GI Cancer Research Lends Insight Into the Future of Chemotherapy Combinations and Sequencing

Mark Lewis, MD

Updated clinical trial findings in gastrointestinal (GI) cancer indicate potentially practice-changing treatment methods and invite more careful consideration of how clinical research is conducted in patients with colorectal cancer (CRC), pancreatic cancer, and rectal cancer, according to Mark Lewis, MD.

Among CRC data shared at the 2023 ASCO Annual Meeting were the negative results of the phase 2/3 NorPACT-1 trial (NCT02919787), in which patients with resectable pancreatic head cancer who received neoadjuvant leucovorin, fluorouracil, irinotecan hydrochloride, and oxaliplatin (FOLFIRINOX) had a median overall survival (OS) of 25.1 months (95% CI, 17.2-34.9) and those who received upfront surgery had a median OS of 38.5 months (95% CI, 27.6-not reached), demonstrating that neoadjuvant chemotherapy did not improve OS compared with upfront surgery (P = .096).¹

“To be honest, and to have some degree of intellectual humility, we need to admit when [trials] didn't work out the way we hoped,” Lewis said of NorPACT-1 in an interview with OncLive^® News Network: On Location during the 2023 ASCO Annual Meeting.

Additional data presented at the meeting included findings from the phase 2/3 PROSPECT trial (NCT01515787), which showed disease-free survival noninferiority with neoadjuvant fluorouracil and oxaliplatin (FOLFOX) vs preoperative chemoradiotherapy in patients with locally advanced rectal cancer (HR, 0.92; 90.2% CI, 0.74-1.14; P = .005).²

In the interview, Lewis discussed his insights on data presented at the meeting, including the contested designs of the NorPACT-1 trial and phase 3 NAPOLI 3 trial (NCT04083235); where fam-trastuzumab deruxtecan-nxki (Enhertu) falls in the HER2-positive metastatic CRC treatment paradigm based on findings from the phase 2 DESTINY-CRC02 trial (NCT04744831); and how the PROSPECT trial results can improve quality of life (QOL) for patients with rectal cancer.

Lewis is the director of Gastrointestinal Oncology at Intermountain Health in Murray, Utah.

OncLive: How do the results of the NorPACT-1 trial highlight continued unmet needs in patients with pancreatic cancer?

Lewis: I'll start with a bit of disappointment. We are still trying to figure out what to do in pancreatic cancer, and specifically in operable pancreas cancer.

Coming into the 2023 ASCO Annual Meeting, I was hopeful that the NorPACT-1 trial would finally give us the clarity we are looking for. It did not. It is still unclear whether we should be [giving] chemotherapy before surgery.

I need to give up biological plausibility if the evidence says otherwise, but my personal bias is that it makes sense to give these patients treatment before surgery [because] you can downstage the tumor and make the operation easier. But also, then we're selecting, by disease biology, patients whose disease is unlikely to metastasize. In my opinion, the worst thing about this disease is it's only cured in the operating room, and yet it has an infamously strong tendency to metastasize. We have not helped these patients if we operate and then they develop metastases months later. We're still trying to figure that out. I'm hoping data that mature later in 2023 will give us that answer.

[The NorPACT-1 trial had] a tricky schema. Many of us have some questions about exactly how the randomization went, and perhaps more importantly, [how the] design [may have affected outcomes]. If you're going to give chemotherapy before pancreatic cancer surgery, you should give probably up to 6 months of it. The [investigators of this] trial, perhaps to make the chemotherapy more tolerable, gave 2 months of chemotherapy and then sent patients to surgery, knowing that most patients would need 4 more months of chemotherapy [after surgery]. That's a big ask of these patients, that they recover from such a major surgery and then jump right back into chemotherapy. That may have been the fatal flaw [of this trial].

What are the implications of the findings from the NAPOLI 3 trial in patients with metastatic pancreatic cancer?

