ASCO 2024: 'The Oncologist Without the Pathologist Is Blind'

This transcript has been edited for clarity. 

Hello. I'm Mark Lewis, director of gastrointestinal (GI) oncology at Intermountain Health in Utah. I'm speaking from the 2024 ASCO Annual Meeting in Chicago, where we've seen some interesting, new data in GI cancers. 

If you allow me, I'd like to go in a craniocaudal fashion. It's my anatomic mnemonic. I think that's appropriate because our plenary session yesterday kicked off with some exciting data in esophageal cancer, specifically esophageal adenocarcinoma. 

This was the long-awaited ESOPEC trial. It's a phase 3 study looking at perioperative FLOT (5-FU/leucovorin/oxaliplatin/docetaxel), a chemo triplet, vs the CROSS protocol, which is neoadjuvant chemoradiation with carboplatin and paclitaxel. The primary endpoint was overall survival, and at first blush, FLOT looked to be the true winner. There were some really remarkable milestones in this study, and I have some reservations about the FLOT arm that I'll raise in just a second. 

The investigators are to be commended because in a truly deadly disease, they reported a 5-year overall survival in half of the patients who were receiving FLOT. That is truly commendable and really a milestone in our field. The reason I take a little bit of issue with the trial is that I still have some questions about methodology.

It wasn't that long ago at ASCO GI that there was a really heated debate called "FLOT or Not" — not in this precise setting, but asking the question, do we think that patients with upper GI malignancy are even fit enough to handle a chemo triplet like FLOT? 

The reason I bring that up now in 2024 is that, to my surprise, and I think to many others', there was a lower-than-expected completion rate of the patients in this trial who were receiving the CROSS regimen. The number of people who were able to complete that in full was about two thirds, which compared with a historical control from a trial scheme that first emerged over a decade ago that used to be over 90% completion. I found that quite strange. 

I also think this trial suffers a little bit, and unavoidably, from the evolution of care that's happened since it was first enrolling. Of course, I refer to adjuvant immunotherapy. Now, the real question is whether there is synergy between patients who receive radiation upfront and then adjuvant nivolumab, as per CheckMate 577. 

In her plenary discussion, I thought Dr Karyn Goodman did a masterful job — I would encourage you to watch it on ASCO's website —discussing how we can take all these data and reconcile them for optimal patient outcome. She ultimately suggested that we might deploy all four modalities in the management of these people. 

She proposed a paradigm with a PET-adapted, upfront induction chemotherapy, then moving to chemoradiation, then moving to surgery, and finally moving to immunotherapy. That is all four of the traditional arms of oncology. I find that really rather remarkable. Watch that space. This is a great trial with really remarkable survival data, but I'm not entirely convinced that the CROSS arm was given its due. 

Next up, I want to talk about pancreas cancer, which is something near and dear to my heart. It affects about 1 in 4 of my patients and it remains, unfortunately, a highly lethal disease. I think the topline news from this meeting is that the KRAS mutation is druggable. I'm probably showing my age, but when I did my fellowship in 2009 through 2012, I was taught that KRAS was sort of the undruggable mutation par excellence. At this meeting, we've seen maturing data in regard to targeting KRAS G12C with both sotorasib and adagrasib. The disease control rates are astounding, at 80% and more, which is really remarkable. I wouldn't have believed that even a few years ago. 

I'm even more excited about how we bring a rising tide that can lift all boats and apply this to other KRAS mutations, and not just KRAS G12C but all KRAS mutations. I think that's coming, hopefully, with the pan-RAS inhibitors, because once that happens — if that happens; I'll try not to be irrationally exuberant — that would take the traditional mutation found in almost all pancreas cancers and really make it its own Achilles heel. I think that could be such a huge leap forward. 

Another matter, however, that remains unresolved at this meeting is in the neoadjuvant setting with pancreatic ductal adenocarcinoma. There's still equipoise, actually, between neoadjuvant gemcitabine, paclitaxel, and FOLFIRINOX. I thought that that was very well spelled out by some of our Dutch colleagues, who continue to do great work in a variety of cancers, including colorectal. 

