**2. Chemotherapy in ovarian cancer**

Despite the emergence of alternate antineoplastic strategies, chemotherapy remains the backbone of EOC treatment. Although EOC is chemosensitive, with most patients responding initially, the majority will eventually relapse and subsequent responses are poorer. Efforts are being made to try and enhance the efficacy of 'traditional' cytotoxic chemotherapy. These include manipulation of dosing schedules, efforts to understand resistance and discovery of novel agents. These strategies are discussed in this subsection.

#### **2.1. Dose-dense chemotherapy**

Dose densification refers to the administration of an agent more frequently than in the 'standard' regimen. It can imply dose intensification (i.e. increasing the net mg/m<sup>2</sup> /week) but some authors use it to describe splitting the standard scheduled dose into weekly fragments while maintaining the same (rather than increased) dose intensity [1].

In JGOG 3016 patients derived both PFS and OS benefit from the dose-dense approach, whereas in GOG 0262, there was no PFS difference in the intention to treat (ITT) population [7−9]. The two trials, however, had key differences. Patients in GOG 0262 were allowed bevacizumab (BEV) in an uncontrolled fashion. Since weekly paclitaxel has an anti-angiogenic effect, this may have been negated by the addition of BEV in 85% of the trial population. Consistent with this, in those who didn't receive BEV, weekly paclitaxel improved PFS (14.2 vs. 10.3 months). Pharmacogenomic differences in the two trial populations may also have been important. There are consequently unanswered questions about dose-dense chemotherapy which may be answered by two phase III trials yet to report. In the 3-arm ICON 8 trial (NCT01654146), q3w carboplatin/paclitaxel is compared to 2 dose-dense regimens without BEV. In ICON 8B

**Table 1.** Comparison of phase III trials testing weekly paclitaxel in the adjuvant setting. All values given as weekly vs. q3w.

**Study Eligibility Treatment Efficacy (months) Safety (grade ≥ 3, P < 0.001)**

PFS 28.2 vs. 17.5 OS 100.5 vs. 62.2

PFS 14.7 vs. 14.0 (not significant)

PFS 18.3 vs. 17.3 (not significant)

(weekly).

Anaemia 69% vs. 44% Discontinuation due to tox.

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333

Anaemia 36% vs. 16% Neutropenia 72% vs. 83%

Neutropenia 42% vs. 50% Thrombocytopenia 1% vs. 7%

60% vs. 43%

Novel Systemic Treatments in High Grade Ovarian Cancer

(weekly). 84% of patients received bevacizumab.

(weekly).

q3w **or** weekly1

bevacizumab2

As above + uncontrolled

either q3w **or** weekly3

(q3w) or 80 mg/m<sup>2</sup>

(q3w) or 80 mg/m<sup>2</sup>

(q3w) or carboplatin AUC 2, paclitaxel 60 mg/m<sup>2</sup>

JGOG 3016 [10] Stage II-IV Carbo q3w + either taxol

resected III or IV

Carboplatin AUC 6, paclitaxel 180 mg/m<sup>2</sup>

Carboplatin AUC 6, paclitaxel 175 mg/m<sup>2</sup>

MITO-7 [12] Stage IC-IV Carobplatin/paclitaxel

GOG 0262 [11] Incompletely

Carboplatin AUC 6, 175 mg/m<sup>2</sup>

1

2

3

EOC is initially chemosensitive so efforts to understand resistance could improve outcomes. Acquired resistance is secondary to diverse mechanisms which includes alterations to DNA repair and/or response to DNA damage. Mk-1775 is an anti-Wee1 tyrosine kinase inhibitor (TKI) that may sensitize cells to chemotherapy by abrogating the G2 checkpoint (crucial in P53 deficient cells) causing premature entry into mitosis [10]. It has shown promising results in several phase II trials [11]. In a different approach, the 2-arm PiSARRO trial (NCT02098343) involves the addition of APR-246 (capable of restoring mutant P53 to wild-type confirmation) to platinum-based therapy with the aim of restoring the apoptotic-response to chemotherapyinduced DNA damage. There are many other pre-clinical and early clinical efforts aiming to reverse chemoresistance including efforts to target primary resistance by targeting cancer

Lurbinectedin is a recently discovered marine-derived antineoplastic agent that has a multimodal mechanism of action similar to trabectedin. It showed promising results in a phase II

(NCT01654146), bevacizumab use is allowed but is controlled and pre-specified.

**2.2. Understanding resistance to facilitate chemosensitization**

stem cells and epithelial to mesenchymal transition [12].

**2.3. Novel chemotherapeutic agents**

The rationale for dose-dense treatment stems from the Norton-Simon hypothesis (**Figure 1**).