This was also an interesting trial. The aspect about NAPOLI 3 that is of interest and importance is the composition of the liposomal irinotecan, 5-fluorouracil, leucovorin, and oxaliplatin [NALIRIFOX] regimen. It is essentially FOLFIRINOX, but conventional irinotecan is [substituted by], at some expense, nanoliposomal irinotecan.

We need to question or critique the study design. I don't think the control arm here [should be] gemcitabine and nab-paclitaxel [Abraxane] as was [designated] in this trial. I think the control arm [should be] conventional FOLFIRINOX, if we're going to move the needle. I think many oncologists feel similarly.

In an interesting and eye-opening discussion of this presentation, the presenter said that in exchanging these 2 drugs, this [regimen costs] roughly $5,000 more per cycle, and that for that increased cost, we expect better efficacy. I don't know if we can see that because it's not being compared against the proper triplet.

How do the primary results from the DESTINY-CRC02 trial augment the data from the phase 2 DESTINY-CRC01 trial (NCT03384940)?

DESTINY-CRC01 investigated trastuzumab deruxtecan, an interesting and exciting antibody-drug conjugate [ADC] with applications in a host of HER2-overexpressing or -amplified cancers, most famously breast cancer. In DESTINY-CRC01, we got the signal of [a 45.3%] response rate when applying this ADC in essentially the last-line setting in HER2-positive metastatic colon cancer. That's a big deal.

DESTINY-CRC02 wasn't dose finding, exactly. However, it's well known that there are 2 dose levels you can start this drug at: 6.4 mg/kg and 5.4 mg/kg. That doesn't sound like a big deal. However, I always tell my patients that in oncology, every milligram matters. In DESTINY-CRC02, it appeared that the 5.4 mg/kg dose was optimal for balancing risk and benefit. Prior anti-HER2 therapy was allowed.

What we learned most of all is that the [patients with] strong HER2 expression, [those with 3+] on immunohistochemistry [IHC] for HER2, do the best, but [patients can still] benefit if they are IHC 2+. That's important and a distinction from the [phase 3] DESTINY-Breast04 trial [NCT03734029], which received a deserved standing ovation at the 2022 ASCO Annual Meeting. That's when we learned that this drug works in HER2-low breast cancer. However, it does not demonstrably work in HER2-low CRC.

What did the PROSPECT trial reveal about preoperative treatments in patients with locally advanced rectal cancer?

This is the second consecutive year that I've seen something presented at ASCO on a Sunday that was simultaneously published in the New York Times. As a GI oncologist, I don't just exist in this world. I have friends and family. My phone erupted with questions and excitement about rectal cancer. What a weird and wonderful world we live in.

Traditionally, rectal cancer has been the GI cancer par excellence for 3 disciplines: radiation, chemotherapy administered by medical oncologists, and surgery. This [research] was prescient; the investigators started this trial over a decade ago. They asked: For high rectal cancer, can you omit radiation, have chemotherapy do the heavy lifting, and still have the same cancer-related outcomes?

The answer was yes. Although chemotherapy is not easy and has its own adverse effects, the omission of radiation to the pelvis has a host of long-term QOL benefits, including for young women interested in fertility preservation. I have many young women in my practice who have had to undergo ovarian transposition to move the ovary out of the radiation field. This is practice changing for them, and it'll be practice changing for our next tumor board.

References

1. Labori KJ, Bratlie SO, Biörserud C, et al. Short-course neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer: a multicenter randomized phase-II trial (NORPACT-1). J Clin Oncol. 2023;41(suppl 17):LBA4005. doi:10.1200/JCO.2023.41.17_suppl.LBA4005
2. Schrag D, Shi Q, Weiser MR, et al. PROSPECT: a randomized phase III trial of neoadjuvant chemoradiation versus neoadjuvant FOLFOX chemotherapy with selective use of chemoradiation, followed by total mesorectal excision (TME) for treatment of locally advanced rectal cancer (LARC) (Alliance N1048). J Clin Oncol. 2023;41(suppl 17):LBA2. doi:10.1200/JCO.2023.41.17_suppl.LBA2