The Expanding Continuum of Care in Metastatic Colorectal Cancer

Colorectal cancer (CRC) is among the most commonly diagnosed malignancies worldwide, representing 10.2% of all cancer cases.^1,2 It is the second most common cancer diagnosed in women and third most in men. In women, incidence and mortality are approximately 25% lower than in men. CRC accounts for 9.2% of cancer-related deaths globally.2 Moreover, because of population growth and aging, mortality rates are expected to increase significantly over the next 15 years.³

Most colorectal cancers start as a growth on the inner lining of the colon or rectum. Gut microbiota regulate many physiological processes in close proximity to the colorectal epithelium, resulting in compositional and ecological changes that may lead to CRC.⁴ Symptoms may be minimal or nonexistent. In fact, most CRC cases are sporadic and develop slowly over several years, pointing to the importance of regular screening.⁵ Early diagnosis of CRC has been associated with treatment success and increased patient survival.^6,7

Approximately 25% of patients present with metastatic disease at the time of diagnosis, and, during the course of the disease, 40% of patients will develop metastases.⁸ The most common sites of metastasis are the liver, lung, and peritoneum.⁹ Five-year relative survival rates for patients with metastatic colorectal cancer (mCRC) is slightly higher than 10%.⁵

Over the last several decades, significant advances have been made in treating mCRC, resulting in improvements in survival.⁹ Yet, according to Axel Grothey, MD, director of gastrointestinal cancer research at West Cancer and Research Institute in Germantown, Tennessee, challenges and unmet needs remain. “The unmet needs that patients have in the metastatic setting is duration of time and quality of life [QOL],” noted Grothey in an Investigator Perspectives video interview with Targeted Therapies in Oncology. “It’s time but also quality of time that really matters, and this does represent an unmet need,” Grothey observed.

Extending survival and QOL often requires the use of many therapeutic modalities, in what Grothey calls the continuum of care. The evolving therapeutic landscape, which now includes targeted therapies, is helping to extend survival and QOL. “The improvements in overall survival [OS] we’ve seen over the last decade, moving from just 5-FU– [intravenous fluorouracil–] based therapy, 12-month survival, now to expecting patients to live 3 years and more, is really related to the idea that we add incremental benefits on top of each other,” noted Grothey. “Over time, with the use of all these agents in this continuum of care—which includes maintenance strategies, reintroduction of chemotherapies, [and] introduction of novel agents—we’ve really moved the bar in terms of OS for our patients,” Grothey said.

Although new therapies to further extend survival and QOL in patients with mCRC are needed, better selection of patients for available treatment choices is also essential. This article, featuring additional insights from Grothey, reviews the evolving treatment landscape and continuum of care for mCRC, with an emphasis on the role of newer agents in the third- and fourth-line settings—particularly the targeted agent regorafenib and the chemotherapy agent TAS-102.

An Evolving Treatment Continuum
Determining a prognosis for a patient with mCRC depends on several variables. Patient factors to consider include age, performance status, and comorbidities.10 Tumor-related factors that may affect prognosis include spread of disease, growth dynamics, symptoms, and localization, in particular liver and/or extrahepatic metastases.^10,11 Biochemical factors should also be considered, such as baseline values of carcinoembryonic antigen, lactate dehydrogenase, platelets, leucocytes, hemoglobin, alkaline phosphatase, and albumin.10

First-Line Therapies
According to Grothey, first-line treatment selection is based on unique patient and tumor characteristics, as well as goals of therapy. “One of the most critical factors is how much treatment does a patient need? How threatening is the disease, in terms of how intense does the treatment need to be? Is the patient threatened by tumor load? Do we need to really shoot for rapid and dramatic response that would potentially really turn things around for the patient?” observed Grothey.

