Throughout 2023, numerous advancements in the field of metastatic colorectal cancer (mCRC), including the FDA approval of fruquintinib (Fruzaqla), have helped expand the treatment armamentarium, according to Cathy Eng, MD, FACP, FASCO.

, the regulatory agency approved fruquintinib

 for the treatment of adult patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if 

 wild-type and medically appropriate, an anti-EGFR therapy.

The decision was backed by data from the phase 3 FRESCO-2 (NCT04322539), which found that fruquintinib in combination with best supportive care (BSC) elicited 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) for placebo plus BSC (HR, 0.662; 95% CI, 0.549-0.800; 

“Our goal as medical providers is always to improve the survival of our patients without compromising quality of life; therefore, I feel quite confident that [fruquintinib] does provide that option for patients,” Eng explained.

, Eng discussed the implications of the fruquintinib approval, as well as other key clinical trial data and regulatory decisions within the CRC realm in 2023; the importance of early molecular testing in this patient population; and the continued importance of enrolling eligible patients onto clinical trials.

Eng is the David H. Johnson Chair in Surgical and Medical Oncology, co-leader of the Gastrointestinal (GI) Cancer Research Program, a professor of medicine in Hematology and Oncology, co-director GI Oncology, vice-chair of the SWOG GI Committee, and director of the Vanderbilt-Ingram Cancer Center Young Adult Cancers Initiative at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

: How have recent data reemphasized the importance of molecular testing in patients with CRC?

: Some of the highlights in CRC [from 2023 revolve around] the fact that, once again, we are very focused on molecular markers, molecular alterations, and trying to make sure that we are providing patients precision oncology as much as possible.

We want to encourage physicians, as soon as they meet a patient, to consider molecular testing because that can dramatically impact your diagnostic approach to the patient, the sequence of therapy, and enrollment to clinical trials. I'm always going to be a big advocate for [clinical trials].

What developments have been seen with KRAS G12C inhibitors in mCRC?

There are ongoing data regarding KRAS inhibitors. Some of them are still early in development. We've seen that there has been some data with the KRAS G12C [inhibitor sotorasib (Lumakras)] in combination [with panitumumab (Vectibix)], and there [have been] data [for adagrasib (Krazati) in combination with cetuximab [Erbitux)]. [The phase 3 CodeBreaK 300 trial (NCT05198934) of sotorasib plus panitumumab] presented at the 2023 ESMO Congress was a positive study.

There's a lot of interest in moving these drugs forward, possibly to the first-line setting. Also, LoxoLilly is developing its own KRAS G12C inhibitor [LY3537982]. Is the new generation [KRAS G12C] inhibitors going to be different than [prior agents]? We're very curious about that. However, keep in mind that [patients with] 

 G12C [mutations comprise] such a small portion of our patient population, at less than 5%. We're very interested in [KRAS] G12D inhibitors, but those are still very early in development. That would also have an impact in pancreatic carcinoma.

What were some of the top highlights in CRC treatment updates in 2023?

At the 2023 Gastrointestinal Cancers Symposium,

data with trifluridine/tipiracil [TAS-102; Lonsurf] plus bevacizumab [Avastin]

 in [patients with refractory mCRC from the phase 3 SUNLIGHT study (NCT0437187)], and it allowed our European colleagues and those outside the United States to adopt [this strategy]. That was based upon the SUNLIGHT data, [where] in the third-line setting, [TAS-102 plus bevacizumab] improved OS vs TAS-102 alone. In the United States, [this strategy] has been largely adopted for a long time because it was already in the National Comprehensive Cancer Network Guidelines.

One study that was more of a general study that was a bit disappointing was lenvatinib [(Lenvima) in combination with] pembrolizumab [Keytruda]. [Data from] 

the phase 3 LEAP-017 trial [NCT04776148] 

were presented at the 2023 ESMO World Congress on Gastrointestinal Cancer.

 It did not fulfill its prespecified end point for OS, and that was a little bit disappointing. There appeared to be a hint that maybe there was more benefit in those patients without liver metastases, although that was a smaller number of patients. At the end of the day, it did not fulfill its primary endpoint for OS.