The rationale for dose densification extends beyond the Norton-Simon hypothesis. Firstly, the pharmacokinetics of a dose-dense approach may reduce toxicity. For example, paclitaxelinduced myelosuppression is dependent on the time during which the plasma level exceeds 50 nM [3]. This is considerably shorter for 80 mg/m<sup>2</sup> weekly compared to 240 mg/m<sup>2</sup> q3w [4]. Secondly, weekly paclitaxel may confer an additional anti-angiogenic effect compared to q3w scheduling [5].

Weekly paclitaxel was initially studied in the recurrent setting. Notably in one trial patients resistant to the q3w regimen achieved an objective response rate (ORR) of 25% with the weekly regimen possibly due to the additional anti-angiogenic effect of this schedule [6].

Weekly paclitaxel has also been studied in the adjuvant setting (**Table 1**).

**Figure 1.** The Norton-Simon hypothesis assumes a Gompertzian model of tumour growth (left). This was combined with their observation that after treatment, smaller tumours regress faster than larger ones. Crucial to their mathematical model is the fact that 'log-kill' is not constant for a given dose of therapy but instead depends on tumour size, being greater for smaller tumours. Their model predicts that a dose-dense approach is more likely to eradicate a tumour [2].


1 Carboplatin AUC 6, paclitaxel 180 mg/m<sup>2</sup> (q3w) or 80 mg/m<sup>2</sup> (weekly). 2 Carboplatin AUC 6, paclitaxel 175 mg/m<sup>2</sup> (q3w) or 80 mg/m<sup>2</sup> (weekly). 84% of patients received bevacizumab. 3 Carboplatin AUC 6, 175 mg/m<sup>2</sup> (q3w) or carboplatin AUC 2, paclitaxel 60 mg/m<sup>2</sup> (weekly).

**Table 1.** Comparison of phase III trials testing weekly paclitaxel in the adjuvant setting. All values given as weekly vs. q3w.

In JGOG 3016 patients derived both PFS and OS benefit from the dose-dense approach, whereas in GOG 0262, there was no PFS difference in the intention to treat (ITT) population [7−9]. The two trials, however, had key differences. Patients in GOG 0262 were allowed bevacizumab (BEV) in an uncontrolled fashion. Since weekly paclitaxel has an anti-angiogenic effect, this may have been negated by the addition of BEV in 85% of the trial population. Consistent with this, in those who didn't receive BEV, weekly paclitaxel improved PFS (14.2 vs. 10.3 months). Pharmacogenomic differences in the two trial populations may also have been important. There are consequently unanswered questions about dose-dense chemotherapy which may be answered by two phase III trials yet to report. In the 3-arm ICON 8 trial (NCT01654146), q3w carboplatin/paclitaxel is compared to 2 dose-dense regimens without BEV. In ICON 8B (NCT01654146), bevacizumab use is allowed but is controlled and pre-specified.

#### **2.2. Understanding resistance to facilitate chemosensitization**

EOC is initially chemosensitive so efforts to understand resistance could improve outcomes. Acquired resistance is secondary to diverse mechanisms which includes alterations to DNA repair and/or response to DNA damage. Mk-1775 is an anti-Wee1 tyrosine kinase inhibitor (TKI) that may sensitize cells to chemotherapy by abrogating the G2 checkpoint (crucial in P53 deficient cells) causing premature entry into mitosis [10]. It has shown promising results in several phase II trials [11]. In a different approach, the 2-arm PiSARRO trial (NCT02098343) involves the addition of APR-246 (capable of restoring mutant P53 to wild-type confirmation) to platinum-based therapy with the aim of restoring the apoptotic-response to chemotherapyinduced DNA damage. There are many other pre-clinical and early clinical efforts aiming to reverse chemoresistance including efforts to target primary resistance by targeting cancer stem cells and epithelial to mesenchymal transition [12].

#### **2.3. Novel chemotherapeutic agents**

**2. Chemotherapy in ovarian cancer**

332 Ovarian Cancer - From Pathogenesis to Treatment

**2.1. Dose-dense chemotherapy**

scheduling [5].

novel agents. These strategies are discussed in this subsection.

maintaining the same (rather than increased) dose intensity [1].

50 nM [3]. This is considerably shorter for 80 mg/m<sup>2</sup>

Despite the emergence of alternate antineoplastic strategies, chemotherapy remains the backbone of EOC treatment. Although EOC is chemosensitive, with most patients responding initially, the majority will eventually relapse and subsequent responses are poorer. Efforts are being made to try and enhance the efficacy of 'traditional' cytotoxic chemotherapy. These include manipulation of dosing schedules, efforts to understand resistance and discovery of

Dose densification refers to the administration of an agent more frequently than in the 'stan-

authors use it to describe splitting the standard scheduled dose into weekly fragments while

The rationale for dose-dense treatment stems from the Norton-Simon hypothesis (**Figure 1**).

