PembRolIzuMab and Stereotactic Body Radiotherapy In Metastatic Non-small-cell lunG Cancer Patients

This is a single centre non-randomised open label phase 1 trial of lung SBRT to part of a lung lesion in patients with advanced NSCLC in combination with pembrolizumab. This study will recruit up to 24 patients whose lung cancer has progressed beyond one line of palliative chemotherapy, and an EGFR or ALK inhibitor if an EGFR driver mutation or ALK gene rearrangement is present, respectively, and now requires further palliative systemic treatment.

The study will be conducted in two parts; an initial lung SBRT dose escalation phase (Part A), followed by a lung SBRT dose expansion cohort (Part B). The dose escalation phase is based on a 3+3 design such that patients will be treated in cohorts of 3-6 patients. A maximum of 12 patients will be allocated to one of two doses of lung SBRT in combination with pembrolizumab to determine the MTD, DLTs and RP2D. If there is more than one DLT in cohort 1, this treatment combination will be deemed as being unacceptable, and it would lead to termination of the study. Note, there is no de-escalation in cohort 1. During the dose expansion cohort, 12 patients will have lung SBRT dosed at the RP2D determined during the dose escalation phase in combination with pembrolizumab to obtain additional safety and response data. Maintenance pembrolizumab will continue until disease progression, unacceptable toxicities, the patient withdraws consent to the trial, or the patient has completed 24 months of treatment. A maximum of 24 patients will be treated in the study.

All patients will receive pembrolizumab on cycle (C) 1 day (D) 1, in Part A and B of the study. All patients will receive lung SBRT on C1D15, C1D17, and C1D19 as per lung SBRT protocol (See Appendix 3). Although C1D1 can occur +/- 3 days, C1D15, C1D17, and C1D19, must be scheduled for a Monday, Wednesday and Friday, respectively. Patients in part A will receive lung SBRT dosed at 30 Gy in 3# in cohort 1, or 54 Gy in 3# in cohort 2. Patients in Part B will receive the RP2D of lung SBRT, determined in Part A. All patients in Part A and Part B will receive pembrolizumab dosed at 200 mg every 3 weeks, until disease progression, unacceptable toxicities, the patient withdraws consent from the trial, or the patient has completed 24 months of treatment.

In the dose escalation phase, a minimum of 3 patients will be required per dose level being assessed. A minimum gap of 1 week will be left between the treatment of the first and the second, and between the second and the third patients with the combination of pembrolizumab and lung SBRT to mitigate against multiple patients suffering from acute toxicity. The DLT period for this study is 12 weeks from the last dose of lung SBRT (i.e. at C6D1). The dose escalation will be considered by the Safety Review Committee (SRC) once the 3rd or 6th patient in the cohort has completed the DLT period. If no DLT is observed at a dose level, then lung SBRT will be dose escalated to the next dosing level (see Table 1). If 1 out of 3 patients experience a DLT, then the cohort will be expanded to 6 patients. If 1 in 6 patients experience a DLT, then the dose will be escalated to the next dosing level. However, if ≥ 2 in 6 patients experience a DLT then the maximum administered dose (MAD) will have been reached, and the RP2D will be the previous dosing level that will be used for the dose expansion cohorts. If the MAD is seen at dose level 1 then the study will be terminated. While waiting for 3 or 6 patients to complete the DLT period, no additional patients will be recruited. Further patients can only be recruited after the SRC has reviewed the toxicity data for the cohort and taken a decision to dose escalate to the next cohort or expand the current cohort to 6 patients.

Once the MTD has been determined the trial enters the dose expansion phase (unless the MTD is dose level 1). Here, 12 patients will be treated with the RP2D of SBRT combined with pembrolizumab.

If there is ongoing clinical benefit at 24 months, the CI/PI will need to discuss with the sponsor and MSD, on a case by case basis for the continuation of pembrolizumab.

Eligibility Criteria:
Inclusion Criteria:

1. Patients should be ≥18 years old on the day of signing the informed consent.
2. Patients must have a histological or cytological diagnosis of NSCLC.
3. Patients should have non-radically treatable stage IIIB or IV disease.
4. Patients must have measurable disease as assessed by RECIST v1.1.
5. Patients must have had disease progression or be intolerant of standard first line palliative chemotherapy for non-small cell lung cancer. If they are known to have a driver mutation for which there is a small molecule targeted therapy, they must have had disease progression or be intolerant of this.
6. Patient should have an ECOG performance status 0-1.
7. Patients should be able to tolerate a course of stereotactic radiotherapy as assessed by the investigator.
8. Patients should have disease within the lung, away from critical structures, suitable for treatment to part of a lesion with lung SBRT.
9. Patients must have adequate organ function including MRC dyspnoea score \<3 and adequate baseline lung function tests, with an FEV1 \> 0.8L or \>30% of predicted and a TLCO \> 30%
10. Demonstrate adequate organ function (based on bloods within 10 days of C1D1).
11. Have provided tissue from an archival tissue sample or newly obtained tissue sample.
12. Female patient of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication (C1D1). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
13. Female patients of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Patients of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year.
14. Male patients should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
15. Be willing to provide informed consent for the trial.

Exclusion Criteria:

1. Patients who have taken any investigational medicinal product or have used an investigational device within 4 weeks of the first dose of pembrolizumab. Patients may participate in additional observational studies.
2. Patients who have received prior chemotherapy, targeted small molecule therapy or radiotherapy within 4 weeks prior to the first dose of pembrolizumab.
3. Patients with a diagnosis of immunodeficiency or be receiving systemic steroid therapy (\>7.5 mg of prednisone / \>1 mg of dexamethasone or their equivalent dose) or any other form of immunosuppressive therapy within 7 days prior to the first dose.
4. Patients with evidence of active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents.
5. Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
6. Patients with evidence of active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided the brain metastases are stable and there is no evidence of new or enlarging brain metastases.
7. Patients who have had previous radiotherapy to the lung or other neighbouring region that would preclude the safe administration of lung SBRT.
8. Patients with evidence of interstitial lung disease, or history of pneumonitis (including non-infectious pneumonitis) that required steroids, or current pneumonitis (including non-infectious pneumonitis).
9. Patients with evidence of additional malignancy that is progressing or requires active treatment.
10. Patients with a history or current evidence of any condition, therapy, or laboratory abnormality that might confound trial results, interfere with the patient's participation or is not in the best interest of the patient.
11. Patients with psychiatric or substance abuse disorders that would interfere with patient's participation.
12. Patients who are pregnant / breastfeeding or expecting to conceive within the duration of the trial, starting with the screening visit through 120 days after the last dose.
13. Patients with a history of HIV, HIV 1/2 antibodies, Hepatitis B or Hepatitis C.
14. Patients who have received a live vaccine within 30 days prior to the first dose of trial treatment.
15. Patients with known hypersensitivity to the active substance pembrolizumab or to any of the excipients listed in the SmPC.