Status Report: Expert Reviews Guideline-Based Options in Advanced CRC

Rona D. Yaeger, MD

Three months of adjuvant chemotherapy could be a viable option for most patients with advanced colorectal cancer (CRC), and the addition of targeted therapy should be considered for those with metastatic disease. All patients diagnosed with CRC should be tested for mismatch repair deficiency (dMMR) and microsatellite instability (MSI) to screen for Lynch syndrome and potential treatment with immune checkpoint immunotherapy.

That was the bird’s eye view of standard therapy for patients with advanced or metastatic disease that Rona D. Yaeger, MD, provided at the 3rd Annual School of Gastrointestinal Oncology™ (SOGO®) in April. Yaeger, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, led her audience through a review of pivotal developments that have shaped the National Comprehensive Cancer Network guidelines in the past several years.

The most debatable recommendation concerns recently published data from the IDEA trial suggesting that a shorter course of treatment is safe and effective. “As we think now about adjuvant therapy,” she said, “the question is, do we need to continue therapy for the entire 6 months of treatment? This has become increasingly important because of the cumulative neuropathy that develops with the oxaliplatin, which can be hard to detect while patients are on treatment and can catch up with you after patients have received most of the course of treatment.”

In the landmark MOSAIC trial, investigators established that combination therapy of bolus plus continuous infusion fluorouracil with leucovorin (LV5FU2) would be improved by adding oxaliplatin (FOLFOX4). Patients with stage III disease who received FOLFOX4 experienced a statistically significant disease-free survival (DFS) benefit of 7.5% compared with those treated with LV5FU2 (P = .005).¹

However, the rate of grade 3 peripheral sensory neuropathy was 12.5% in the FOLFOX4 group compared with 0.2% in the LV5FU2 group. Eighteen months after study completion, the rate of grade 3 neuropathy was 24.1% versus 0.7%, respectively.¹

These results inspired investigators and clinicians to reconsider the necessity of 6 months of adjuvant treatment for these patients. In IDEA, a prospective pooled analysis of 6 phase III trials, patients with stage III disease were randomly assigned to investigator’s choice of FOLFOX (5-fluorouracil plus leucovorin and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) for 3 or 6 months. The primary endpoint was noninferiority for the 3-month regimen.

DFS rate in the 3-month arm was 74.6% versus 75.5% in the 6-month arm (HR, 1.07; 95% CI, 1.00-1.15). The 3-year difference in DFS was —0.9% (95% CI, –2.4 to 0.6). The prespecified boundary for noninferiority was 1.12, so IDEA technically did not con rm noninferiority for the broad population.²

However, in the subgroup analysis, the DFS rate for the FOLFOX arm was 81.9% in the 3-month arm and 83.5% in the 6-month arm for patients with low-risk disease (tumor stage 1-3; nodal status 1). The DFS rate was slightly better for low-risk patients in the CAPOX group assigned to 3 months versus 6 months of treatment (85.0% vs 83.1%, respectively).³ “Even with 3 months, they have a better disease-free survival,” Yaeger said.

In patients with high-risk disease, the DFS rate in the FOLFOX group was slightly poorer with 3 months of treatment (61.5% vs 64.7%), but there was no clear difference between 3 and 6 months of CAPOX (64.1% vs 64.0%).

“There’s been a lot of discussion about this trial, and it leads us to have longer conversations and more informed discussions with our patients,” Yaeger said. “But it’s reasonable to consider 3 months of treatment based on patient choice and based on the risk of disease.”

Targeted Therapies in Metastatic Disease

The findings raise the question of whether CAPOX is a better regimen, she said, noting that combination is more frequently administered in Europe, where familiarity may result in higher adherence rates.Combination therapy is the preferred modality for metastatic CRC (mCRC), according to NCCN guidelines. Yaeger said the FOLFOX or FOLFIRI (5-fluorouracil plus leucovorin and irinotecan) chemotherapy regimens produce equal outcomes with similar response rates in about 50% of patients. “Whatever regimen is chosen, the other can be used in a second-line setting,” she added.

SWOG 80405 explored investigator’s choice of FOLFOX or FOLFIRI combined with cetuximab (Erbitux) or bevacizumab (Avastin) as first-line therapy for patients with mCRC and KRAS wild-type tumors (codons 12 and 13). Cetuximab targets EGFR; bevacizumab, VEGF.

Median OS was 31.2 months with bevacizumab compared with 32.0 months with cetuximab (HR, 0.9; 95% CI, 0.7-1.1; P = .40).⁴ Investigators concluded that the OS in both arms set a new benchmark for this patient popula- tion, with the 2 combinations equally effective as first-line therapy.

Subgroup analysis showed the importance of tumor sidedness. For patients with KRAS wild-type tumors, the median OS was 19.4 months for right-sided tumors versus 34.2 months for left-sided. Similarly, PFS was stronger in patients with left-sided tumors (11.5 vs 8.9 months).⁵

For patients with right-sided tumors, median OS was superior for those treated with bevacizumab compared with cetuximab (24.5 months vs 16.4 months, respectively). In left-sided tumors, cetuximab was superior to bevacizumab (37.5 months vs 32.1 months, respectively).

Subsequent retrospective analyses of other trials suggest that patients with right-sided tumors do not do as well with anti-EGFR treatment. Yaeger said those findings have changed the NCCN guidelines, which now recommend that patients whose tumors harbor hotspot mutations in RAS, including KRAS and NRAS in and beyond exon 2, should not receive EGFR antibodies (TABLE). Tumors with right-sided primaries do not respond to EGFR antibodies, particularly in the first-line setting, she added.

