First-Line Therapy Options for mCRC
Dr Bekaii-Saab discusses therapy options for first-line treatment of metastatic colorectal cancer.
Tanios Bekaii-Saab, MD, FACP: For the first-line options, there are several options for patients [with metastatic colorectal cancer]. Things that we have to take into consideration include the age of the patient, the symptoms, the performance status, and the molecular profiling. This is a relatively younger patient, age 65, who presented with obstruction; that’s why he ended up in surgery. He was quite symptomatic. Although he had recovered by the time of the decision to proceed with chemotherapy, he was still closer to 1 on his performance status. There are a number of options for this patient who’s healed: FOLFOX [5-fluorouracil, leucovorin, oxaliplatin], FOLFIRI [5-fluorouracil, leucovorin, irinotecan], capecitabine-oxaliplatin, FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan] plus bevacizumab. I’ve been moving more patients in my clinic who are younger and healthier into FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan]–bevacizumab based on the TRIBE2 data, and those data certainly confirm the value of the triplet over doublet.
In this case, it appears that the patient was still relatively symptomatic, so moving to a doublet of FOLFOX [5-fluorouracil, leucovorin, oxaliplatin] or FOLFIRI [5-fluorouracil, leucovorin, irinotecan] is a reasonable first-line option. Bevacizumab appears to add value to FOLFOX [5-fluorouracil, leucovorin, oxaliplatin], FOLFIRI [5-fluorouracil, leucovorin, irinotecan], and capecitabine-oxaliplatin for that matter. Although the addition is relatively modest, it’s there and it’s important to add bevacizumab to those agents, to the chemotherapy backbone. The choice of chemotherapy typically depends on all these factors, and the differences between FOLFOX [5-fluorouracil, leucovorin, oxaliplatin] and FOLFIRI [5-fluorouracil, leucovorin, irinotecan] are very minimal. They’re mostly based on toxicities. I prefer FOLFIRI [5-fluorouracil, leucovorin, irinotecan] over FOLFOX [5-fluorouracil, leucovorin, oxaliplatin] for most patients, but a lot of second-line studies appear to favor FOLFOX [5-fluorouracil, leucovorin, oxaliplatin] in the first line.
In terms of the patient’s recovery, at least from the wound-healing standpoint, it’s sufficient enough to proceed with chemotherapy and no concerns about bevacizumab. EGFR inhibitors in this case would be contraindicated because of the presence of KRAS. Interestingly, we’re seeing these KRAS G12Cs in about 2.5% of patients with colorectal cancer. That doesn’t change how I would treat someone in the first line. But I can tell you that this patient did not have a G12C, and that isn’t something that was of concern for this particular patient, but it’s important for many patients, especially when we’re thinking about lines beyond first with agents being developed in that stage.
The chemotherapy regimen was started with FOLFOX [5-fluorouracil, leucovorin, oxaliplatin]. Unfortunately, the patient appeared to have a significant neuropathy that led to the drop of oxaliplatin. Typically, in my practice, I aim for 6, maybe 8 cycles of FOLFOX [5-fluorouracil, leucovorin, oxaliplatin] before I drop to a maintenance strategy. In this particular patient, the toxicity came earlier, and the patient ended up with only 4 cycles of FOLFOX [5-fluorouracil, leucovorin, oxaliplatin]. The decision was to switch him to capecitabine and bevacizumab, the maintenance strategy in this case. Unfortunately, it didn’t seem to hold his cancer for too long, and he ultimately progressed.
Six cycles of oxaliplatin is probably more than optimal. In fact, the way I discuss this with colleagues and trainees is if we look at the totality of the data across multiple studies over the last 2 decades, 1 thing 1 can say with certainty is that in the first-line setting, patients did not need exposure beyond 3 to 4 months with FOLFOX [5-fluorouracil, leucovorin, oxaliplatin], FOLFIRI [5-fluorouracil, leucovorin, irinotecan], and now FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan].
Whichever of those 3 backbones you choose, patients do not need to be exposed beyond 3 to 4 months. I tend to go for 3. The studies have been mostly around the fourth month, but many are around the third. It seems that you reach your plateau of efficacy around 3 months, but you also start to see worse toxicities at that level. Should we have changed the patient by a couple of cycles that could that have affected the outcome? Probably not. I don’t think so, but you didn’t have a choice since the patient developed this significant neuropathy.
This transcript has been edited for clarity.
Case: A 65-Year-Old Man With Metastatic Colorectal Cancer
Initial presentation
- A 65-year-old man reported a 2-month history of constipation, bloating, abdominal pain, and 10-pound unintentional weight loss
- PMH: Mild hypertension controlled with calcium channel blockers
Clinical workup
- Labs: Hg 9.4 g/dL, LFTs elevated and CEA 80 ng/mL
- Colonoscopy revealed a 5-cm completely obstructing mass in sigmoid colon
- Patient underwent left hemicolectomy with diverting ostomy
- Pathology: undifferentiated adenocarcinoma tumor invading through muscularis propria and extending into the pericolorectal tissue with5 of 12 resected nodes positive
- CT scan showed several lesions in both lobes of the liver, measuring up to 15 mm in diameter, and 3 small lesions (<5 mm) in the left lower pulmonary lobe
- Molecular testing: KRAS mutation in codon 12 of exon 2; microsatellite stable
- Diagnosis: Stage 4 colorectal cancer
- ECOG PS is 1
Treatment
- The patient received systemic therapy with FOLFOX + bevacizumab in the first line for 4 cycles
- The patient developed neuropathy and was switched to capecitabine + bevacizumab for 4 months and then unfortunately progressed, residual neuropathy at G1
- At that time he was switched to FOLFIRI + bevacizumab
- 6 months later, clinical progression is confirmed when new lung metastases are seen on chest CT
- The patient was switched to regorafenib
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