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Second Line CRC
Biologic Therapies in Metastatic Colorectal Cancer: Mastering Your Moves Beyond First Line

Released: June 10, 2016

Expiration: June 09, 2017

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When managing patients with colorectal cancer, selecting treatment through subsequent lines of therapy can often feel like a chess match. Much like a chess player, you must understand the capabilities and limitations of each game piece, you must understand your opponent, and you must tailor your moves to each unique match. If we consider the biologic therapies available for colorectal cancer among our most powerful chess pieces, we must carefully consider how to use these drugs and in what order.

Second-Line Options in Patients With RAS Mutations
We now have 3 VEGF inhibitors (bevacizumab, ziv-aflibercept, and ramucirumab) approved for second-line treatment, and 2 EGFR inhibitors (panitumumab and cetuximab) approved for first-line and refractory treatment. When selecting among these therapies, we know the EGFR monoclonal antibodies will not benefit patients with RAS mutations, nor are they optimal in patients with BRAF mutations. In those patients, it is important to understand whether VEGF inhibition through subsequent lines of therapy is clinically meaningful. We have 3 large studies demonstrating a small (1-2 months) survival advantage with the use of second-line VEGF inhibitors in patients who previously received a VEGF inhibitor. The TML study is perhaps most relevant to our experience in the United States. In this study, patients who received frontline bevacizumab plus chemotherapy were randomized to receive second-line chemotherapy with or without continuing bevacizumab. Those who received second-line bevacizumab demonstrated a slight but statistically significant improvement in OS (1.4 months; P = .006). Because the improvements seen with continuing VEGF inhibition are small, this approach remains controversial. What we need in this setting is a biomarker to help discern which patients are benefitting. But for now, we must use our best clinical judgement. Personally, I would continue VEGF inhibition in patients with RAS mutations who have demonstrated a clear benefit from a frontline VEGF inhibitor. This includes patients with a very good initial response and a good maintenance therapy window with perhaps a year or more until progression. On the other hand, those patients with a much shorter course of first-line treatment before progression who do not respond as well to first-line VEGF inhibition would, in my opinion, not be good candidates for continuing VEGF inhibitors in second-line therapy.

When continuing VEGF inhibition into second-line therapy, the next logical question is, which of the 3 drugs should we use? Although they do have slightly different mechanisms of action, clinically they have not demonstrated any differences. I would argue that bevacizumab is the best choice because it has the most minimal adverse event profile and the lowest cost. Currently, an outstanding question for me is whether there is a benefit of switching VEGF inhibitors in second-line therapy. I have yet to see evidence, anecdotal or otherwise, that switching adds benefit.

Second-Line Options in Wild-Type RAS Patients
In patients with wild-type RAS who have progressed beyond first-line therapy, we can choose among the VEGF inhibitors and the EGFR inhibitors. Although the FDA has not approved EGFR inhibitors in the second-line setting, the NCCN guidelines do recommend them. Thus, if a patient did not receive an EGFR inhibitor as first-line treatment, they may be a good candidate for second-line treatment with one of these agents. I consider the EGFR inhibitors to be very useful chess pieces in the wild-type RAS patient. They have significant impact on tumor regression (although they are associated with a rash adverse event). In some cases, it makes sense to use the EGFR inhibitors in the second-line setting. In others, it is wise to hold this valuable piece for subsequent lines of therapy. In my practice, I employ second-line EGFR inhibitors in wild-type RAS patients who have symptomatic progression into second line. Even if they may have responded fairly well to first-line therapy with bevacizumab, I choose to give second-line irinotecan plus panitumumab to ensure a response in this scenario. Indeed, we can get very good responses with this strategy and then back off on the treatment into a maintenance setting. Again, the order of therapies is not set in stone. As clinicians, we must decide when to play the pieces available to us.

Third-Line Options
Finally, there is now a third-line option with VEGF inhibition. Regorafenib can be considered for third-line treatment in patients with RAS mutations who have received VEGF inhibition in the first- and second-line settings. The evidence supports survival improvement with regorafenib in the refractory setting, which may be related to continuing VEGF inhibition. Alternatively, if you have not used an EGFR inhibitor in a patient who has progressed beyond second-line therapy, I would recommend playing that chess piece in the third-line setting. It would not be wise to hold that powerful piece any longer; it is better to get a response.

Your Thoughts
How do you use biologic therapies for metastatic colorectal cancer through subsequent lines of therapy? Answer the polling question and post your thoughts in the comments section below. And check back soon for my next ClinicalThought™ commentary on managing metastatic colorectal cancer.