However, we've also had some other exciting aspects in regard to [current] care. We saw tucatinib [(Tukysa) plus trastuzumab (Herceptin) approved] for our HER2-positive patient population, which [accounts] for about 4% of all patients with mCRC, emphasizing the importance of molecular testing. In this case, you just want to make sure your patient is HER2 [immunohistochemistry] 2+ or 3+; those are the patients who benefit from this oral TKI. Based upon the phase 2 MOUNTAINEER trial [NCT03043313], which was a single-arm study presented at the 2022 ESMO World Congress on Gastrointestinal Cancer, [this combination] was 

Now we're looking forward to seeing the results of the phase 3 MOUNTAINEER-03 trial [NCT05253651], which is [evaluating] trastuzumab plus tucatinib and mFOLFOX6 vs standard chemotherapy in newly diagnosed [patients with] HER2-positive mCRC. We want to encourage [you to look for opportunities to enroll] patients to that clinical trial.

What is the significance of the FDA approval of fruquintinib for the treatment of select patients with previously treated mCRC?

[Having] another drug for our mCRC patient population is just a huge win. In general, for providers and patients, we do not have as many treatment options as we would like in mCRC, unless you have a specific molecular alteration that is actionable, such as HER2 [positivity] or 

 [mutations]. When you have a patient who has gone through multiple lines of therapy or doesn’t have a specific molecular marker, we need additional treatment options.

The reality is that for patients who are not surgically resectable, we need to provide them some type of therapy to improve their OS. Our [other] top goal is to not compromise their quality of life.

[Fruquintinib] provides a new opportunity for our patient population, as it appears to be well tolerated. It's an oral agent, and that's an advantage for patients as well. It has demonstrated improved OS.

How do you see fruquintinib fitting into the current mCRC treatment paradigm?

Providers will have to make that decision on their own. However, it is available in the third-line setting and beyond. It is an oral agent, which is advantageous when it's given by itself, so that may have an impact on decision making for some patients. There are going to be different adverse effects that need to be discussed with patients, and at the end of the day, it just adds into armamentarium for our patient population.

It gives a lot of hope to patients that additional drugs are being designed. So many of these newer drugs are focused on very small molecular subsets, but [some subsets account for] less than 10% of our [overall] patient population. The reality is that most of our patients need other options. Here, we hope that [fruquintinib] will give some optimism to patients about improving their OS, having good quality of life, and living their life, despite their diagnosis.

What ongoing trials could be pivotal in the advancement of the treatment landscape for patients with CRC?

 V600E mutation, there is an ongoing international trial called the phase 3 BREAKWATER study [NCT04607421], and the investigational arm is for newly diagnosed patients. That [is evaluating chemotherapy] in combination with encorafenib [Braftovi] and cetuximab [Erbitux]. [BREAKWATER] is the only phase 3 trial open globally for newly diagnosed [patients with] 

There is [additional] interest right now in 

 [mutations], as there is a new adjuvant [phase 2/3] trial [NCT05710406] for patients that test positive for 

 mutations in the stage III setting, and that recently opened nationwide.

We still have the phase 2/3 CIRCULATE-US study [NCT05174169], which is evaluating [patients with] stage III CRC and investigating the role of circulating tumor DNA [on decisions to escalate or de-escalate treatment].

We also have recently just opened [the phase 3] EA2222 [PUMP] trial [NCT05863195], which is looking at the role of hepatic arterial infusion pump in the frontline setting [for patients with unresectable CRC liver metastases]. There is also the phase 3 ERASur study [NCT05673148], which is looking at the role of stereotactic radiation therapy or any type of liver-directed therapy other than hepatic artery infusion in a newly diagnosed patients with mCRC and liver metastases.

We once again want to encourage patients to enroll to clinical trials. These are of key importance and how we make a difference in our field. Whether it's industry-sponsored or National Cancer Institute [NCI]–sponsored, please proceed to enroll patients to clinical trials.

What is the incentive for testing patients for targetable alterations in the up-front setting?