Typically, frontline chemotherapy options include fluoropyrimidine (5-FU or oral capecitabine) used in various combinations, and schedules with irinotecan or oxaliplatin. This combination option provides higher response rates and better progression-free survival (PFS) times than does fluoropyrimidine alone. Some first-line treatments can combine bevacizumab, a monoclonal antibody (mAB) that binds VEGF-A, with leucovorin, 5-FU, oxaliplatin (FOLFOX) or with leucovorin, fluorouracil, and irinotecan (FOLFIRI).11 In some studies, bevacizumab in combination with a fluoropyrimidine plus oxaliplatin has been shown to increase PFS, although other studies were unable to demonstrate an improved outcome.^11-14 According to Grothey, frontline choices are more granular than they have ever been. “What I see here, especially in the United States, is that most patients receive FOLFOX plus bevacizumab as their frontline treatment, [but] that is not correct anymore. FOLFOX plus bevacizumab is one-size-fits-all. It’s no longer appropriate for the majority of patients,” Grothey noted. “We need to really look for molecular parameters, patient needs, how intense does the treatment need to be, sidedness factors, [and] goals of therapy.”

In considering molecular factors, the presence of RAS mutations, seen in 49% to 82% of CRCs, as well as BRAF mutations, seen in approximately 5% to 9% of patients,¹⁵ should direct clinicians to certain agents that may be more beneficial for patients with these mutations. Tumor sidedness, recognized as a predictive marker of response to anti-EGFR drugs, can also have an impact on the efficacy of certain treatments.¹⁶ “Right-sided tumors do not benefit from EGF receptor antibodies, at least not in first-line treatment,” noted Grothey. “Left-sided tumors, however, if they are RAS and BRAF wild-type, do benefit from EGF receptor antibody therapies in first-line treatment.”

Maintenance Therapies
Another key to extending survival and optimizing benefits of frontline agents is maintenance therapy, which plays an essential role in the continuum of care. One example of the importance of maintenance therapy arises when using an oxaliplatin-based regimen, FOLFOX/bevacizumab.¹¹ “We know that patients need to stop oxaliplatin even before they have progression of disease to manage [potential] neurotoxicity,” said Grothey. “One of the strategies that I personally employ is when I start with FOLFOX or FOLFOXIRI plus bevacizumab, I take oxaliplatin out after 8 cycles, meaning 2 months of therapy, and then use a fluoropyrimidine-plus-bevacizumab maintenance therapy…Randomized data show that this maintenance therapy can actually delay progression of disease, and this ties again into this continuum of care: we want to expose patients continuously to well-tolerated treatment, using the least amount of treatment necessary to control the disease in the palliative setting.”

Second-Line Therapies
When moving on to second-line therapies, Grothey noted that offering a new option might present benefits, and, therefore, treatment selection is generally dependent on first-line treatments. “Second-line choices clearly 4 depend on first-line treatments, and, of course, on biologic parameters and molecular parameters—for instance, BRAF mutation testing,” Grothey said. If bevacizumab was not used in the first-line setting, it should be considered in the second-line in combination with FOLFOX; results of a phase 3 trial showed that the combination improved OS compared with FOLFOX alone.^11,17 Another second-line combination that can be beneficial for BRAF V600E–mutant tumors, according to Grothey, is an EGF receptor antibody inhibitor plus a BRAF inhibitor. “We have second-line data now [showing] that these patients actually benefit from a biologic approach more than second-line chemotherapy,” he said.

Exploring the Utility of Third- and Fourth-Line Therapies
According to Grothey, the addition of new therapies to the treatment spectrum in the third and fourth line has enabled the possibility of extending survival and QOL. “Until recently, we didn’t have a lot of interesting third-line or fourth-line options. Now we actually have 2 distinct agents, and those agents are now [essentially] competing for the third-line space,” said Grothey.

Regorafenib
Approved in 2012,¹⁸ regorafenib is a multikinase inhibitor that is indicated for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if the tumor is KRAS wild-type, an anti-EGFR therapy.¹⁸ Regorafenib inhibits key signaling, such as BRAF and RAF1.¹⁹

The phase 3 CORRECT trial (NCT01103323) evaluated the safety and efficacy of regorafenib in heavily pretreated patients with mCRC who received 4 or more previous lines of therapy. Eligible patients also had progressed during or within 3 months of previous standard-of-care therapy (ie, a fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and cetuximab or panitumumab if the tumor was KRAS wild-type). The primary end point was OS.²⁰ Patients received regorafenib 160 mg once daily for 3 weeks and 1 week off for every 4-week cycle plus best supportive care. The primary end point was OS.

