ESMO Colorectal Cancer

KEYNOTE-177 Study – Health-related quality of life

In the KEYNOTE-177 study, reported at the ESMO 2020 Virtual Meeting, pembrolizumab monotherapy significantly improved progression-free survival (PFS) vs standard chemotherapy as first-line treatment in patients with microsatellite instability-high and/or deficient mismatch repair metastatic colorectal cancer (mCRC).

Patients with confirmed microsatellite instability-high and/or deficient mismatch repair metastatic colorectal cancer (mCRC) with no prior systemic therapy were randomized 1:1 to pembrolizumab 200 mg every 3 weeks for up to 2 years or investigator’s choice (SOC) of mFOLFOX6 or FOLFIRI twice weekly plus or minus bevacizumab or cetuximab. Health-related quality of life (HQoL) scales were administered at baseline and at various time points up to one year or end of treatment, whichever came first, and at 30 days after treatment discontinuation.

Data for 294 patients (152, pembrolizumab; 142 SOC) were available for HRQoL analyses. Compliance at baseline was >90% in the pembrolizumab and SOC arms and remained high at week 18.

The change from baseline to week 18 showed clinically meaningful improvement in all HRQoL scores, including QLQ-C30 global health status and EQ-5D VAS, for patients receiving pembrolizumab vs standard of care. Prolonged time to deterioration for patients receiving pembrolizumab vs standard care was observed for GHS/Qo, physical functioning, social functioning, and fatigue.

The investigators concluded that pembrolizumab monotherapy demonstrated clinically meaningful improvements in HRQoL compared with standard of care chemotherapy in patients with previously untreated microsatellite instability-high and/or deficient mismatch repair metastatic colorectal cancer (mCRC).

The Phase 2 CAVE (Cetuximab-Avelumab) mCRC Study

A preliminary analysis demonstrated that avelumab plus cetuximab as a rechallenge strategy is effective and well tolerated in chemo-refractory RAS/BRAF wild type metastatic colorectal cancer (mCRC) patients. The data were presented at the ESMO 2020 Virtual Congress.

The purpose of CAVE mCRC, a single arm, multi-center, phase 2 study was to evaluate the efficacy of avelumab and cetuximab in RAS wild-type mCRC patients treated in first line with chemotherapy in combination with anti-EGFR drugs and who achieved a complete response (CR) or partial response (PR). The primary endpoint was median overall survival (OS), secondary endpoints were overall response rate (ORR) according to RECIST 1.1, progression free survival (PFS) and safety profile. This study sought to demonstrate a median OS of 11 months for the experimental combination in comparison with historical median OS of 8.0 months with standard third-line treatments, which corresponds to an improvement in median OS of 37.5 %.

From August 10, 2018 to February 21, 2020, 77 patients have been enrolled and started treatment with avelumab 10 mg/kg every 14 days and cetuximab at 400 mg/m2 and subsequently 250 mg/m2weekly until progression of disease or unacceptable toxicity. Kaplan-Meier curves estimated for the whole intention-to-treat (ITT) population (77 pts): median OS was 13.1 months (95% CI, 7.4, 18.8 months, 32 events); median PFS, 3.6 months (95% CI, 3.3, 3.9 months; 62 events). Among 65 patients evaluable for response, one (1.5%) experienced CR, 3 (4.6%) had PR, 32 patients had stable disease (SD) (49.2%); and 29 patients had partial disease (44.6%); 18.5% of patients had PFS ≥6 months. Grade-3 adverse events were reported in 16/77 patients (22%), the most common being skin rash 10/77 (13%) and diarrhea 3/77 (4%).

PRODIGE 131 — an FFCD (Fédération Francophone de Cancérologie Digestive) phase 3 Trial

Intensive follow-up of patients after curative surgery for CRC is recommended by various scientific societies. These recommendations are mainly based on expert opinions and results of the few clinical trials performed are controversial. Moreover, no survival benefit has been demonstrated.

