Continued CRC Research Informs Later-Line Disease Management

Howard S. Hochster, MD

Tumor placement and response to neoadjuvant chemotherapy can help clarify and personalize later-line colorectal cancer (CRC) treatment approaches, according to Howard S. Hochster, MD, FACP, who also emphasized the potential benefits of the paradigm’s expansion to include VEGF inhibitors, such as fruquintinib (HMPL-013).

“[Later lines of therapy are] still areas where we can test new drugs,” Hochster said. “For appropriate patients, please keep clinical trials in mind.”

In an interview with OncLive®, Hochster highlighted key updates in CRC research and management from the 2023 ASCO Annual Meeting, including findings from the phase 2/3 PROSPECT trial (NCT01515787), long-term follow-up data from the phase 3 PRODIGE 23 trial (NCT01804790), and results of the phase 3 NeoCol study (NCT01918527).

PROSPECT investigated neoadjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) vs neoadjuvant chemoradiotherapy in adult patients with T2 node-positive, T3 node-negative, or T3 node-positive rectal cancer who were eligible for sphincter-sparing surgery. At a median follow-up of 58 months, FOLFOX alone was noninferior to chemoradiotherapy for disease-free survival (DFS; HR, 0.92; 90.2% CI, 0.74-1.14; P = .0051).¹ Hochster contextualized these data within the greater rectal cancer treatment landscape, which he noted has largely shifted away from radiation approaches in patients eligible for chemotherapy and surgery alone.

He also discussed the potential future for fruquintinib, which was evaluated in patients with pretreated, metastatic CRC in the phase 3 FRESCO-2 trial (NCT04322539). In this study, fruquintinib generated a median overall survival (OS) of 7.4 months (95% CI, 6.7-8.2) vs 4.8 months (95% CI, 4.0-5.8) with placebo (HR, 0.66; 95% CI, 0.55-0.80; P < .0001).²

Hochster is a distinguished professor of medicine, the associate director for clinical research, and the director of Gastrointestinal Oncology at Rutgers Cancer Institute in New Brunswick, New Jersey, as well as the director of Oncology Research at RWJ Barnabas Health in New Jersey.

OncLive: Could you summarize some of the most exciting and informative updates in the management of CRC?

Hochster: The presentations at the 2023 ASCO Annual Meeting had some new information and some not-so-new information. The most important study, as highlighted by its presentation at the keynote session, was the PROSPECT trial. That was an important trial because it was a noninferiority trial of 1128 patients. [This trial asked]: Does every patient need to receive chemotherapy, radiation, and surgery for rectal cancer? Can we get rid of 1 of these modalities, namely radiation, for some patients?

The standard at that time was the 6-week chemotherapy/radiation program, 6 weeks of radiation with usually 5-fluorouracil or capecitabine [Xeloda] followed by surgery. That was the control arm. In the experimental arm, they gave neoadjuvant FOLFOX, and if patients had up to 20% [tumor] shrinkage on scans, they could skip the radiation. It was a noninferiority trial with many patients, showing no difference in DFS, maybe [DFS that was] a little better, with the neoadjuvant treatment, but certainly not worse. Therefore, we could save many patients from getting radiation.

How do the PROSPECT data compare with data and patient perspectives regarding nonoperative management of rectal cancer?

PROSPECT is a trial that’s time has passed. We’ve moved beyond that paradigm where most patients are getting neoadjuvant chemotherapy and chemoradiation with the hope of having nonoperative treatment, especially patients with low-lying rectal cancer. Essentially, at this point, instead of trying to spare patients radiation, we’re trying to spare patients surgery, such as an abdominal perineal resection. For patients with mid rectal cancer, where it’s an easy, low anterior resection, it’s perfectly reasonable at this point to treat with chemotherapy and if they have a good response, go on to surgery and avoid radiation. Patients have 2 different options, and for low-lying cancers, we have the option of nonoperative management and trying to have sphincter preservation.

How do the 7-year follow-up data from PRODIGE 23, which were presented at ASCO, inform treatment sequencing with chemotherapy, radiation, and surgery?