The median OS was 6.4 months in the regorafenib group versus 5.0 months in the placebo group (hazard ratio [HR], 0.77; 95% CI, 0.64-0.94; P = .0052). Treatment-related adverse events (AEs) occurred in 93% and 61% of patients in the regorafenib and placebo arms, respectively.²⁰ The most common AEs in the regorafenib group were grade 3 or higher; the most common AEs were hand-foot skin reaction (17%), fatigue (10%), diarrhea (7%), hypertension (7%), and rash (6%).²⁰

The CORRECT trial results demonstrate the potential of regorafenib to extend survival in patients with mCRC.²⁰ However, the elevated risk of toxicity in patients who
received regorafenib cast doubt on a positive QOL benefit. This compelled investigators to design a trial with the goal of achieving the observed benefits of regorafenib with an improved tolerability profile. The phase 2 ReDOS trial (NCT02368886) evaluated 116 patients with refractory mCRC at various dose ranges, from lower doses to the standard dose.²¹ Patients were randomized evenly among 4 groups with 2 different dosing strategies and 2 clobetasol usage plans. Patients in arm A1 received 80 mg regorafenib per day with weekly escalation of 40 mg up to 160 mg/d (if no significant AEs occurred) and preemptive twice-daily topical clobetasol applied to palms and soles for 12 weeks. The only difference between arms A2 and A1 is that in the former, clobetasol was a reactive regimen rather than preemptive. Patients in arm B1 received 160 mg regorafenib per day for 21 days of a 28-day cycle and preemptive twice-daily topical clobetasol applied to palms and soles for 12 weeks. Again, the only difference in the B arms was that clobetasol was a reactive rather than preemptive regimen in arm B2.²¹

The primary end point was the proportion of patients who initiated a third cycle in arm A (A1 + A2) compared with arm B (B1 + B2), and QOL was measured using Linear Analogue Self-Assessment over 8 weeks.21 Findings indicated that 43% of patients in arm A initiated the third cycle versus 25% of patients in arm B (P = .028). Progressive disease was the most common reason for not initiating cycle 3 (arm A, 35%; arm B, 47%). The median OS was improved in arm A compared with arm B (9.0 vs 5.9 months; P = .094), and multiple QOL parameters were more favorable in arm A versus arm B at week 2 of cycle 1.22 Grade 3/4 AEs were fatigue (13% in the dose-escalation group vs 18% in the standard-dose group), hand-foot skin reaction (15% vs 16%, respectively), abdominal pain (17% vs 6%), and hypertension (7% vs 15%). Investigators also noted 1 probable treatment-related death in the standard-dose group, due to myocardial infarction.²¹ These results suggest that weekly dose escalation of regorafenib from 80 mg/d to 160 mg/d was found is a superior regimen compared with a starting dose of 160 mg/d.

The results of the ReDOS trial established a new standard for optimizing regorafenib dosing through dose escalation.²² Reflecting on the utility of regorafenib, the difference in drug class agents in previous lines of therapy contributes to its effect. According to Grothey, patients who do not benefit from chemotherapy alone may experience an improved response if targeted therapy is added to treatment in a later line of therapy. “The benefit of regorafenib by itself is that it’s not chemotherapy,” said Grothey. “When patients come to the point of third-line treatment, [they] might have had a lot of exposure to chemotherapy, bone marrow suppression, etc. So regorafenib could be a nice interval to bridge [between therapies].” A more speculative potential benefit that is also being explored is whether regorafenib’s unique mechanism may increase efficacy of chemotherapies. “We are trying to explore right now whether regorafenib, this multikinase inhibitor—which really targets a lot of different kinases involved in tumor biology, [such as] tumor progression, tumor host interaction, immunology, etc—might actually resensitize tumors to chemotherapy.”