A Closer Look At Targeting VEGF

“Treatment with EGFR inhibitors may accelerate growth of RAS-mutated tumors, further suggesting that we shouldn’t be using these drugs in these patients,” Yaeger said. “The presence of a BRAF V600E mutation within the tumor makes it unlikely that patients will respond to EGFR antibody, and perhaps in this setting, we should save these drugs for targeted therapy combinations.”Investigators have explored anti-VEGF therapy in first-and second-line settings. A study published in 2008 looked at investigator’s choice of CAPOX or FOLFOX4 followed by bevacizumab (n = 699) or placebo (n = 701). Bevacizumab was associated with a 1.4-month increase in PFS (9.4 vs 8.0 months; HR, 0.83; 97.5% CI, 0.72-0.95; P = .0023).⁶

Although the response rate was 47% in the bevacizumab arm compared with 49% with placebo, the median duration of response for the 2 arms was 8.45 versus 7.4 months, respectively (P = .0307). “Bevacizumab does not lead to more responses but increases the duration of response,” Yaeger said.

In the second-line setting, the ML18147 study explored bevacizumab with standard oxaliplatin- or irinotecan-based chemotherapy until progression, followed by a chemotherapy switch with bevacizumab (n = 409) or without (n = 410). Adding bevacizumab beyond progression led to a 1.3-month improvement in median OS in the intent-to-treatment (ITT) population (11.2 vs 9.8 months; unstrati ed HR, 0.81; 95% CI, 0.69-0.94; log-rank P = .0062).⁷

In the VELOUR study, investigators compared FOLFIRI plus ziv-aflibercept (Zaltrap), which also inhibits VEGF, or placebo for patients with previously treated mCRC. Median OS in the ITT population was 13.5 months with ziv-a ibercept versus 12.06 months with FOLFIRI alone (HR, 0.817; 95.34% CI, 0.713-0.937; P = .0032).⁸

“What this says is that it makes sense to continue VEGF inhibitors in the second-line setting, even in patients who received it in the first-line setting. There is a survival advantage to continuing the VEGF inhibitor,” Yaeger explained. “It does not say that switching from bevacizumab to ziv-aflibercept improves outcomes, since this hasn’t been studied. The effect we see is very similar, suggesting they play a similar role in the second-line setting.”

Beyond the second-line setting, phase III results from the CORRECT trial showed that regorafenib (Stivarga), which inhibits VEGF and other kinases, was associated with a median OS benefit of 1.4 months (6.4 vs 5.0 months; HR, 0.77; 0.64-0.94; P = .0052) in patients with mCRC that progressed after prior therapy.⁹ Responses were rare due to stability of disease, she said, but 42.8% of patients on regorafenib had stable disease compared with 14.5% of those assigned to placebo. The FDA has approved regorafenib for patients with mCRC who have been treated with chemotherapy, anti-VEGF therapy, and, if RAS wild-type, with EGFR-targeting therapy.

Immune Checkpoint Inhibitors in MSI-High CRC

The FDA also has approved the combination of TAS-102 (trifluridine and tipiracil; Lonsurf) for this population, based on an improvement in median OS of 7.1 months compared with 5.3 months with placebo (HR, 0.68; 95% CI, 0.58-0.81; P <.001).Two PD-1—targeting antibodies have been approved for patients with CRC whose tumors are MSI-high or dMMR, which has been observed in up to 15% of sporadic CRC cases.¹⁰

In May 2017, the FDA granted accelerated approval to pembrolizumab (Keytruda) for the treatment of adult and pediatric patients with unresectable or metastatic MSI-H or dMMR solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options, as well as for patients with MSI-high or dMMR CRC following progression on a fluoropyrimidine, oxaliplatin, and irinotecan. In 40 patients with CRC, pembrolizumab induced a response rate of 52%, including a 12% rate of complete responses.

About 2 months later, nivolumab (Opdivo) gained an accelerated approval for adult and pediatric patients with MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. The response rate in 74 patients with CRC was 31% at 12 months.

Table. Limitations of Anti-EGFR Therapy in CRC

Patients whose tumors harbor mutations in RAS (KRAS and NRAS) should not receive antibodies that target EGFR.

• Right-sided primary CRC tumors do not respond to anti-EGFR therapy, particularly in first-line settings.

• Using EGFR inhibitors may accelerate the growth of RAS-mutated tumors.

• It is highly unlikely that tumors harboring a BRAF V600 mutation will respond to EGFR-targeting antibodies.

Immunotherapy combinations may be a logical next step for this population. Yeager noted ndings from the CheckMate-142 study, which evaluated the combination of nivolumab plus ipilimumab (Yervoy), a CTLA-4 immune checkpoint inhibitor, in patients (N = 119) with MSI-H or dMMR mCRC who had received prior treatment (not including immunotherapy). The combination induced an investigator-assessed objective response rate of 55% (95% CI, 45.2-63.8) at a median follow-up of 13.4 months. The 12-month PFS rate was 71%, and the 12-month OS rate was 85%. Median duration of response was not reached.¹¹

Yaeger noted that patients seem to have a similar response to immune checkpoint inhibitors irrespective of BRAF V600E mutation status.

References

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2. Shi Q, Sobrero AF, Shields AF, et al. Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): the IDEA (International Duration Evaluation of Adjuvant chemotherapy) collaboration. J Clin Oncol. 2017;35(suppl; abstr LBA1). meetinglibrary. asco.org/record/147028/abstract.
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