The incentives for testing patients for molecular sequencing up-front is extremely advantageous. Number 1, it is quicker to take that specimen and analyze it before it gets sent off to storage, and then months down the line, you're trying to retrieve it. Number 2, when I talk about molecular testing, I include blood and tissue, because blood has fewer mutations to analyze. However, [blood] is also a quicker test, and it will give you a general idea of what may be possible for the patient.

Testing of the tissue with next-generation sequencing is extremely important because there are so many more molecular analyses that can be completed. It is a huge advantage for the patient because we are trying to provide them with more precision oncology. We're trying to give them care that is appropriate based upon their own molecular analysis. Understanding what mutation that they may have that may be actionable can make a big difference in how we sequence our therapies. That [information is] critical to make that decision.

When you have a patient with surgically unresectable disease, you have to think about what your plans are moving forward in regard to first-line or second-line [treatments] because you need a backup plan just in case things are proceeding in the wrong direction once treatment has been initiated. You want to have a discussion [with a patient] about what their options are down the road.

I always try to encourage individuals to enroll to clinical trials; a lot of these clinical trials now are specific to various molecular markers, which is a good thing, but [that means] the pie is getting much smaller. We're talking about patient populations of 4%, 5%, 9%, or 2% [of the overall CRC population], making it challenging for a lot of medical centers to consider opening up all these trials for [tumors with] rare mutations. However, [these studies] do make a difference for patients.

If you're out in the community and you cannot open all those small molecular subsets, we completely understand. However, [we encourage you to] reach out to the academic institutions nearby, because they are likely the ones to have a clinical trial available that you may not be able to conduct.

Takeda receives U.S. FDA approval of Fruzaqla (fruquintinib) for previously treated metastatic colorectal cancer. Takeda. News release. November 8, 2023. Accessed November 16, 2023. 

https://www.takeda.com/newsroom/newsreleases/2023/Takeda-Receives-US-FDA-Approval-of-FRUZAQLA-fruquintinib-for-Previously-Treated-Metastatic-Colorectal-Cancer/

Dasari NA, Lonardi S, Garcia-Carbonero R, et al. LBA25 FRESCO-2: a global phase III multiregional clinical trial (MRCT) evaluating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer. 

. 2022;33(suppl 7):S1391-S1392. doi:10.1016/j.annonc.2022.08.021

Tabernero J, Prager GW, Fakih M, et al. Trifluridine/tipiracil plus bevacizumab for third-line treatment of refractory metastatic colorectal cancer: The phase 3 randomized SUNLIGHT study. 

. 2023;41(suppl 4):4. doi:10.1200/JCO.2023.41.3_suppl.4

Merck and Eisai provide update on phase 3 trials of Keytruda (pembrolizumab) plus Lenvima (lenvatinib) in certain patients with advanced melanoma (LEAP-003) and metastatic colorectal cancer (LEAP-017). News release. Merck. April 7, 2023. Accessed November 16, 2023. 

https://www.merck.com/news/merck-and-eisai-provide-update-on-phase-3-trials-of-keytruda-pembrolizumab-plus-lenvima-lenvatinib-in-certain-patients-with-advanced-melanoma-leap-003-and-metastatic-colorectal-cance/

Seagen announces FDA accelerated approval of Tukysa (tucatinib) in combination with trastuzumab for people with previously treated RAS wild-type, HER2-positive metastatic colorectal cancer. News release. January 19, 2023. Accessed November 16, 2023. 

https://www.businesswire.com/news/home/20221222005382/en/Seagen-Announces-FDA-Accelerated-Approval-of-TUKYSA%C2%AE-tucatinib-in-Combination-with-Trastuzumab-for-People-with-Previously-Treated-RAS-Wild-Type-HER2-Positive-Metastatic-Colorectal-Cancer

Articles

Cathy Eng, MD, FACP, FASCO, discusses the implications of the fruquintinib approval, as well as other key clinical trial data and regulatory decisions within the colorectal cancer realm in 2023; the importance of early molecular testing in this patient population; and the continued importance of enrolling eligible patients onto clinical trials.

