Pembrolizumab and Lenvatinib in Patients With High Risk Locally Advanced Cervix Cancer

Rationale Chemoradiation (CRT: combined external beam radiotherapy with weekly cisplatin) followed by brachytherapy has remained the standard first line treatment for locally advanced cervical (LACC) patients. Over the last decades, major improvements in radiotherapy have been pioneered through the EMBRACE studies. Most recently the outcome data of 1318 patients undergoing response adapted advanced MRI image guided intracavitary +/-interstitial brachytherapy (MR-IGABT) over and above CRT have been reported. This dose escalated approach resulted in 5-year local control of 92%, pelvic control of 87% and disease-free survival (DFS) of 68%. In this cohort, a 5-year OS of 64% was observed for stage IIIB and 67% for node positive patients. These results essentially confirm both the effectiveness of MR-IGABT for pelvic control but also the need of more effective systemic therapy approaches. Patients most at risk for recurrence and reduced 3-year DFS include patients with presence of multiple nodes in pelvic and paraaortic region or adeno/adenosquamous carcinoma histological type and those with a poor response to CRT.

Considering that both anti-angiogenesis and immune checkpoint blockade work independently in cervix cancer, a combination approach may be associated with synergy and improved outcomes. Recently, the phase III randomized placebo-controlled KEYNOTE A-18 trial investigated the combination of CRT with anti-PD-1 Pembrolizumab in patients with high-risk locally advanced cervical cancer defined as FIGO 2014 stage IB2-IIB with node-positive disease or stage III-IVA regardless of nodal status. With a median follow-up of 17·9 months a 11% progression free survival (PFS) benefit at 2-years was demonstrated (68% vs 57%). Timing immunotherapy during radiotherapy and close to brachytherapy (where high dose per fraction is utilised) may allow to maximally synchronize "immunotherapy response" by taking advantage of the "inflamed" tumour microenvironment and a high radiotherapy dose fraction that is administered using brachytherapy. Lenvatinib will be initiated not earlier than 8 weeks after the last CRT and brachytherapy, to allow for sufficient healing of acute side effects of CRT.

The study hypothesizes that over and above concurrent and Pembrolizumab monotherapy, the addition of Lenvatinib administered after CRT and brachytherapy will lead to improved outcomes in this high-risk population of patients with locally advanced cervical cancer.

Objective The primary objective of the trial is to evaluate progression free survival (PFS) at 24 months (by investigator assessed RECIST 1.1) in women with high-risk locally advanced cervical cancer treated with chemoradiotherapy and Pembrolizumab followed by Pembrolizumab and Lenvatinib. Secondary Objectives include overall survival (OS), local and regional control; physician reported toxicity (CTCAE v5.0) and patient reported outcomes (EORTC QLQ-C30 and CX-24); and associated tissue, blood and imaging based translational research.

Interventions Patients will undergo standard of care chemoradiation (CRT: combined external beam radiotherapy with weekly cisplatin). Initial tumor imaging at pre-screening must have been performed within 28 days prior to the date of registration. The site study team must review pre-treatment images to confirm the participant has measurable disease per RECIST 1.1 at diagnosis. Target definition and dose reporting follow ICRU-89 and are detailed in the protocol. The elective node target volume is risk based and follows EMBRACE-II, that includes elective para-aortic radiotherapy up to the crossing of the renal vessels in patients with: ≥ 1 pathologic node at common iliac or above OR ≥ 3 pathologic nodes. With regard to organs at risk (OAR) for bowel the outer loops are contoured including the mesenteric, and for bones the whole bone from ischial tuberosity to 25mm superior of the PTV is contoured.

Use of image guided intensity modulated radiotherapy (IG-IMRT) preferably with rotational IMRT is mandatory. 3D image guidance (Cone Beam CT (CBCT) or equivalent image guidance) before each EBRT fraction is mandatory. This allows for use of reduced PTV margins (5mm from ITV45). The dose to the PTV45 should be homogenous, with at least 95% of the PTV covered by the 95% prescription isodose, and dose maximum less than 107% of the prescribed dose. Special attention is needed for the OAR irradiation in close proximity to the CTV-T HR (bladder, rectum, sigmoid and bowel). A help contour with a margin of 10 mm is generated around the CTV-T HR (CTV-T HR +10mm). The dose within this help contour should be less than 103% of 45Gy to avoid hotspots in OAR walls which are likely to also receive considerable BT dose. Lymph nodes will be boosted by simultaneous integrated boost (SIB) technique. Use of coverage probability (CoP) dose planning principles for lymph node boosting is mandatory.

Although institutional practise for nodal boosting and dose levels can be followed, the recommendation given within this protocol for the nodal boost is that total EBRT + BT dose should preferably be in the range 55-60 Gy EQD2.Total dose to PTV-Ns of about 60 Gy EQD2 can be achieved with the following fractionation schedules:

• Inside true pelvis: EBRT with SIB 25x2.2Gy= 55Gy physical dose. This schedule is equivalent to 56 Gy EQD2 EBRT + 3-4 Gy EQD2 from BT which results in a total dose of ~60 Gy EQD2.
• Outside true pelvis: EBRT with SIB 25x2.3Gy =57.5 Gy physical dose. This schedule is equivalent to ~59 Gy EQD2 and BT dose contribution is negligible.

