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ASCO 2020: Major trials in GI cancer for Indian Oncologists: Dr. Vishwanath S

M3 India Newsdesk Jun 05, 2020

Dr. Vishwanath Sathyanarayanan picks notable trials in gastrointestinal cancer presented at this year's American Society of Clinical Oncology (ASCO) 2020 live virtual meeting and lends his take to each of them.

Oesophageal and gastric cancer

RAMSES/FLOT-7

A larger phase III trial is required before we draw conclusions and use this regimen in the clinic.

This phase 2 trial looked at FLOT plus ramucirumab vs FLOT followed by surgery in esophagogastric adenocarcinoma. 40% of the cohort had signet ring cell carcinoma. Results showed an improved R0 resection rate (97 vs 83%) and it was considered safe in majority.


DESTINY-Gastric01 phase 2 trial

In patients with HER2-positive metastatic gastric cancer previously exposed to trastuzumab, trastuzumab deruxtecan seems to be a reasonable option with impressive response rates and 4.1 months of survival advantage.

Approximately 15 to 20% of gastric adenocarcinomas express HER2. Trastuzumab deruxtecan significantly improved ORR (51% v 14%) and OS (12.5 v 8.4 mo), as compared with standard therapies, among patients with previously treated HER2-positive gastric cancer.


Pancreatic cancer

SWOG S1505: Results of perioperative chemotherapy (peri-op CTx) with mFOLFIRINOX versus gemcitabine/nab-paclitaxel (Gem/nabP) for resectable pancreatic ductal adenocarcinoma (PDA)

Both mFOLFIRINOX or gemcitabine/nab-paclitaxel (Gem/nabP) seem to give equivalent results in locally advanced, resectable pancreatic-ductal carcinoma in the neoadjuvant setting. The decision on choosing either regimen should be based on the patient's age, ECOG performance status and comorbities, as mFOLFIRINOX is better tolerated in younger and fit patients.

S1505 was a randomised phase II trial of peri-op CTx (12 weeks pre-, 12 weeks post-op) with either mFOLFIRINOX or Gem/nabP. Two-year OS was 41.6% and 48.8%; median OS was 22.4 months and 23.6 months statistically not significant). Median disease-free survival (DFS) after resection was 10.9 months and 14.2 months (p=0.87). Percentage of R0 resection is both arms was 85% and surgical resection rate of 73% and 70%.


ESPAC 5F

Neoadjuvant FOLFIRINOX may be considered in selected fit patients as a neoadjuvant approach.

Phase 2 trial of neoadjuvant GemCAP or FOLFIRINOX or CT/RT Vs immediate surgery in borderline resectable pancreatic adenocarcinoma:No difference in resection rate of immediate surgery vs neoadjuvant therapy (62 vs 55%, p-NS). Neoadjuvant treatment showed OS advantage at 1 yr (77 vs 42%) with FOLFIRINOX demonstrating the best survival with higher toxicity.


Colorectal cancer

IDEA study: Updated results for 3 months vs 6m adjuvant chemotherapy with a 6-year follow up

This trial is definitely practice changing. 3 months of adjuvant CAPOX may be sufficient for a vast majority of stage III colon cancer patients. In case FOLFOX is used, for high risk disease, 6 months is advisable.

Patients (12,835) were randomised, 3 months of treatment was 2-6 times less toxic and less neurotoxic (14 vs 46%). Three months of adjuvant chemotherapy led to similar 3 year DFS and 5 year OS and DFS for most stage 3 colonic malignancies.

  • Low risk (T1/T2/T3;N1): 3 months of CAPOX sufficient
  • High risk (T4/N2 or both): Minimal loss in DFS and OS with 3 months of CAPOX and significant loss with 3 months of FOLFOX

KEYNOTE-177

The new era for 1st-line immunotherapy in MSI-high/MMR-deficient metastatic colorectal cancer dawns. Pembrolizumab has doubled the PFS as compared to chemo (median 16.5 months vs 8.2 months; HR 0.60; 95% CI, 0.45-0.80; P=0.0002). The overall response rate was also impressive at 44% with 11% achieving a complete response. Moreover, it was well tolerated.

Note: MSI-high colorectal cancer patients represent only 5% of all metastatic colorectal cancers.

A total of 307 pts with MSI-H/dMMR mCRC as determined locally and ECOG PS 0 or 1 were randomly assigned 1:1 to first-line pembro 200 mg Q3W for up to 2 years or investigator’s choice of mFOLFOX6 or FOLFIRI Q2W ± bevacizumab or cetuximab (chemo chosen prior to randomisation). Treatment continued until PD, unacceptable toxicity, pt/investigator decision to withdraw, or completion of 35 cycles (pembro only). Patients receiving chemo could crossover to pembro for up to 35 cycles after confirmed PD. Primary end points were PFS (RECIST v1.1, central review) and OS. Key secondary end points included ORR (RECIST v1.1, central review), and safety.