Fruquintinib Approval Highlights Strides Made in mCRC Armamentarium in 2023

Cathy Eng, MD, FACP, FASCO, the David H. Johnson Chair in Surgical and Medical Oncology, co-leader, Gastrointestinal (GI) Cancer Research Program, professor, medicine, Hematology and Oncology, co-director, GI Oncology, Vanderbilt-Ingram Cancer Center; vice-chair, SWOG GI Committee; director, Vanderbilt-Ingram Cancer Center Young Adult Cancers Initiative, discusses the ongoing investigation of fruquintinib (HMPL-013) in patients with relapsed/refractory metastatic colorectal cancer (mCRC).

At the 2023 ASCO Annual Meeting, investigators presented updated data

 on the use of fruquintinib in patient with mCRC from subgroup analyses of the phase 3 FRESCO-2 trial (NCT04322539). Data from this analysis showed that treatment with fruquintinib and best supportive care (BSC) elicited improvements in overall survival (OS) and progression-free survival vs placebo plus BSC in this patient population, irrespective of the number of prior lines of therapy or types of prior treatment patients had received. Among all 461 patients treated with fruquintinib, the median OS was 7.4 months (95% CI, 6.7-8.2) vs 4.8 months (95% CI, 4.0-5.8) with placebo (n = 230; HR, 0.662; 95% CI, 0.549-0.800; 

in May 2023, the FDA granted priority review to a new drug application

 seeking the approval of fruquintinib forthe treatment of patients with previously treated mCRC.

Eng states that this is a current area of anticipation as investigators await final data from the FRESCO-2 trial. She explains that she and other investigators are eagerly awaiting the potential FDA approval of fruquintinib in the relapsed/refractory mCRC patient cohort. This treatmentconsists of a selective oral TKI designed to target VEGF receptors 1, 2, and 3, Eng explains. The data obtained from the trial show an improved OS with fruquintinib, particularly in patients who had received an average of 4 prior lines of therapy, she emphasizes.

Notably, in FRESCO-2, treatment with fruquintinib wasn't limited by number of prior lines of therapy. Given the oral formulation of fruquintinib, investigators are hopeful for its approval, Eng concludes.

Videos

Cathy Eng, MD, FACP, FASCO, discusses the ongoing investigation of fruquintinib in patients with relapsed/refractory metastatic colorectal cancer.


Dr Eng on the Ongoing Investigation of Fruquintinib in Relapsed/Refractory mCRC

Tanios Bekaii-Saab, MD, FACP, professor, medicine, senior associate consultant, Hematology and Oncology, co-leader, Gastrointestinal Cancer Program, Mayo Clinic, discusses the evolution of treatment for patients with 

 G12C–mutant and HER2-overexpressing colorectal cancer (CRC).

The CRC field has become increasingly intriguing because of the emergence of various actionable genomic alterations and their corresponding therapeutic matches, Bekaii-Saab begins. Two significant updates that occurred in the realm of CRC in 2023 revolved around 

G12C mutations and HER2 overexpression, which have garnered substantial attention, he states. The combination of adagrasib (Krazati) and cetuximab (Erbitux) is effective against 

G12C mutations, which are found in a small percentage of patients, Bekaii-Saab says.

Notable, although less striking, outcomes have occurred with sotorasib (Lumakras) and panitumumab (Vectibix) treatment combinations, which yield response rates ranging from 30% to approximately 50%, along with durable responses, Bekaii-Saab expands. These developments represent a significant shift in the approach of targeting a specific 

 mutation subtype within CRC. Consequently, these advances have been incorporated into the National Comprehensive Cancer Network guidelines, transforming the armamentarium of clinical practice for this patient subgroup, he emphasizes.

Another exciting focus within CRC is the subgroup of patients characterized by HER2 amplification, which accounts for approximately 3% to 4% of metastatic CRC cases, Bekaii-Saab continues. This subgroup has seen much progress in the past year. Notably, in January 2023, 

the FDA granted approval to the combination of tucatinib (Tukysa) and trastuzumab (Herceptin)

 wild-type disease with HER2 overexpression, he explains. This approval followed the promising results of the phase 2 MOUNTAINEER trial (NCT03043313), which demonstrated high response rates, enduring responses, and favorable outcomes in patients who received this treatment approach, Bekaii-Saab explains.

