Results from FOCUS4-N

The full report of the FOCUS4-N trial has been published.111 Parts of this chapter have been reproduced by Adams et al.111 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text.

Scientific rationale for FOCUS4-N

Treatment breaks in patients receiving palliative chemotherapy for metastatic CRC reduce toxicity burden and improve quality of life.16 However, current standards either mandate or recommend a strategy of continuing therapy until disease progression or excess toxicity. Standard maintenance strategies in high-income countries favour a combination of capecitabine orally with intravenous bevacizumab thrice weekly,112,113 based on the Phase III CAIRO3114 and AIO-0207102 studies. Health economic evaluation of this approach has previously indicated a lack of cost-effectiveness driven by the non-significant improvement in OS and relatively high cost of intravenous bevacizumab (drug plus administration); a 93% cost reduction would be required for this strategy to become cost-effective.115 Prior studies have evaluated a range of strategies to either completely stop therapy as a ‘treatment holiday’, reducing toxicities and visits to hospital, or attenuate the therapy, removing certain drugs as a maintenance therapy in comparison with the historic standard of care of continuing maximum tolerated dose of treatment. Meta-analysis of these approaches overall shows no difference in OS.116 Notably, maintenance strategies, almost uniformly, demonstrate an improvement in PFS but at the expense of ongoing, yet attenuated, toxicity and unending, multiple visits to hospital for intravenous therapy. To the best of our knowledge, the FOCUS4-N trial is the first trial to explore the oral strategy of capecitabine only versus active monitoring to assess the potential impact on PFS, toxicity and quality of life, and enable patients and clinicians to choose an optimum approach tailored to the individual.

FOCUS4-N was the non-stratified comparison in the FOCUS4 trial programme and was designed for patients in whom a molecularly stratified comparison was unavailable or the biomarker tests failed for the patient’s tumour tissue. FOCUS4-N investigated the efficacy of capecitabine as a maintenance therapy compared with active monitoring in patients with metastatic CRC. The methods used for patient registration and biomarker testing in FOCUS4-N have been described in Chapter 2.

Study methods

Trial approvals, patient eligibility and recruitment

The trial and subsequent amendments were approved by the UK National Ethics Committee Oxford – Panel C and by the relevant regulatory body MHRA (CTA# 20363/0400/001 and EudraCT# 2012-005111-12).

Patients aged ≥ 18 years with newly diagnosed locally advanced or metastatic CRC were eligible for registration in the FOCUS4 trial programme.20 Patients whose tumours had remained stable or responded to treatment according to their 16-week CT were assessed for eligibility for the FOCUS4-N comparison. In addition to the registration eligibility criteria, patients were required to have a baseline randomisation CT scan performed within 4 weeks prior to randomisation; a minimum 3-week washout period after the last dose of chemotherapy or biological therapy and before the first dose of capecitabine; adequate renal (creatinine clearance > 50 ml/minute) and liver function; and a WHO performance status of 0–2. Patients who were eligible for either FOCUS4-N or a molecularly stratified trial were offered entry into either trial and given the option of which study to participate in.

In the first phase of the FOCUS4 trial, between January 2014 and June 2017, patients with a raised baseline platelet count (thrombocytosis) were considered ineligible based on previous data from the COIN trial, which indicated a significant detriment in survival in this group of patients receiving an intermittent strategy.16 A subsequent individual-patient data meta-analysis of Phase III intermittent strategy trials did not confirm this observation in COIN.117 Thus, between June 2017 and March 2020, eligibility criteria were adapted to allow this group of patients with thrombocytosis to be included.

Trial procedures

Patients randomised to receive capecitabine were asked to continue taking the drug until disease progression, death or intolerable toxicity. Capecitabine was sourced from local hospital stock and dosed in accordance with standard cycle guidelines: oral capecitabine twice per day for 14 days, followed by a 7-day rest period of no capecitabine tablets.

Patient tumour status was assessed every 8 weeks by CT scan, which was reviewed at the treating hospital site in accordance with RECIST, version 1.1.118 Toxicities and symptoms were assessed locally every 4 weeks from randomisation or the start of treatment, using the NCI common terminology criteria for adverse events (version 3.0). Patients were followed until progressive disease occurred, at which point the patient was recommended to restart first-line chemotherapy.