PRODIGE 13 is a phase 3, prospective multicenter controlled trial conducted in France and Belgium between September 2009 and April 2015. Patients (n=1,995) were evaluated by double randomization the impact of intensive radiological monitoring (CT-scan/6m) versus standard monitoring (abdominal ultrasound/3m thoracic radiography/6m); and a carcinoembryonic antigen (CEA) assessment versus none, in the follow-up of resected stage II or III CRC with no evidence of residual disease on post-surgical investigation. The primary endpoint was 5-year overall survival (OS).

Patients in the trial included <75 years old (75.9%), 16% rectal, 44% left colon cancer. Among the colon cancer patients, 52% were stage II (25% received adjuvant chemotherapy). With a median follow-up of 6.5 years, cancer recurrence was detected in 22% of the cases and second CRC in 1.7%.

Among recurrences in colon cancer, 8.4% were localized, 74.7% were metastatic, and 15.7% were both. These patients were treated with the intent to cure, respectively in 86.7%, 52.3%, and 44.6%.

Surgical treatment of recurrence with curative intent was 40.9% in the minimum follow-up group (no CEA and standard imaging), 66.3% in the CEA and standard imaging group, 50.7% in the no CEA and CT, and 59.5% in the maximum follow-up group (CEA & CT) (p=0.0035). Among recurrences in rectal cancer, 19.3% were localized, 65% metastatic, and 15.7% both. These patients were treated with curative intent, respectively in 50%, 53.7% & 38.5%.

Surgical treatment of recurrence with curative intent was 42.9% in the minimum follow-up group, 57.9% in the CEA group and standard imaging, 55% in the no CEA and CT, and 47.8% in the maximum follow-up group (NS). None of the follow-up modalities resulted in a difference in OS (second interim analysis - 455 events).

The investigators concluded that after curative surgery, the addition of CEA and/or CT does not provide any benefit in 5-year OS but allows more curative intent secondary surgeries for patients with a more intensive follow-up.

Subgroup Analysis from TOSCA Trial

Previous studies stating the combination of oxaliplatin and fluoropyrimidines as the standard of care for the adjuvant therapy of stage III colon cancer (CC) patients obtained non-convergent results and a reduced benefit for those over the age of 70 years.

Investigators assessed the impact of age (categorized as less or more than 70 years) on relapse free interval (RFI), defined as time from random to relapse or last disease assessment, in stage III colon cancer patients randomized to receive 3 or 6 months of FOLFOX (FULV plus oxaliplatin) or CAPOX (capecitabine plus oxaliplatin) in the Italian, multicenter, phase 3, TOSCA study.

The investigators used data from the 3,759 patients with colon cancer participating in the study. In TOSCA, the patients were randomized to receive either 3 or 6 months of FOLFOX (FULV plus oxaliplatin) or CAPOX (capecitabine plus oxaliplatin).

The analysis at ESMO comprised 2,360 patients with stage III disease; of these 1,667 patients were aged under 70 (younger cohort) and 693 were aged 70 or more years (elderly cohort).

Comparison of the cohorts regarding patient characteristics showed 10.5% of elderly versus 3.3% younger patients had ECOG performance status (PS) 1 (p<0.001), 40.8% versus 45.1% female patients (p=0.057), and 90.9% versus 84.3% more T3/T4 tumors (p<0.001), respectively.

Elderly patients also had a greater number of poorly differentiated (G3) tumors than younger patients (28.3% vs 24.2%; p=0.039) and tumors that were located on the right side of the colon (40.9% vs 26.6%; p<0.001) respectively. Disease recurrence occurred more frequently in patients >70 years; recurrence rates were 24.2% in elderly compared with 20.3% in younger patients (p=0.033).

A significant impact on RFI was observed only with stage III high-risk versus low-risk colon cancer (HR 2.05; 95% CI, 1.71–2.46; p<0.001)

Compared with younger patients, elderly stage III colon cancer patients treated with an oxaliplatin-based adjuvant therapy had a different treatment tolerability and a potential reduction of benefit. Considerations should be made about the patient's general health status, comorbidities and the management of the expected side effects.