COMMENTARY

ASCO 2020: GI Cancer Highlights From David Kerr

David J. Kerr, CBE, MD, DSc, FRCP, FMedSci

Disclosures

June 26, 2020

This transcript has been edited for clarity.

I'm David Kerr, a professor of cancer medicine at the University of Oxford, working from my kitchen table as I look at the virtual ASCO meeting.

I wanted to mention a couple of presentations and some of the excellent work presented from around the world. I'll review the colorectal cancer data that I found interesting and I think will be impactful for the future, including some data that support some of the clinical decisions that we are already making in our multidisciplinary team in Oxford.

The first of these was a report of a phase 2, multicenter, open-label study of a drug-antibody conjugate, trastuzumab deruxtecan, a topoisomerase I inhibitor, in patients with HER2-expressing metastatic colorectal cancer.

We know that these patients are a relative minority, but again, if we can start to segment the total population of colorectal cancer patients with targeted personalized medicine, this has to be the future. To an extent, we're doing this already.

These were patients who had progressed on two prior treatments and all had received previous treatment with irinotecan, so you'd expect that they may be relatively resistant at a cellular level to further treatment with topoisomerase I inhibitors.

The investigators recruited 78 patients. Importantly, despite being heavily pretreated and receiving third-line treatment, these were patients who were in relatively good shape in terms of having a performance status of 0-1. They had a response rate of 44%, which is fantastic. They had a median progression-free survival of almost 7 months. In the third-line setting, these are pretty remarkable results.

Overall, the drug-antibody conjugate was pretty well tolerated. There was neutropenia and anemia, and there was an unusual side effect that you need to watch out for very carefully. Five patients (6.4%) developed interstitial lung disease, which was attributed to the therapeutic treatment. Nevertheless, it's one that we should watch out for in the future and one that I'm sure will enter phase 3 randomized trials.

The next study that caught my eye was the PANDA study, coming from a distinguished group of Italian investigators, suggesting that we should pay more care to how we look after our elderly patients. These are patients who have reduced muscle mass, altered pharmacokinetic profiles in terms of drug clearance, lost renal mass, etc.

Therefore, it would seem reasonable pharmacologically to think about how we might be able to reduce the intensity of treatment in these patients. That's what the Italian investigations looked at in a relatively good prognostic group.

The trial was a first-line FOLFOX plus panitumumab versus 5-FU/leucovorin plus panitumumab in RAS-BRAF wild-type metastatic colorectal cancer in patients who were aged 70 years and above. They managed to randomize 185 patients.

They demonstrated that the response rates were approximately equivalent. Median progression-free survival for the FOLFOX/panitumumab arm was 9.6 months and in the other arm it was 9.1 months, so no difference at all.

There was a big difference in the pattern of side effects, hugely favoring the 5-FU/leucovorin/panitumumab arm compared with the FOLFOX arm, which had more neutropenia, diarrhea, mucositis, and, of course, neuropathy.

These authors suggest an infusion of 5-FU, leucovorin, and panitumumab with panitumumab maintenance until disease progression as an entirely reasonable treatment to offer elderly patients, in whom we are perhaps a little worried about the additional toxic burden from adding oxaliplatin.

Of course, it requires further investigation in phase 3 trials looking at survival and so on. Nevertheless, it was an interesting observation in a group that we must pay increasing attention to.

The next study is from a colleague of mine, Charlie Fuchs. We were interested in the possibility that by inhibiting the COX-1/COX-2 pathway by altering the tumor microenvironment with these anti-inflammatory drugs, we might be able to reduce recurrence in the adjuvant setting.

This is a report of celecoxib in addition to standard adjuvant therapy with 5-FU, leucovorin, and oxaliplatin (FOLFOX) in stage III colon cancer. This was the CALGB/SWOG 80702 study and it was reported by Jeff Meyerhardt. They randomized 2500 patients into a nice 2 x 2 design: celecoxib versus placebo; 3 versus 6 months of FOLFOX. And yet, the addition of celecoxib was of no advantage whatsoever.

We now have our negative rofecoxib study that we reported in the New England Journal of Medicine some years ago and a negative celecoxib study. We still have some aspirin studies out there. Of course, aspirin benefits by inhibiting both COX-1 and COX-2 rather than the more COX-2–selective celecoxib and rofecoxib.

We'll have to wait and see what happens with the aspirin studies. This study was well designed from a great group, but ultimately this was a rather disappointing result.

The next study is from Japan and it does very much reflect our clinical practice in our hepatobiliary multidisciplinary tumor board, where we see all of our patients presenting for potential hepatic metastasectomy or ablation. I think the literature is muddied about the use of postoperative adjuvant chemotherapy.

In Bernard Nordlinger's very nice EORTC study, preoperative chemotherapy, surgery, and postoperative chemotherapy improved progression-free survival but had no impact on overall survival. Therefore, is it worthwhile to apply that chemotherapy?

This Japanese group came together to compare hepatectomy followed by mFOLFOX6 versus hepatectomy alone for liver metastases from colorectal cancer. This is a very distinguished group, again, with several of my friends contributing to this trial.

They randomized 300 patients 1:1 to surgery versus surgery plus postoperative chemotherapy. Interestingly, the 3-year disease-free survival was 52% with chemotherapy and 41.5% with surgery alone, so there was a difference in disease-free survival.

However, median overall survival did not change. In fact, median overall survival after recurrence was 38.4 months in the chemotherapy arm and 87.6 months in the surgery-alone arm.

We see no correlation between disease-free and overall survival in this setting. Postoperative chemotherapy with mFOLFOX6 within the confines of this trial improves disease-free survival but worsens overall survival compared with surgery alone. Therefore, I don't think there's any role for the use of postoperative adjuvant FOLFOX or other associated chemotherapies after hepatectomy for liver metastases.

I think that's clear. We have tended not to offer that in our clinic in Oxford because my interpretation of the data was in line with the results that our Japanese colleagues have just produced. It reinforces the clinical practice that we have adopted.

As always, ASCO was a good meeting. There was an interesting mixture of the old — celecoxib — and the new, with the drug-antibody conjugate. The reassuring fact is that I think we have definitive evidence now that we should not be offering postoperative adjuvant chemotherapy for patients with resected liver metastases.

Thanks for listening. I'm interested in what other highlights you picked up at ASCO in terms of colorectal cancerology, and whether you agree with my rather black-and-white interpretation of these data that were presented from the studies I mentioned.

I'm looking forward to any comments that you might have to post. Thanks for listening.

David J. Kerr, MD, is a professor of cancer medicine at the University of Oxford in Oxford, England. He is recognized internationally for his work in the research and treatment of colorectal cancer, and has founded three university spin-out companies: COBRA Therapeutics, Celleron Therapeutics, and Oxford Cancer Biomarkers. In 2002, he was appointed Commander of the British Empire by Queen Elizabeth.

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