Treatment was stopped in the event of grade 3 or worse toxic effects or persistent toxicities judged medically significant or not tolerated by the patient, until the toxicity resolved to grade 1 or better. After stopping treatment (for a maximum of 28 days), capecitabine could be re-initiated at a reduced dose. Any stoppage for ≥ 28 days was not permitted, and the patient was discontinued from trial therapy but remained under follow-up.

Quality-of-life data were collected using EuroQol-5 Dimensions (EQ-5D) at multiple time points: at randomisation, every 8 weeks until progression, 4 weeks after end of trial treatment (progression, toxicity or patient choice), 3 months after progression and 6-monthly.

Statistical methods

Treatment allocation

Patients were allocated to capecitabine or active monitoring by a centrally managed telephone service at the MRC CTU at UCL, using a 1 : 1 allocation ratio by minimisation with a random element of 20%. Minimisation factors were treating hospital site, site of primary tumour (right colon, left colon or rectum), WHO performance status (0–2), 16-week CT scan result (stable disease, partial response or complete response), number of metastatic sites (none, one, or two or more) and first-line chemotherapy regimen (fluorouracil, capecitabine or neither; both oxaliplatin and irinotecan, oxaliplatin only, irinotecan only or neither; and cetuximab or panitumumab, bevacizumab or no monoclonal antibody).

Outcome measures

The primary outcome for FOCUS4-N was PFS, defined as the time from randomisation to either disease progression (in accordance with RECIST criteria) or death from any cause. Patients without a PFS event were censored at the time of their last recorded CT scan. OS was a secondary outcome, defined as time from randomisation to death from any cause, with patients censored at last recorded disease assessment, blood measurement or anti-cancer treatment. Other secondary outcomes included safety, toxicity, quality of life and tumour response. Quality of life was analysed using mixed-effects linear modelling with patient-level random intercepts and time slopes, with differences by treatment arm tested by evaluating the area under the curve from the model.

Sample size calculation

The target sample size for FOCUS4-N was calculated using the analysis of resources for trials programme implemented in Stata software. Given that the rate of recruitment into FOCUS4-N was dependent on the availability of other molecular comparisons, failure of biomarker testing or patient choice, exact recruitment figures were not known at the start of the trial. Various scenarios were used to estimate the recruitment rate over 5 years and a median PFS of 4 months was assumed in the active monitoring arm (based on data in the COIN trial). A total of 644 patients (635 events) would provide 80% power of detecting a HR of 0.8 at the two-sided 5% significance level.

In March 2020, the COVID-19 pandemic resulted in temporary closure of FOCUS4 to new recruitment and, following IDMC review and recommendation, a decision was taken to close recruitment permanently in April 2020 because trial funding was nearing its end. A previous review of the implications of reduced recruitment on the statistical power of FOCUS4-N had been reviewed by the funders, who recommended that, despite reduced power, the trial should close in 2020 and report the data accrued up to that point.

Statistical analysis

All analyses were performed in accordance with a predefined SAP that was agreed before database lock. Analyses were performed using Stata statistical software, version 16.1. The primary analysis was performed in accordance with ITT, with a secondary per-protocol analysis defined by patients who completed at least one cycle of trial treatment (≥ 28 days). Patients were censored in accordance with the following criteria. For survival status, patients were censored on the date that they were last known to be alive, either via collection of prescription from their hospital pharmacy or attendance at a follow-up visit or CT scan. For PFS, patients were censored without progression on the date of the last CT scan showing no progression. For patients who died before any follow-up visit or CT scan, the date of death was used as the date of the event and assumed death without progression providing that the death occurred within 3 months of randomisation or any previous CT scan confirming no progression.

Kaplan–Meier curves were used to present survival data and Cox regression modelling was used to estimate the HR between randomised groups. Unadjusted HRs were estimated, as well as HRs adjusted for the stratification factors that were used to minimise patients into allocated groups (primary analysis). A further analysis also adjusted for resection status, timing of metastatic disease, alkaline phosphatase, white blood cell count, age of tumour sample and use of aspirin at baseline. Deviation from non-proportional hazards was assessed using regression of scaled Schoenfeld residuals against the log of time.

Study results

Recruitment and compliance

Across 88 UK hospitals, between January 2014 and March 2020, a total of 1434 patients were registered into the FOCUS4 trial, of whom 924 underwent successful biomarker assessment and completed 16 weeks of first-line therapy with stable disease, partial response or complete response. Of these patients, 254 were randomised into FOCUS4-N (Figure 13), 127 patients to active monitoring and 127 patients to maintenance capecitabine monotherapy.

