.8%) in the placebo-chemotherapy arm.

The estimated event-free survival after 36 months was 84.5% in the adjuvant pembrolizumab group and 76.8% in the placebo arm, giving a hazard ratio, HR, for an event or death = 0.63, 95% CI 0.48 – 0.82, p < 0.001.

Data on overall survival were described as immature at the time of the analysis and the estimated overall survival at 36 months was 89.7% in the adjuvant pembrolizumab group and 86.9% in the placebo-chemotherapy group. With respect to safety, the authors reported that the reported adverse events were consistent with the established safety profile of both pembrolizumab and chemotherapy.

The authors concluded that among those with early triple negative breast cancer, neoadjuvant pembrolizumab plus chemotherapy and then followed by adjuvant pembrolizumab after surgery, was associated with a significantly longer event-free survival than neoadjuvant chemotherapy alone.

Citation
Schmid P et al. Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer N Engl J Med 2022

Apatinib neoadjuvant chemotherapy effective in advanced gastric cancer

15th July 2021

Positive findings that apatinib neoadjuvant chemotherapy produces an R0 section rate of 75% in advanced gastric cancer required confirmation.

Internationally, data from 2018 reveal how there were just over 1 million cases of gastric cancer, leading to 782,000 deaths. Fortunately, early treatment of gastric cancer either through endoscopic resection or surgery, provides a cure rate of over 90%. In contrast, in patients with locally advanced gastric cancer, prognosis is poor, with a 5-year overall survival rate of 20–30% for surgery-only patients. Among those with advanced gastric cancer, systemic chemotherapy has become the standard treatment, in particular, the combination of S-1, which is an oral fluoropyrimidine derivative and oxaliplatin (SOX) and this regime has been shown to be effective. Another therapeutic approach involves treatments targeting vascular endothelial growth factor (VEGF), which has been shown to have an important role in promoting tumour angiogenesis. Apatinib is a small molecule tyrosine kinase inhibitor that selectively binds to vascular endothelial growth factor receptor 2 and which inhibits the action of VEGF. In fact, early data suggest that apatinib can improve overall survival in advanced gastric cancer.

In a review of 14 trials, the use of neoadjuvant chemotherapy, has been shown to improve tumour stage and survival in patients with advanced gastric cancer. However, little is known about the value of Apatinib in combination with neoadjuvant chemotherapy. This led a team from the Department of Gastric Surgery, Fujian Medical University Union Hospital, Fujian Province, China, to examine the effectiveness of this combination in patients with locally advanced gastric cancer. They conducted a multi-centre, open-label phase II, non-randomised controlled trial, in patients with confirmed primary gastric adenocarcinoma, without previous surgery, chemotherapy, radiotherapy or targeted therapy and no evidence of metastases. Patients with MO (i.e., no metastases) and either T2 to T4 (where the tumour has spread through the layers of the muscle into the connective tissue outside the stomach. All enrolled participants received 2 to 5 preoperative and 6 postoperative cycles of apatinib plus SOX every three weeks. Apatinib was given at a dose of 500 mg daily for 21 days and S1 twice daily on days 1 to 14 and intravenous oxaliplatin 130mg/square metre on day 1. Patients achieving a good response underwent surgery whereas those with a poor response received two further courses of adjuvant chemotherapy. The primary endpoint was the RO section rate (i.e., margin-negative resection with no tumour in the primary tumour bed) and which is the goal of surgery. The radiologic response was assessed using contrast-enhanced CT or magnetic resonance imaging.

Findings
A total of 48 patients with a mean age of 63.2 years (77.1% male) were included. All participants received 156 preoperative cycles neoadjuvant chemotherapy. The majority of patients (39.5%) had stage T3 cancer and nearly a third (36.9%) had stage T4 disease. Overall, 40 underwent surgery (38 radical gastrectomy and 2 exploratory laparotomy), with an R0 section rate of 75%. The radiological response rate was 75% and the pathological response rate, 54.2%.

Commenting on these early findings, the authors stated how the data indicated the effectiveness of apatinib and SOX chemotherapy as a neoadjuvant therapy for locally advanced gastric cancer. They concluded that apatinib plus SOX appeared to be an effective and well-tolerated regime and called for more studies to confirm this preliminary conclusion.

Citation
Lin JX et al. Effectiveness and Safety of Apatinib Plus Chemotherapy
as Neoadjuvant Treatment for Locally Advanced Gastric Cancer A Nonrandomised Controlled Trial
. JAMA Oncol 2021