All patients should receive concurrent weekly cisplatin (40 mg/m2) during the 5 weeks of EBRT, based on standard institutional protocol. If possible, it may be advantageous to initiate EBRT and concomitant chemotherapy in the beginning of a week to avoid loss of 2 days in overall treatment time (OTT) already during the first weekend.

EBRT is followed by MRI guided adaptive brachytherapy (IGABT). The overall treatment time (OTT), defined from the first external beam fraction to the final external beam or brachytherapy fraction dose is delivered should be < 50 days. To obtain maximal regression the treatment should always be initiated with EBRT and concomitant chemotherapy for 4-5 weeks before BT is applied in weeks. Systematic use of combined intracavitary and interstitial applicators (based on individual mould, ring, ovoids) is a preferred approach for appropriate dose adaptation which is dose escalation in particular for advanced parametrial disease and/or dose sparing in adjacent organs at risk. The first BT fraction has to be planned based on MRI with applicator in situ. Contouring for both tumour and OAR is performed for each insertion/implant of BT applicators by contouring on T2 weighted (para)-transversal MRI sequences in a dedicated 3D brachytherapy dose-planning system according to the GEC ESTRO Recommendations and the ICRU-89 report. Soft and hard dose planning constraints are detailed in the protocol. Doses are expressed as total EBRT and BT dose (each converted to EQD2). Hard constraints should be achieved in at least 90-95% of patients (per parameter), whereas soft constraints should be achieved in at least 70-80% of patients (per parameter). The priorities and balance between different DVH parameters are based on the therapeutic priorities (chance of tumor control versus risk of morbidity) as well as the level of evidence of dose effect for a given endpoint. Dose recording and reporting follows the recommendations of ICRU-89 report.

Standard of care CRT will be combined with the following study drugs:

Pembrolizumab: 5 intravenous administrations of Pembrolizumab (200 mg) every 3 weeks with the first administration at the start of chemoradiotherapy, followed by subsequent doses of 400 mg IV Pembrolizumab at 6 weeks intervals, starting week 16 up to week 102 with a maximum of 15 cycles. Pembrolizumab may be withheld after 1st year (week 54) in case of no evidence of disease. Lenvatinib: the combination with Lenvatinib will start after recovery of CRT, along with the 6 weekly cycles of Pembrolizumab, e.g. around 8-9 weeks after brachytherapy (week 16), at a dose of 20 mg daily oral and will continue up to week 48. Patients will be provided with a dosing card for Lenvatinib to complete during the treatment period. All patients will be asked to fill the dosing card once daily at the time of administrating Lenvatinib. It will include following information: dosing date, dose, dosing time, dosing missed and reason of missed dosing. They will be asked to bring the dosing card, along with their used medication packs, during their subsequent visit and will be used to assess compliance.

Haematology parameters and organ function will be checked through blood tests prior to each administration of Pembrolizumab and urine analysis prior to every other administration.

Tumor imaging is preferred to be acquired by computed tomography (CT) for uniform response evaluation. For the abdomen and pelvis, contrast-enhanced magnetic resonance imaging (MRI) may also be used when CT with iodinated contrast is contraindicated, or when local practice mandates it. MRI is the preferred modality for imaging the primary tumor when indicated. Initial tumor imaging at pre-screening (MRI and CT) must have been performed within 28 days prior to the date of registration. The site study team must review pre-treatment images to confirm the participant has measurable disease per RECIST 1.1 at diagnosis. Tumor imaging performed as part of routine clinical management is acceptable for use as screening tumor imaging if they are of diagnostic quality and performed within 28 days prior to the date of registration. Follow-up tumor imaging should be performed as per standard clinical practice. MRI is performed at 3 months and at 12 months (SOC), CT thorax/abdomen is performed at 12, 24 and 36 months. Based on clinical indications MRI may be repeated at 6 months (SOC).

Ethical considerations Ethical considerations relating to the clinical trial including the expected benefit to the individual subject or group of patients represented by the trial subjects as well as the nature and extent of burden and risks Pembrolizumab and Lenvatinib are cancer drugs that have proven to be effective against other cancers, both alone and in combination, such as for uterine cancer. Pembrolizumab also works well in combination with chemotherapy for advanced or metastatic cervical cancer and has been shown to be beneficial during and after chemoradiation for locally advanced cervical cancer. The study hypothesizes that over and above concurrent and Pembrolizumab monotherapy, the addition of Lenvatinib administered after CRT and brachytherapy will lead to improved outcomes in this population of locally advanced cervical cancer patients that are deemed to be at high risk of recurrence based on established risk factors.

Pembrolizumab and Lenvatinib may cause side effects (detailed in the protocol). Patients may experience side effects that can sometimes be serious or life-threatening, and/or side effects that may occur after you stopping Pembrolizumab. The side effects can occur in several tissues and organs at the same time. The following side effects of Pembrolizumab are common (may affect more than 10-20 people in 100 people receiving Pembrolizumab): Itchy skin; loose or watery stools, diarrhea, cough. The following side effects with Lenvatinib are common (may affect more than 1 in 10 people): high blood pressure; bleeding; bladder irritation or discomfort (cystitis); weight loss; diarrhoea.

Apart from side effects of the study drugs, taking part in the study will cost patients extra time, requires more and potentially longer stays in the hospital, and involves some discomfort from the additional measurements that are part of the study.