FIGURE 13 Patient flow through the FOCUS4-N trial. CR, complete response; PR, partial response. (Figure not reproduced here; see the original article.)

Baseline demographic and clinical characteristics were well balanced between the study arms (Table 12). The majority of patients had widespread synchronous metastatic disease, with approximately half of the patients having no resection of their primary tumour. A right-sided PTL was present in approximately one-third of patients. The majority of patients were treated with doublet chemotherapy (irinotecan based, 57%) without a monoclonal antibody because bevacizumab is not reimbursed in the UK. The molecular characteristics are shown in Table 12, which shows that only 37% had a RAS wild-type tumour, reflecting the NHS England policy not to allow treatment breaks for patients on EGFR monoclonal antibodies.

Compliance with randomised allocation was good for only one patient in the active monitoring arm receiving capecitabine approximately 6 months prior to progression. Patients in the capecitabine arm received a median of four cycles (IQR 2–8 cycles).

Primary outcome: progression-free survival

There were 122 PFS events in the active monitoring arm (n = 127 patients) and 117 in the capecitabine arm (n = 127 patients). The median PFS in the capecitabine arm was 3.88 months (IQR 2.10–7.39 months) and 1.87 months (IQR 1.64–3.65 months) in the active monitoring arm. The unadjusted and adjusted HRs were 0.44 (95% CI 0.33 to 0.57; p = 2.8 × 10^–10) and 0.40 (95% CI 0.21 to 0.75; p = 3.9 × 10^–10), respectively; the Kaplan–Meier curves are presented in Figure 14. Per-protocol analyses demonstrated very similar findings: the unadjusted and adjusted HRs were 0.42 (95% CI 0.32 to 0.55; p = 6.9 × 10^–10) and 0.38 (95% CI 0.28 to 0.51; p = 9.5 × 10^–11), respectively. There was no evidence to suggest that there was deviation from the proportional hazards assumption (p = 0.084).

FIGURE 14 Kaplan–Meier curve for PFS in FOCUS4-N. Minimisation factors: location of primary tumour (left, right, rectum), baseline WHO performance status, baseline disease assessment, number of metastases, first-line therapy (fluoropyrimidine, oxaliplatin or irinotecan, monoclonal antibody), Biomarker cohort and stratified for FOCUS4 trial time points. (Figure not reproduced here; see the original article.)

Overall survival

There were 90 deaths in the active monitoring arm (n = 127 patients) and 99 deaths in the capecitabine arm (n = 127 patients). The median time to death was 15.2 months (IQR 8.8–24.0 months) in the active monitoring arm, compared with 14.8 months (IQR 10.2–21.8 months) in the capecitabine arm, with a non-significant difference in survival between the two arms. The unadjusted and adjusted HRs were 1.00 (95% CI 0.75 to 1.33; p = 0.98) and 0.93 (95% CI 0.69 to 1.27; p = 0.66), respectively; the Kaplan–Meier curves are presented in Figure 15. There was no evidence to suggest that there was deviation from the proportional hazards assumption (p = 0.58).

FIGURE 15 Kaplan–Meier curve for OS in FOCUS4-N. Minimisation factors: location of primary tumour (left, right, rectum), baseline WHO performance status, baseline disease assessment, number of metastases, first-line therapy (fluoropyrimidine, oxaliplatin or irinotecan, monoclonal antibody), biomarker cohort and stratified for FOCUS4 trial time points. (Figure not reproduced here; see the original article.)

Subgroup analyses

The pre-planned subgroup analysis for PFS (Figure 16) demonstrated a non-significant trend towards better PFS with a maintenance strategy in left-sided tumours (HR 0.38 vs. 0.56 for right sided; interaction p = 0.13); a similar trend was seen with OS (HR 0.82 for left sided vs. 1.37 for right sided; interaction p = 0.076; Figure 17). There was a suggestion that patients with loss of PTEN and PIK3CA-mutant tumours may show less benefit than other molecular subgroups of maintenance capecitabine (PFS HR 0.74, OS HR 1.47), although this was not statistically significant. Patients with the double mutation in RAS and TP53 – that is, the same molecular characteristics as selected for the FOCUS4-C trial27 – showed the same beneficial effect of maintenance capecitabine as for the whole trial (PFS HR 0.44, 95% CI 0.30 to 0.63). For OS, the only other notable subgroup effect was that those with stable disease at randomisation appeared to benefit from maintenance capecitabine, whereas those with partial response did not (OS HR 0.63 and 1.42, respectively; interaction p = 0.005; see Figure 17). Swimmer plots showed the distribution of individual patient PFS duration and timing of CT scans by left-sided versus right-sided disease (Figure 18).