The rationale for dose densification extends beyond the Norton-Simon hypothesis. Firstly, the pharmacokinetics of a dose-dense approach may reduce toxicity. For example, paclitaxelinduced myelosuppression is dependent on the time during which the plasma level exceeds

Secondly, weekly paclitaxel may confer an additional anti-angiogenic effect compared to q3w

Weekly paclitaxel was initially studied in the recurrent setting. Notably in one trial patients resistant to the q3w regimen achieved an objective response rate (ORR) of 25% with the weekly regimen possibly due to the additional anti-angiogenic effect of this schedule [6].

**Figure 1.** The Norton-Simon hypothesis assumes a Gompertzian model of tumour growth (left). This was combined with their observation that after treatment, smaller tumours regress faster than larger ones. Crucial to their mathematical model is the fact that 'log-kill' is not constant for a given dose of therapy but instead depends on tumour size, being greater for smaller tumours. Their model predicts that a dose-dense approach is more likely to eradicate a tumour [2].

/week) but some

q3w [4].

weekly compared to 240 mg/m<sup>2</sup>

dard' regimen. It can imply dose intensification (i.e. increasing the net mg/m<sup>2</sup>

Weekly paclitaxel has also been studied in the adjuvant setting (**Table 1**).

Lurbinectedin is a recently discovered marine-derived antineoplastic agent that has a multimodal mechanism of action similar to trabectedin. It showed promising results in a phase II trial in platinum-resistant EOC and is being investigated in a phase III trial against either PLD or topotecan [13]. It has also shown *in vitro* synergy with cisplatin raising hopes of clinical application to reverse platinum resistance [14]. Trabectedin itself is undergoing phase III testing in patients with platinum partially-sensitive disease (NCT01379989).

There were similarities and differences between these trials. Both suggested greater benefit in a subpopulation with higher stage and suboptimal debulking. They also agreed that QoL was not improved with BEV. Conversely, different doses and durations of treatment were used and overall survival data also differed, perhaps confounded by the 40% crossover in GOG 218. BEV received regulatory approval from the EMA using 15 mg/kg [25] although ESMO guidelines supported the 7.5 mg/kg dose used in ICON7, which is also prescribed in the UK currently [26]. Analysis of both trials showed greatest separation of the PFS curves at the end of BEV treatment (12 or 15 months), raising questions about extending maintenance duration.

Novel Systemic Treatments in High Grade Ovarian Cancer

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Bev has also been studied for recurrence. In AURELIA [27], patients with platinum-resistant disease and ≤2 prior lines of chemotherapy were given single agent investigator-choice chemotherapy either alone or with BEV continued until progression/toxicity. Median PFS was higher in the BEV arm, 6.7 vs. 3.4 months with an ORR of 27.3 vs. 11.1%. Of the 113 patients with baseline ascites 17% required paracentesis in the control arm vs. 2% in the BEV arm and PROMs for GI symptoms were better with BEV [28]. OS was not significantly different in the context of 40% crossover but a recent exploratory analysis suggestive a survival advantage in those who received BEV during or after the study [29]. Adverse events were consistent with previous studies. BEV has been granted FDA and EMA approval for this

In the OCEANS study [30], the addition of BEV to carboplatin/gemcitabine in patients with platinum-sensitive disease resulted in a median PFS of 12.4 months vs. 8.4 months. OS was not significantly (38% crossover). Hypertension, proteinuria and non-CNS bleeding were significantly more common in the BEV arm. BEV was also tested in the platinum-sensitive setting with carboplatin/paclitaxel, in the factorial GOG-213 trial [31]. Median OS with BEV was 42.2 months compared to 37.3 months without (p = 0.056). BEV has EMA regulatory approval

Whereas BEV binds directly to VEGF, VEGFR TKIs affect signalling via competitive inhibition of the intracellular kinase domain. They have the advantage of being orally bioavailable and multitargeted. Conversely, plasma concentration is unpredictable and off-target effects nar-

Cediranib inhibits VEGR-1,2 and 3 and c-Kit. ICON 6 [32] randomised patients with recurrent platinum-sensitive disease to chemotherapy plus: placebo concurrently + maintenance (Arm A), cediranib concurrently + placebo maintenance (Arm B) or cediranib concurrently + maintenance (Arm C). Median PFS was 11 months in Arm C vs. 8.7 months in Arm A (p < 0.0001). Recent OS data [33] by restricted means showed 34.2 months vs. 29.4 months in Arms C and A respectively (95% CI for the difference: −0.1-9.8). During chemotherapy grade ≥ 3 fatigue (16 vs. 8%), diarrhoea (10 vs. 2%), hypertension (12 vs. 3%), febrile neutropenia (7 vs. 3%) and thrombosis (3 vs. 1%) were higher with cediranib. 48% discontinued treatment due to toxic effects in Arm C compared to 17% in Arm A and 37% in B. Although recent analysis showed no detriment in

This is being investigated in the phase III BOOST study (NCT01462890).

indication.

in this setting.

row the therapeutic window.

**3.2. VEGFR tyrosine kinase inhibitor (TKI) therapy**