Currently, the combination of tucatinib and trastuzumab is progressing into the phase 3 research arena with the MOUNTAINEER-03 trial (NCT05253651), which aims to randomly assign patients to receive mFOLFOX6 (5-Fluorouracil, leucovorin, and oxaliplatin) with or without the treatment combination. This trial promises further insights into the efficacy of this treatment approach, Saab concludes.

Tanios Bekaii-Saab, MD, FACP, discusses the evolution of treatment for patients with KRAS G12C–mutant and HER2-overexpressing colorectal cancer.


Dr Bekaii-Saab on Treatment Evolutions in KRAS G12C–Mutant and HER2-Overexpressing CRC

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.”

®, 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; 

 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; 

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.

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

: 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 

mutations in patients with early-onset disease?

DESTINY-CRC01 was [performed in patients with metastatic disease] who’ve had prior regimens for 

-overexpressing colon cancer. That’s approximately 4% or 5% of all colon cancer. If you just test patients with 

 overexpression occurs in] approximately 8% to 10% of patients. You might miss a few [patients with] 

-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 

 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. 

 G12C still comprises a relatively small fraction of 

G12V–directed drugs that will give us some good opportunities for patients with 

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.

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). 

. 2023;41(suppl 17):LBA2. doi:10.1200/JCO.2023.41.17_suppl.LBA2

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. 

. 2023;402(10395):41-53. doi:10.1016/S0140-6736(23)00772-9

Howard S. Hochster, MD, highlights key updates in CRC research and management from the 2023 ASCO Annual Meeting, including findings from the phase 2/3 PROSPECT trial, long-term follow-up data from the phase 3 PRODIGE 23 trial, and results of the phase 3 NeoCol study. 

Continued CRC Research Informs Later-Line Disease Management 

Marwan G. Fakih, MD, Judy & Bernard Briskin distinguished director, Clinical Research, associate director, Clinical Research, codirector, Gastrointestinal Cancer Program, medical director, Judy & Bernard Briskin Center for Clinical Research, City of Hope, expands on long-term findings from 

the phase 2/3 PROSPECT trial (NCT01515787)

, and how these findings may influence the optimal use of nonoperative management strategies in locally advanced rectal cancer.

The PROSPECT trial compared the efficacy of neoadjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) and selective chemoradiation with preoperative pelvic chemoradiation and concurrent chemotherapy, which was previously the standard treatment approach for this patient population at the time of the trial's inception, Fakih begins. Since then, the standard has shifted to a total neoadjuvant therapy approach, Fakih notes. Although highly effective, pelvic chemoradiation is associated with several long-term toxicities that can decrease patient quality of life.

Accordingly, the trial aimed to assess whether the selective use of chemoradiation may still provide benefit to patients eligible for sphincter-sparing surgery, Fakih explains. The trial enrolled patients with previously untreated, pathologically confirmed, locally advanced rectal cancer who

were diagnosed with T2 node-positive, T3 node-negative, or T3 node-positive (cT3N+) disease, and were eligible for surgical resection. Notably, the trial targeted a lower-risk patient population by excluding patients with 4 or more lymph nodes with a short axis of more than 1 cm, as well as those with involved circumferential radial margins, Fakih states.

Long-term findings demonstrated that 3 months of neoadjuvant FOLFOX prior to surgery was non-inferior to pelvic chemoradiation in patients who had a response consisting of a tumor reduction of 20% or greater, , Fakih reports. Patients receiving neoadjuvant chemotherapy experienced a lower local recurrence rate of 1.8% vs 1.6% in those receiving chemoradiation therapy. Moreover, the study's primary end point of disease-free survival did not significantly differ between the neoadjuvant chemotherapy and perioperative chemoradiation groups, Fakih details.