FIGURE 16 Forest plot of subgroup analyses for PFS (unadjusted HRs) in FOCUS4-N. CET, cetuximab; PAN, panitumumab; WHO, World Health Organization. (Figure not reproduced here; see the original article.)

FIGURE 17 Forest plot of subgroup analyses for OS (unadjusted HRs) in FOCUS4-N. CET, cetuximab; PAN, panitumumab; PTEN, phosphatase and tensin homologue; WHO, World Health Organization. (Figure not reproduced here; see the original article.)

FIGURE 18 Swimmer plot for FOCUS-N, by location of primary tumour in FOCUS4. Light blue horizontal strip, right-sided; navy strip, left-sided (including rectum). (Figure not reproduced here; see the original article.)

Toxicity

Cumulative toxicities were significantly less in the active monitoring arm, with increased toxicities associated with capecitabine maintenance, including diarrhoea, dry skin, fatigue, nausea and palmar–plantar erythema, as presented in Figure 19. Ideally, a maintenance therapy should result in no toxicity. The incidences of grade zero toxicity as the worst toxicity reported per patient are, therefore, instructive and were as follows for active monitoring and capecitabine maintenance, respectively: nausea 74% versus 67%; diarrhoea 72% versus 46%; stomatitis 90% versus 77%; dry skin 83% versus 77%; palmar–plantar erythema 87% versus 44%; and anaemia 69% versus 54%. There were no notable differences in the incidence of grade zero toxicities for neutropenia, skin rash, nail dystrophy or vomiting.

FIGURE 19 Cumulative reported toxicity by randomised group in FOCUS4-N. (a) Active monitoring; and (b) capecitabine. PPE, pruritic papular eruption. (Figure not reproduced here; see the original article.)

During the trial, 51% of capecitabine patients had at least one cycle delayed, 37% had a dose reduction and 34% had at least one missed dose (within a cycle). A total of 50% of capecitabine patients commenced at least four cycles and 25% commenced at least eight cycles.

Quality of life

The EQ-5D quality-of-life forms were completed for 93% (active monitoring) and 90% (capecitabine) of patients at baseline (pre randomisation but post induction chemotherapy). The protocol mandated 8-weekly completion until progression and 6-monthly thereafter; for analysis purposes, all available forms were forced into an 8-weekly schedule. On this basis, 63%, 45% and 33% of randomised patients had data available at 8, 16 and 24 weeks, respectively, with continued decline thereafter. Modelling was applied to data up to 48 weeks, given that data became too sparse beyond that point. No notable differences were seen in mobility, self-care, usual activities, anxiety and depression. A non-significant difference (p = 0.11) was seen in pain and discomfort in favour of the capecitabine maintenance strategy (Figure 20). This may be a result of symptoms associated with increased rates of progression in the active monitoring arm.

FIGURE 20 Quality of life measured by EQ-5D by randomised group in FOCUS4-N. (a) Mobility; (b) self-care; (c) usual activities; (d) pain and discomfort; and (e) anxiety and depression. (Figure not reproduced here; see the original article.)

Discussion and conclusions

Choices on how to proceed with palliative treatment in the majority of patients with metastatic, incurable CRC, with responding or stable disease after 16 weeks of first-line chemotherapy, need careful consideration with the patient at the core. Discussions must be informed by the impact of receiving systemic anti-cancer therapy over the preceding period. This should include an evaluation of the burden of toxicity and quality of life, as well as the response to treatment. Pooled data from key Phase II and III trials suggest minimal impact on OS from a maintenance or continuation strategy but do show the ability to delay a return to ‘full’ combination therapy by implementation of a maintenance therapy. Notably, the FOCUS4-N data support the use of an oral-only therapy, ‘capecitabine’, to extend PFS and delay a return to combination therapy by an average of 2 months. There is a clear cost to the patient for this improvement in PFS seen with maintenance oral capecitabine, which includes worse toxicity in terms of diarrhoea, fatigue, nausea, skin rash and plantar–palmar erythema, albeit most frequently at grade 1 and 2 levels; these factors should be used to further inform decision-making processes. There was no difference in quality-of-life scores between the two arms. It is notable that the swimmer plots suggested that approximately one-third of patients gain a significant increment in PFS with maintenance capecitabine, suggesting significant fluoropyrimidine sensitivity, while one-third of patients demonstrate relative insensitivity to a fluoropyrimidine monotherapy and may indicate a further need to explore predictive biomarkers of efficacy for this strategy. Pre-planned subgroup analysis suggests that patients with stable disease at the end of the 16-week induction period may gain a significant survival benefit from maintenance capecitabine, but this was not borne out in other studies in which the same phenomenon was assessed.117