TAS-102
Another agent in the therapeutic armamentarium for mCRC in the third and fourth lines is TAS-102. Approved by the FDA in 2015, TAS-102 is a combination of trifluridine, a nucleoside metabolic inhibitor, and tipiracil, a thymidine phosphorylase inhibitor. It is indicated for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and, for patients with RAS wild-type tumors, an anti-EGFR therapy.²³

The FDA approval of TAS-102 was based on results of the phase 3 RECOURSE trial (NCT01607957), which was conducted in 3 regions: the United States, European Union, and Japan. Investigators used a Cox proportional hazards model in prespecified subgroups to measure primary and key secondary end points. A total of 800 patients were enrolled in the study, all 65 years and older. Those who had mutant KRAS tumors composed 51% of all patients in the regions. The final OS analysis illustrated a survival benefit with TAS-102 (HR, 0.69; 95% CI, 0.59-0.81; P = .0001),²⁴ with median OS and PFS across the 3 regions of 6.5-7.8 months and 2.0-2.8 months, respectively, in the TAS-102 arm, and 4.3-6.7 months and 1.7-1.8 months, respectively, in the placebo arm.

The most common AE reported was neutropenia, which occurred in 31.3%, 29.3%, and 1.7% of patients in the United States, European Union, and Japan, respectively. Interestingly, however, those with neutropenia appeared to have better efficacy results. “We actually know the patients who develop neutropenia have better outcome on TAS-102 than patients who don’t develop neutropenia,” said Grothey, who also pointed out that the observed neutropenia was relatively asymptomatic, while febrile neutropenia was uncommon. TAS-102 was also associated with a lower rate of infection, while some patients also experienced diarrhea and/or fatigue. “TAS-102 is quite well tolerated and it is a reliable fallback for patients [with mCRC],” noted Grothey.

Sequencing Considerations and New Combinations
A key principle of treating mCRC, according to Grothey, is ensuring that patients receive all active agents for which they are eligible. When evaluating the sequence in which to use the agents, Grothey noted that toxicity should be an important consideration. “I do believe that a patient who is a candidate for regorafenib in the third-line setting should receive regorafenib before TAS-102. If we choose TAS-102 first when patients’ performance status deteriorates, these patients might not be a good candidate for regorafenib,” said Grothey, who further pointed out that the pool of patients who are considered for third-line treatment is probably larger for TAS-102 than for regorafenib.

The importance of sequencing with regorafenib, in particular, was demonstrated by results of the recent REVERCE study (NCT04117945), which evaluated efficacy and safety of the therapeutic sequence of regorafenib followed by cetuximab, compared with cetuximab followed by regorafenib.²⁵ Patients with KRAS exon 2 wild-type mCRC were randomized to receive sequential treatment with regorafenib followed by cetuximab alone or in combination with irinotecan (RC), or the reverse sequence—cetuximab alone or in combination with irinotecan followed by regorafenib (CR)—after failure of fluoropyrimidine, oxaliplatin, and irinotecan. The primary end point was OS.²⁵

Although sequential treatment was successful in 86% of patients in both arms, the disparity in median OS is worth noting. The median OS for RC was 17.4 months compared with 11.6 months for CR (HR, 0.61 95% CI, 0.39-0.96; P = .0293). Grothey said, “[It] was a sequential study [that] randomized comparison and had a very surprising result, [with the] 6-month benefit in OS for the earlier use of regorafenib before EGF receptor antibodies.” Grothey noted that investigators still aren’t certain why the reverse sequencing yielded such different results, but they may have implications for future studies with regorafenib and
other agents.

Aside from potential opportunities related to sequencing possibilities, recent research has revealed new approaches via combination regimens involving TAS-102 and regorafenib. One combination that was investigated in 2019 is TAS-102 4 plus bevacizumab. A randomized study evaluated TAS-102 alone versus TAS-102 plus bevacizumab as last-line therapy in 80 patients with chemorefractory unresectable mCRC. The main inclusion criteria included histologically confirmation of chemorefractory mCRC as well as disease progression during or after therapy with fluoropyrimidine, irinotecan, oxaliplatin, an EGFR inhibitor (for patients with RAS wild-type), and bevacizumab. In arm A, TAS-102 was administered orally at a dose of 35 mg/m²/dose twice daily from day 1 to day 5 and from day 8 to day 12; in arm B the same doses of TAS-102 were combined with bevacizumab at a dose of 5 mg/kg on days 1 and 15 of a 28-day treatment cycle. The primary end point was to increase PFS from 1.8 months to 3.8 months; secondary objectives included OS and safety.²⁶