PRODIGE 23 had 6 cycles of induction FOLFIRINOX vs standard chemoradiation, surgery, and then adjuvant therapy. [This trial] moved half the chemotherapy before radiation in the experimental arm, and they made it more aggressive with FOLFIRINOX or FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, and irinotecan] for half the chemotherapy. This, according to the 7-year results, is better in almost every regard compared with standard treatment. That’s noticeable.

The DFS rate at seven years was 62.5% in the control arm and 67.6% in the chemotherapy arm. The OS estimate at 7 years was 76.1% with standard [treatment] vs [81.9% in the investigational chemotherapy arm]. [There is] a bit of a survival benefit that should be considered.

Today, for rectal cancer, one should consider starting with neoadjuvant chemotherapy. The only fly in that ointment is the randomized [phase 2] OPRA trial [NCT02008656] from Memorial Sloan Kettering Cancer Center [in New York, New York] that [asked whether we] should give chemotherapy then chemoradiation for nonoperative management or [whether we] should start with radiation and follow that with chemotherapy. It seems like radiation had a bit of a higher response. The problem there is, it takes longer for the radiation effects to have their full benefit, and you’re introducing some time bias by starting with radiation.

In general, if you start with chemotherapy and go on to radiation second, you may have lower complete response [CR] rates, but no difference in survival or local recurrence, so that’s probably a reasonable approach. For patients who you are trying to save from surgery, starting with radiation and going on to chemotherapy is also well supported by the literature and reasonable. We’re doing a trial at Rutgers Cancer Institute of chemoradiation first, then FOLFIRINOX of FOLFOXIRI, as you prefer, for 8 cycles, and then evaluation for surgery. We hope we’ll have a high pathologic CR rate with that approach.

In the metastatic setting, how do the findings from the phase 2 DESTINY-CRC01 trial (NCT03384940) intertwine with the results of abstract 3511 from ASCO, which showed a high prevalence of HER2 and HER3 mutations in patients with early-onset disease?

DESTINY-CRC01 was [performed in patients with metastatic disease] who’ve had prior regimens for HER2-overexpressing colon cancer. That’s approximately 4% or 5% of all colon cancer. If you just test patients with RAS wild-type disease, then [HER2 overexpression occurs in] approximately 8% to 10% of patients. You might miss a few [patients with] RAS-mutated, HER2-overexpressing [disease], but that doesn’t happen often.

DESTINY-CRC01 showed that the lower dose [of fam-trastuzumab deruxtecan-nxki (Enhertu) had a bit of a better response rate and was tolerated much better, so that’s what should be used. How that relates to early colon cancer with HER2 expression is hard to say because we have no adjuvant therapy based on HER2. That would be a hard trial to do and would take a long time, but it could be done.

Do you see the results of the NeoCol trial affecting your use of neoadjuvant chemotherapy in the locally advanced population?

This was a Scandinavian trial [that gave] chemotherapy before surgery for colon cancer. We have batted this around institutionally and in the cooperative groups for a long time. The problem is, we don’t know how to select patients for this approach. It’s hard to see the nodes. There’s a high inaccuracy rate for just computed tomography scans in that setting. You can’t do a good magnetic resonance imaging. [It’s difficult to see, especially in patients with] colon lesions that are higher up, who could benefit from neoadjuvant [therapy].

Additionally, today, with laparoscopic surgery, surgical resection is not as big a deal as it used to be. We need to have better imaging. If you just take clinical T3 and N0 patients, [who were allowed in] that study, you will be treating many patients with chemotherapy who don’t need it. I’d much rather use circulating tumor DNA postoperatively in stage II colon cancer to decide who needs treatment and who doesn’t, than trying to give all patients chemotherapy upfront. When we have better imaging, that’s a good approach that will potentially be beneficial, but we don’t know who great candidates will be.