RAPIDO trial

This may become practice changing in certain high-risk rectal carcinomas with impressive pCR rates. However, longer follow up is required to assess OS.

This was a phase 3 trial in locally advanced high risk rectal adenocarcinomas and patients were randomised to the conventional NACT/RT followed by surgery and adjuvant chemotherapy vs pre-operative short-course radiotherapy followed by chemotherapy and TME. The results showed a lower rate of disease-related treatment-failure (7% lower) and distant metastasis (7% lower)and higher pCR rate over conventional CRT (14% higher) and similar 3 year OS at 89% with no added toxicity.


DESTINY-CRC01 study

Though Her2 positivity is seen in <5% of patients with mCRC, T-DXd will be a valuable addition in these patients. However, this drug is currently not available in India.

In this phase II trial presented by Siena and colleagues, patients with metastatic CRC with Her2 expression and RAS/BRAF wild type and having with atleast 2 prior chemotherapeutic regimens with prior Her2 based therapy allowed were randomised to trastuzumab deruxtecan (T-DXd, a novel antibody drug conjugate-humanized anti-Her2 IgG1 mAb) at 6.4 mg/kg q 3 weekly. Close to 90% of the patients had a left sided tumour. IHC 3+ was seen in 75% and 25% had IHC 2+ with FISH positivity. The ORR amongst 53 patients was 45.3% with 1.9% achieving a CR. The disease control rate was impressive at 83% and DOR not reached (4.2 m-NE). The median PFS was 6.9 months and median OS not reached. The responses were mainly noted in Her2 IHC 3+ and very minimal in IHC2+ and 1+. It was well tolerated except for ILD which was seen in 6.4% of the patients which requires careful monitoring.


PANDA study

The PANDA study supports the use of less cytotoxic chemotherapy in older patients with metastatic colon cancer. The elderly generally do not tolerate oxaliplatin and this study has shown that oxaliplatin can possibly be avoided without compromising the outcome. 70% of patients had abnormal geriatric screening. Larger phase 3 studies are required to further justify this observation and its usage.

This phase 2 study was done specifically to address the role of simplified FOLFOX vs 5FU/LV in combination with panitumumab in elderly (>70 years of age) unresectable/metastatic RAS/BRAF wild type CRC. At a median follow up of 20.5 months, the median ORR was 65% vs 57%; disease control rate 88% vs 86%; PFS 9.6 months vs 9.1 months (FOLFOX +Pan Vs 5FU/LV + Pan respectively). Neutropenia, diarrhoea, stomatitis and neurotoxicity were higher in the FOLFOX with Pan arm. The trial met its primary endpoint of non-inferiority in ORR, DCR, and PFS


PRODIGE 23

Neoadjuvant mFOLFIRINOX plus CRT is safe and significantly increased ypCR rate, DFS and MFS in resectable, locally advanced rectal cancer. It may represent a new standard of care in young and fit patients with locally advanced rectal cancer who are able to tolerate mFOLFIRINOX.

In this phase III trial, neoadjuvant mFOLFIRINOX before preoperative (preop) chemoradiation (CRT), with TME-surgery and adjuvant chemotherapy (CT) was compared with neoadjuvant CT/RT followed by surgery and adjuvant chemotherapy in resectable locally advanced rectal cancer. 3-yr DFS was significantly increased in the FOLFIRINOX arm (HR 0.69, 95% CI 0.49-0.97, p=0.034): 75.7% (CI: 69.4-80.8) vs 68.5% (CI: 61.9-74.2). 3-yr MFS was also significantly higher in the mFOLFIRINOX arm 78.8% vs 71.7 % (HR 0.64, CI 0.44-0.93, p<0.02).


BEACON CRC (Encorafenib, BRAF -) plus cetuximab with or without binimetinib, MEK -) for BRAF V600E metastatic colorectal cancer in comparison with chemo+ cetuximab (control arm)

The doublet of BRAF- with cetuximab gives equivalent OS as a triplet of BRAF- with MEK- with cetuximab.

Results of this phase 3 trial showed that ORR, PFS and OS better in doublet and triplet vs SOC (control arm). Updated overall survival analysis from BEACON trial, showed no difference in median OS (both 9.3 months) for encorafenib/binimetinib/cetuximab vs encorafenib + cetuximab without binimetinib (post-hoc analysis) and ORR 27% vs 20% respectively.

 

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The writer, Dr. Vishwanath Sathyanarayan is a Medical Oncologist from Apollo Hospitals, Bangalore with a fellowship from MD Anderson Cancer Center.

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