Based on these data, patients who are willing to undergo primary surgical resection may not require radiation therapy provided they have non-bulky nodal disease and no threatened circumferential resection margin, Fakih concludes. He emphasizes the importance of offering this potential radiation-sparing strategy when designing individualized treatment plans based on patient preferences and clinical evaluation.

Marwan G. Fakih, MD, expands on long-term findings from the phase 2/3 PROSPECT trial and how these findings may influence the optimal use of nonoperative management strategies in locally advanced rectal cancer.
 

Dr Fakih on the Significance of the PROSPECT Trial in Rectal Cancer

Howard S. Hochster, MD, distinguished professor of medicine, associate director, Clinical Research, director, Gastrointestinal Oncology, Rutgers Cancer Institute, director, Oncology Research, RWJ Barnabas Health, discusses data from the phase 3 FRESCO-2 trial (NCT04322539) of fruquintinib (HMPL-013) plus best supportive care (BSC) in metastatic colorectal cancer (mCRC).

the FDA granted priority review to the new drug application for the highly selective and potent oral VEGF-targeted agent based on findings from the FRESCO-2 study

 The FRESCO-2 trial, which was conducted in the United States, confirmed findings from the phase 3 FRESCO trial (NCT02314819), which was conducted in China. In the FRESCO trial, the agent was shown to be an effective treatment alternative for patients in the third line or later line, following standard chemotherapy and targeted therapy.

FRESCO-2 enrolled patients with mCRC who were previously exposed to chemotherapy with fluoropyrimidine, oxaliplatin, or irinotecan; a VEGF inhibitor; or an EGFR inhibitor, provided they had 

 wild-type disease. The trial was double-blinded, except for instances in which patients developed uncontrollable hypertension. This rigorous methodology reinforces the credibility of the results. Notably, most patients on the trial who responded to the fruquintinib combination had been previously treated with regorafenib (Stivarga) or trifluridine/tipiracil (TAS-102; Lonsurf).

Results from the FRESCO-2 study showed that fruquintinib plus best supportive care produced superior overall survival (OS) and progression-free survival (PFS)benefit vs placebo and best supportive care. The median OS in the fruquintinib arm was 7.4 months (95% CI, 6.7-8.2 compared with 4.8 months (95% CI, 4.0-5.8) in the placebo arm (n = 230; HR, 0.662; 95% CI, 0.549-0.800; 

Data from subgroup analyses of the phase 3 FRESCO-2 trial

(NCT04322539) revealed that improved OS was observed regardless of the number of prior lines of therapy patients received or the type of prior treatment administered. Heavily pretreated patients with prior exposure to more than 4 prior lines of therapy experienced a median OS of 7.1 months (95% CI, 6.3-8.5) with fruquintinib (n = 214) vs 4.6 months (95% CI, 3.4-5.9) with placebo (n = 107; HR, 0.595; 95% CI, 0.453-0.781; 

 < .001). The agent was deemed tolerable, and its safety profile is consistent with previously reported data.

Positive outcomes from the FRESCO-2 trial have the potential to support any future FDA approval of fruquintinib in mCRC, Hochster says. The regulatory decision is anticipated to be made by November, 2023, and it is expected that an Oncologic Drugs Advisory Committee (ODAC) meeting will not be necessary, he notes. This suggests that patients may have access to this promising therapy in the near future. If approved, fruquintinib could provide patients who have exhausted other eligible therapies with another effective treatment option, Hochster concludes.

Howard S. Hochster, MD, discusses data from the phase 3 FRESCO-2 trial of fruquintinib plus best supportive care in metastatic colorectal cancer.

Clinical Updates in Colorectal Cancer | Supplements and Featured Publications

Fruquintinib Approval Highlights Strides Made in mCRC Armamentarium in 2023

Dr Eng on the Ongoing Investigation of Fruquintinib in Relapsed/Refractory mCRC

Dr Bekaii-Saab on Treatment Evolutions in KRAS G12C–Mutant and HER2-Overexpressing CRC

Continued CRC Research Informs Later-Line Disease Management

Dr Fakih on the Significance of the PROSPECT Trial in Rectal Cancer

Dr Hochster on the FRESCO-2 Trial in mCRC