Where I'd like to move next is colorectal cancer. Of course, immunotherapy remains a hot topic at all of these conferences. There were three different aspects of immunotherapy I'd like to highlight at this conference in regard to colon and rectal cancer. 

First, Dr Heinz-Josef Lenz presented updated data from CheckMate 8HW, which looked at nivolumab and ipilimumab (nivo/ipi) vs chemotherapy in the first line for MSI-high or mismatch repair–deficient colon cancer. Once again, the data we've had now for several years at the 2-year mark are incredibly impressive. The 2-year progression-free survival (PFS) rates for nivo/ipi are above 70% and down at around 14% for chemo. 

What was impressive about this meeting is that Dr Lenz presented PFS2, trying to determine the impact, if any, of subsequent therapy. What was going on here, which I think was ethically responsible by the investigators, was crossover. About two thirds of the chemo arm crossed over to any form of immuno-oncology (IO), and just under a half crossed over to nivo and ipi. The PFS benefits continued with upfront IO. The way that Dr Lenz phrased it is that you really never get the chance to win back the benefit that you would derive by giving immunotherapy first line to someone who has MSI-high or mismatch repair–deficient metastatic colon cancer. 

One thing that's still not settled in my mind, though, is, does this really dethrone single-agent immunotherapy, such as pembrolizumab in KEYNOTE-177? What I'm really driving at is the ipilimumab. Is the juice worth the squeeze? Is the addition of an anti-CTLA4 agent worth the toxicity that we know comes along with that mechanism of action? Watch this space. 

I was also really interested in NEOPRISM-CRC, which looked at the role of immunotherapy in neoadjuvant downstaging of radiographically high-risk stage II or stage III colon cancer. Here, the investigators really make a strong case that, up front in these potentially respectable cases, not only should we know about mismatch repair deficiency but we should actually be interrogating further for tumor mutational burden (TMB). 

They had TMB-high patients. In fact, the median TMB was 42 mutations per megabase, with really impressive downstaging using three cycles of every-3-week pembrolizumab before surgery. Again, I really think we're at an exciting time where, even for colon cancer that looks operable up front, we might actually have the opportunity to improve pathologic and clinical complete responses before and after surgery. 

Finally, I want to bring up what continues to amaze me. Two years ago, at ASCO 2022, we heard from Dr Andrea Cercek and the Memorial Sloan Kettering group about the incredible experience they were having with neoadjuvant, or frankly, definitive dostarlimab in mismatch repair–deficient locally advanced rectal cancer. 

I remember being at the conference and there was simultaneous publication of that abstract in The New York Times because it was so remarkable. There was a 100% clinical complete response. The patients didn't require radiation, they didn't require chemotherapy, and they didn't require surgery for locally advanced rectal cancer, provided there was this vulnerability of mismatch-repair deficiency. 

Now, 2 years later, Dr Cercek and her group have updated those data with more than 40 patients, and again, a 100% clinical complete response, including mature, complete responses at over a year in about 20 patients. Again, we are really doing our rectal cancer patients a disservice if we're not checking for mismatch-repair deficiency upfront, and especially if we're not talking about them in multidisciplinary conferences. 

One of the things that absolutely blows my mind about rectal cancer is just how complicated it's becoming. I think it is the standard of care to discuss these cases upfront with radiation oncology, surgical oncology, medical oncology, and pathology. 

Maybe the overarching message I would take from everything I've said today is that the oncologist without the pathologist is blind. It's really a dyad, a partnership that guides optimal medical oncology care. As much as I love ASCO, I often wish we had more of our pathology colleagues here. I look forward to taking all the findings from this meeting back to the tumor board and really having a dynamic dialogue. 

With that, I thank you for joining me. This is Mark Lewis, speaking for Medscape at the 2024 ASCO Annual Meeting in Chicago. Thank you.