TAS-102 plus bevacizumab was associated with significant and clinically relevant improvements in PFS and OS with tolerable toxicity. Median PFS was 2.6 months in arm A and 5.9 months in arm B (HR, 0.51; 95% CI, 0.28-0.92; P <.03), while median OS was 7.3 months in arm A and 10.3 months in arm B (HR, 0.42; 95% CI, 0.18-0.99; P <.05). Regarding toxicity, patients who received TAS-102 plus bevacizumab had more grade 3/4 neutropenia (56% in arm B vs 30% in arm A; P = .03), while 3 patients in arm B developed febrile neutropenia as compared with 0 patients in arm A.²⁶ “[The findings] show that the addition of bevacizumab to TAS-102 improved survival and progression-free survival in what I believe a was a clinically relevant way, [with] not a lot of toxicity,” said Grothey.

Another compelling avenue of potential combination therapy for mCRC involves immunotherapy, such as vaccines and checkpoint inhibitors, which target the immunosuppressive pathways and enable an antitumor immune response.²⁷ Agents being investigated in the treatment of CRC include levamisole, which is thought to induce antibodies against tumor antigen; nivolumab, a fully human immunoglobulin (Ig) G4 mAB directed against PD-1; and pembrolizumab, a humanized IgG4 mAB that binds and prevents the interaction of PD-L1 and PD-L2, resulting in immune recognition and response.²⁷

A recent phase 1b trial used the immunotherapy nivolumab in combination with regorafenib. In the open-label, dose-finding trial, investigators evaluated 50 patients with previously treated advanced gastric cancer or CRC. First, they received regorafenib plus nivolumab to estimate the maximum tolerated dose (MTD). A dose-expansion phase further established the combination’s safety and determined its preliminary efficacy; patients received regorafenib 80 mg to 160 mg administered once daily for 21 days on, 7 days off, with the addition of intravenous nivolumab 3 mg/kg every 2 weeks. The primary end point was dose-limiting toxicity (DLT) during cycle 1 (4 weeks) to estimate the MTD and the recommended dose. During dose escalation, 3 DLTs were observed with regorafenib 160 mg: grade 3 maculopapular rash, mucositis, and proteinuria. No DLTs were observed with 80 mg or 120 mg doses. In the dose-expansion cohort with regorafenib 120 mg, the dose was reduced to 80 mg because of frequent grade 3 skin toxicities. Grade 3 and higher treatment-related AEs occurred in 17 patients; the common AEs were rash (14%), palmar-plantar erythrodysesthesia (10%), and proteinuria (8%).²⁸

Because regorafenib plus nivolumab was demonstrated to have a manageable safety profile and encouraging antitumor activity in patients with mCRC, Grothey noted that this combination warrants further investigation in a larger cohort.²⁸ “The combination of regorafenib and nivolumab showed very interesting activity, particularly in microsatellite stable tumors, which are tumors we normally do not consider immunogenic at all,” he said. “We need to have more validated [studies] and more information about these patients.” Another notable study finding, according to Grothey, is that the dose of regorafenib needed to mediate this immune activation was only 80 mg.

In general, the role of immunotherapy in CRC has expanded, specifically in subsets of CRC with microsatellite instability for which newer agents like PD-1 inhibitors are efficacious.²⁷ According to Grothey, augmented immunotherapy represents a potentially significant advance in the treatment of mCRC. “I do believe that augmented immune therapy, enhanced immune response, is really the Holy Grail of where we’d like to go in the management of colorectal cancer,” he said.

Conclusions

The recent addition of third- and fourth-line therapies that extend survival and improve QOL has opened up new possibilities in the growing continuum of care for mCRC. These possibilities include new potential sequencing strategies and combination approaches that could extend survival even longer. According to Grothey, these developments collectively suggest a brighter future for patient care. “When we look into the future, I’m really excited about what’s happening in colorectal cancer,” he said.

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