Data from Advances in Precision Cancer Care - Curated by EPG Health - Last updated 23 October 2018

In our final report from ESMO 2018 we share insights from the Proffered paper session - Gastrointestinal tumours, colorectal, moderated by Dirk Arnold (Hamburg, DE) and Alfredo Falcone (Pisa, IT). Here, we cover survival data from the MODUL trial, comparing maintenance fluorouracil-bevacizumab and fluorouracil-bevacizumab plus atezolizumab in BRAF wild-type disease, and [in TRIBE2] consider the impact on PFS2 of an intensified treatment strategy versus a standard, sequential treatment strategy.

Scroll down for key data and insights from each presentation.

LBA19 - Fluoropyrimidine (FP) + bevacizumab (BEV) + atezolizumab vs FP/BEV in BRAFwt metastatic colorectal cancer (mCRC): Findings from Cohort 2 of MODUL – a multicentre, randomized trial of biomarker-driven maintenance treatment following first-line induction therapy

Dr Grothey presented survival results comparing maintenance fluorouracil-bevacizumab and fluorouracil-bevacizumab plus atezolizumab in the BRAF wild-type cohort of the MODUL trial, a randomised phase III trial of biomarker-driven maintenance treatment following first-line induction chemotherapy. 

The rationale for combining atezolizumab with bevacizumab-based maintenance chemotherapy is that by targeting the VEGF pathway we may reverse VEGF-immune-suppression, promote T cell tumour infiltration and possibly render MSS colon cancer more sensitive to PD-L1 inhibition. 

In the MODUL trial, metastatic colorectal cancer patients who had achieved stale disease or better following completion of a 16-week 1st line induction regimen of FOLFOX plus bevacizumab were randomised to 4 different, biomarker-driven maintenance strategies. 

In the BRAF wild-type cohort, patients were randomly allocated in a 1:2 ratio to:

  • Maintenance fluorouracil-bevacizumab, or 
  • Fluorouracil-bevacizumab plus atezolizumab

The primary endpoint was PFS as measured from the time of randomisation. 634 patients were included in the BRAF wild-type cohort. Baseline characteristics were well balanced between treatment groups. Approximately 60% of patients had RAS-mutant tumours while only 2% had MSI tumours. 

After a median follow-up of 18.7 months, median PFS was 7.20 months in the investigational arm and 7.39 months in the control arm (stratified HR 0.96, p=0.727). Subgroup analysis was not able to identify a subgroup of patients who benefitted from maintenance immunotherapy. Similarly, no difference in OS was observed between treatment arms (22.05 months in the investigational arm and 21.91 months in the control arm, stratified HR 0.86, p=0.283). All grade, treatment-related AEs were reported more frequently in the investigational arm (37.5%) as compared to the control arm (30.1%), especially diarrhoea and arthralgia. Immune-related AEs were relatively uncommon in both arms.  

Dr Grothey concluded by saying MODUL was the largest randomised umbrella study of 1st line maintenance treatment in metastatic colorectal cancer. Although combining immunotherapy with maintenance bevacizumab-based therapy was safe, no survival benefit from this strategy was observed. Alternative treatment strategies should be explored to reverse the inherent immune-refractoriness of MSS colorectal cancers.   

LBA20 - TRIBE2: a phase III, randomized strategy study by GONO in the 1st- and 2nd-line treatment of unresectable metastatic colorectal cancer (mCRC) patients (pts)

Dr Cremolini presented results from TRIBE2, a randomised, open-label, phase III study comparing an intensified versus a sequential treatment strategy in chemotherapy-naive metastatic colorectal cancer patients. Since the results of the previous TRIBE trial were presented, concerns have been raised regarding the feasibility and efficacy of a rechallenge with FOLFOXIRI-bevacizumab following initial progression to the same regimen. 

In TRIBE2, patients were randomised in a 1:1 ratio to:

  • FOLFOXIRI-bevacizumab for 8 cycles followed by maintenance fluorouracil-bevacizumab and rechallenge with FOLFOXIRI-bevacizumab upon progression, or
  • FOLFOX-bevacizumab for 8 cycles followed by maintenance fluorouracil-bevacizumab and switch to FOLFIRI-bevacizumab upon progression

The primary endpoint was PFS2 as measured from the time of randomisation to the time of disease progression to second line treatment (either pre-planned treatment or any other treatment decided by the local investigator). If no second line treatment was initiated within 3 months of progression to first line therapy PFS2 was considered equal to PFS on first line treatment.  

In line with the pivotal TRIBE trial, patients were eligible if they were <75 years and had an ECOG performance status of 0–2 (or 0 if age between 71–75 years). Of note, previous adjuvant oxaliplatin-based chemotherapy was not allowed. 679 patients were randomised. Of these, approximately 60% had RAS mutant tumours while 10% had tumours harbouring BRAF mutation. 

The trial met its primary endpoint: median PFS2 was 18.9 in the intensified treatment group and 16.2 months in the sequential treatment group (HR 0.69, p<0.001). Median PFS and rate of objective response after 1st line therapy was also higher in the intensified treatment arm (12.0 vs 9.9 months [0.73, p<0.001] and 61% vs 50% [p=0.005], respectively). 

As expected, first line triplet therapy was associated with an increased risk of neutropenia, febrile neutropenia and diarrhoea. For second line therapy, 86% of patients in the sequential treatment arm and 74% of patients in the intensified treatment arm received further treatment and, of these, 88% and 76%, respectively, adhered to the study protocol recommendation. Of note, no difference in median PFS for second line therapy was observed between the study arms (6.0 in the intensified treatment group and 5.5 months in the sequential treatment group (HR 0.86, p<0.12)).

Dr Cremolini concluded stating TRIBE2 demonstrated the superiority of an intensified treatment strategy as compared to a standard [sequential] treatment strategy. Data on OS are not mature yet and will be presented next year.

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