Although this study was underpowered to evaluate OS, it demonstrated very similar median OS values of 14.8 versus 15.2 months in the capecitabine arm and active monitoring arm, respectively, with a HR of 0.93 (p = 0.66) when adjusted for minimisation factors. It is informative to compare these data with those of CAIRO3, which is a very similar study that compared an active monitoring strategy with capecitabine plus bevacizumab maintenance with comparable effects on PFS (HR 0.38; p < 0.0001), akin to the adjusted HR (0.40, p < 0.0001) in FOCUS4-N and OS (HR 0.86, p = 0.1).114 Although cross-trial comparisons carry significant caveats and need to be undertaken with caution, this does suggest that the main driver of PFS improvement when using capecitabine plus bevacizumab is from the capecitabine. IPD meta-analysis has also shown no OS benefit from current maintenance therapy strategies.117

Based on a subgroup analysis from the much larger Phase III COIN study,16 which demonstrated a survival detriment in those patients with a baseline thrombocytosis receiving a complete treatment break (HR 1.55; p = 0.0018), it was decided not to recruit patients to the FOCUS4 trial programme from January 2014 to June 2017. Wishing to validate or refute this finding, an IPD meta-analysis was undertaken to assess thrombocytosis as a predictive marker of the benefits or otherwise of an intermittent or continuous therapy strategy.117 This evaluation did not validate the COIN finding on thrombocytosis and, thus, the trial eligibility was adapted to allow these patients to enter the study. Within FOCUS4-N overall, 3% (n = 8) of patients had a baseline thrombocytosis and, therefore, this study was underpowered to explore this predictive phenomenon further. Because of the conservative approach, FOCUS4-N under-represents the approximately 25% of patients with metastatic CRC who typically have thrombocytosis at baseline and form a poorer prognosis group. However, given the findings in the IPD meta-analysis, this is not considered to undermine the more general conclusions, which are independent of baseline platelet count.

Owing to funding restrictions in the UK NHS, bevacizumab is not routinely available for patients with metastatic CRC, and in patients with RAS wild-type tumours EGFR monoclonal antibodies are available only in the first-line setting, with restrictions in England also preventing treatment interruption of cetuximab or panitumumab for longer than 6 weeks. In addition, during the FOCUS4-D trial recruitment period,88 patients with RAS wild-type and BRAF wild-type tumours were eligible for randomisation and were preferentially recruited to that trial. These factors make for a slightly selective group of patients recruited to FOCUS4-N during that time. From a molecular perspective, 59% of patients randomised in the FOCUS4-N trial had a RAS mutation and 15% had a BRAF mutation. Reassuringly, the forest plots (see Figures 16 and 17) do not show any significant differences in PFS based on these molecular criteria.

The molecular stratification of patients in the FOCUS4 trial programme has allowed us to explore the impact of a capecitabine maintenance therapy from FOCUS4-N in the same molecular subgroup of patients who would otherwise have been able to receive novel maintenance therapy as a parallel cohort. Thus, patients recruited to FOCUS4-N who had a RAS and TP53 mutation within their tumour were compared with patients recruited into FOCUS4-C who had the same double-mutant status but were randomised to receive the novel Wee1 inhibitor AZD1775 (adavosertib, AstraZeneca UK) versus active monitoring.27 There was no evidence to suggest a treatment benefit difference between these trials; however, subgroup analyses have demonstrated interesting differences between the trials, which are explored more fully in the FOCUS4-C paper.27

Despite strong evidence of disease control with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as a safe management alternative for patients entering treatment de-escalation after 16 weeks of induction therapy for metastatic CRC. If maintenance therapy is selected following consideration of the advantages and disadvantages in consultation with a particular patient, capecitabine without bevacizumab may be used to extend PFS in the interval after doublet or triplet therapy, essentially doubling the period prior to recommencing full-dose induction therapy. Notably, these data also provide the tools to best inform the dialogue between patients and clinicians on the pros and cons of the different approaches and their trade-offs.