In addition, the NeoCol trial was small. There were only [approximately] 125 patients in each arm, and it was a phase 3 trial, but [that population size is hardly that of] a randomized phase 2 trial, especially for this comparison between sequencing of modalities. The [investigators] didn’t show [that neoadjuvant chemotherapy] was worse.

We know from the [phase 2/3] FOxTROT trial [NCT00647530] that was previously presented by European investigators that [administering chemotherapy first] could be a little better for response rates and so forth, but it didn’t seem to make any major difference in survival in either trial. It’s not bad. If you have a patient who you’re concerned is not fit for surgery now that they’ve had a recent myocardial infarction or coagulopathy, [for example], you can give them chemotherapy before surgery, and the results are not worse. However, at this point, it seems like this is not the right approach for everyday patients with colon cancer.

What novel therapies are coming down the pipeline in the metastatic setting?

There are always great developments coming along. It’s an exciting time, because we have many treatments, and more are coming. Fruquintinib is an oral VEGF inhibitor. We were part of the phase 3 FRESCO-2 trial, which was a repeat of the Chinese trial that showed a survival benefit [with this agent]. This [trial] seems to also show a survival benefit in the US and Europe. That’ll be a new drug in the later-line setting after standard chemotherapy and targeted therapy.

All the patients [in that trial] had at least regorafenib [Stivarga] or trifluridine/tipiracil [TAS-102; Lonsurf], and some had both. This is a powerful VEGF inhibitor that has good response data and a survival benefit compared with placebo in a double-blind trial. Nobody knew what patients were getting, unless patients had a lot of hypertension that you couldn’t control. [Fruquintinib may] be approved by the FDA before November 2023. There will not be an Oncologic Drugs Advisory Committee meeting on that trial, so hopefully we’ll hear about the approval soon.

Other agents that are more investigational [include] KRAS inhibitors. We have KRAS G12C inhibitors approved in lung cancer, and [there is] some evidence of [the efficacy of these agents in] colon cancer. [These agents are] not approved yet [in CRC], but they may be. KRAS G12C still comprises a relatively small fraction of KRAS mutations [in CRC]. There are KRAS G12D– and KRAS G12V–directed drugs that will give us some good opportunities for patients with RAS mutations.

Also, a couple different companies are working on the use of personalized vaccines, which are based on neoantigens. Patients’ tumors are sequenced and run through a computer algorithm to determine the likely neoantigens. If they can synthesize those into a vaccine, [the patients] get a personalized vaccine. We hope that [vaccines, in combination] with PD-1 [inhibition], will be another way after chemotherapy and targeted therapies to better harness the immune system. That is a longer shot in terms of efficacy, but it’s certainly an exciting one, and hopefully will be an approach that shows us how to use immunotherapy in colon cancer, which so far is limited to patients with microsatellite instability–high tumors.

If fruquintinib gains FDA approval, what advice would you give to practicing oncologists regarding adverse effect (AE) management, based on your involvement in the FRESCO-2 trial?

Think of it as [similar to] bevacizumab [Avastin]. Half the patients didn’t get the drug, and it was hard to tell who got the drug and who didn’t. The main AEs are hypertension and some fatigue. In this patient population, fatigue is an issue anyway, and it’s hard to know how much fatigue is attributable to the drug. Proteinuria [is another AE]. Those are AEs that we know how to manage from bevacizumab, [and they are] not particularly worse [with fruquintinib], except for the 5% to 10% of patients with more refractory hypertension.

What is your main message for colleagues regarding the future of CRC therapy?

There are more and more options for treating patients with colon cancer. In the later lines, many drugs are being tested in addition to our [available] options. [Soon], we’ll have 3 options: regorafenib, TAS-102, and fruquintinib. I’d like [oncologists] to keep in mind clinical trials for patients with late-line colon cancer. After we have exhausted the standard treatments, we still need those patients to help move the field forward and bring even more drugs into the clinic.

References

1. 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
2. Dasari A, Lonardi S, Garcia-Carbonero R, et al. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Lancet. 2023;402(10395):41-53. doi:10.1016/S0140-6736(23)00772-9