Combination of An Agonist Anti-PD-1 Antibody With a GnRH Agonist or Antagonist to Treat Cancer

Abstract

The present disclosure relates to a novel method of treatment of a cancer patient in which the patient is subjected to both an inhibitor of an immune check point molecule, preferably “Programmed Death 1” (PD-1) or its ligand “programmed death ligand 1” (PD-L1), and a Gonadotropin-Releasing Hormone (GnRH, also known as LHRH or FSH-RH) agonist or antagonist.

Claims

1. A method of treatment of a human patient having a cancer, the method comprising administering to the patient an effective dose of an anti-PD-1 molecule in association with an effective dose of a GnRH agonist or a GnRH antagonist.

2. The method of treatment of claim 1, wherein the cancer is any cancer except a prostate cancer.

3. The method of treatment of claim 1, wherein the cancer is selected from a melanoma, a lung cancer, a kidney cancer, a bladder cancer, an ovarian cancer, a head and neck cancer, a gastric cancer, a colorectal cancer, a triple-negative breast cancer, a mesothelioma and a Hodgkin's lymphoma.

4. The method of treatment of claim 3, wherein the cancer is a melanoma.

5. The method of treatment of claim 1, wherein the anti-PD-1 molecule is an anti-PD-1 antibody or an anti-PD L1 antibody.

6. The method of treatment of claim 5, wherein the anti-PD-1 molecule is nivolumab.

7. The method of treatment of claim 5, wherein the anti-PD-1 molecule is pembrolizumab.

8. The method of treatment of claim 5, wherein the anti-PD-1 molecule is atezolizumab.

9. The method of treatment of claim 5, wherein the anti-PD-1 molecule is durvalumab.

10. The method of treatment of claim 5, wherein the anti-PD-1 molecule is avelumab.

11. The method of treatment of claim 1, wherein the anti-PD-1 molecule is associated with an effective dose of a GnRH agonist.

12. The method of treatment of claim 11, wherein the GnRH agonist is leuprolide, buserelin, histrelin, goserelin, deslorelin, nafarelin or triptorelin.

13. The method of treatment of claim 1, wherein the anti-PD-1 molecule is associated with an effective dose of a GnRH antagonist.

14. The method of treatment of claim 13, wherein the GnRH antagonist is cetrorelix, ganirelix, abarelix, degarelix, elagolix, relugolix, KLH-2109 or ASP-1707.

15. The method of treatment of claim 12, wherein the GnRH agonist is triptorelin.

16. The method of treatment of claim 15, wherein triptorelin is administered in the form of a one-month sustained-release formulation.

17. The method of treatment of claim 16, wherein the anti-PD1 molecule is nivolumab, the nivolumab is administered biweekly at a dose of 3 mg/kg body weight or at 240 mg flat dose, and the triptorelin is administered once every month.

18. The method of treatment of claim 16, wherein the anti-PD1 molecule is pembrolizumab, the pembrolizumab is administered triweekly at a dose of 2 mg/kg body weight or at 200 mg flat dose, and the triptorelin is administered once every month.

19. The method of treatment of claim 11, wherein the patient is further administered an effective amount of an anti-androgen during a period of two to four weeks, said period beginning at the time of first administration of the GnRH agonist.

20. The method of treatment of claim 19, wherein the anti-androgen is bicalutamide, cyproterone acetate, enzalutamide, apalutamide or darolutamide.

21. The method of treatment of claim 1, wherein the human patient has previously been subjected to treatment including an anti-PD-1 molecule and has been found refractory or has become resistant to such treatment.

22-43. (canceled)

Description

DETAILED DESCRIPTION OF THE INVENTION

[0034] The present disclosure relates to a method of treating cancer patients with an anti-PD-1 molecule in association with a GnRH-A or a GnRH-At. Without wishing to be bond to any theory, the GnRH-A or GnRH-At is added to modify the immune system of the cancer patient, resulting in increasing the potential targets of the anti-PD-1 molecule (in particular the tumor infiltrating lymphocytes — TILs). As a consequence, the combination of GnRH-A or GnRH-At and anti-PD-1 molecule is expected to result in a better therapeutic effect compared with the individual active agents, without causing the severe immune-related toxicity that combinations of immune checkpoint inhibitors produce.

Definitions

[0035] The term “in association with”, as used herein in reference to administration of an anti-PD-1 molecule with a GnRH-A or GnRH-At, means that the GnRH-A or GnRH-At is administered prior to, concurrently with, or after administration of the anti-PD-1 molecule. Within a therapeutic regimen, one of the active agents may be administered at shorter intervals than the other. Both agents may be administered independently by any suitable route, e.g., orally or parenterally, e.g., intramuscularly, intraperitoneally, subcutaneously or intravenously. Anti-PD-1 molecules are administered preferably by intravenous infusion, GnRH-A formulations are preferably administered, depending on the formulation, intramuscularly, subcutaneously or intranasally and GnRH-At formulations are preferably administered intramuscularly, subcutaneously or orally.

[0036] A “complete response” or “complete remission” or “CR” indicates the disappearance of all signs of tumor or cancer in response to treatment. This does not always mean the cancer has been cured. Complete response is generally measured using the RECIST v1.1 criteria. Eisenhauer, E. A., Eur. J. Cancer, 45: 228-47 (2009).

[0037] A “partial response” or “PR” refers to a decrease of at least 30% in the sum of the diameters of target lesions, in response to treatment. Eisenhauer, E. A., Eur. J. Cancer, 45: 228-47 (2009).

[0038] “Progressive disease” or “disease that has progressed” or “disease progression” refers to the appearance of one or more new lesions or tumors and/or the unequivocal progression of existing non-target lesions and/or at least a 20% increase in the sum of diameters of target lesions. Eisenhauer, E. A., Eur. J. Cancer, 45: 228-47 (2009).

[0039] “Stable disease” refers to disease without progression or relapse. In stable disease there is neither sufficient tumor diameter decrease to qualify for partial response nor sufficient tumor diameter increase to qualify as progressive disease. Eisenhauer, E. A., Eur. J. Cancer, 45: 228-47 (2009).

Methods of Use and Pharmaceutical Compositions

[0040] The present disclosure relates to a method of treating cancer patients with an anti-PD-1 molecule in association with a GnRH-A or a GnRH-At.

[0041] Various sustained release formulations are available for different GnRH-A, mostly using polymeric drug delivery systems. For example, triptorelin formulations based on poly-(D,L-lactide-co-glycolide) (PLGA) microparticles: one-month triptorelin formulations delivering 3 mg of triptorelin (in acetate form) or 3.75 mg triptorelin (in pamoate form), 3-month triptorelin formulations delivering 11.25 mg triptorelin (in pamoate or acetate form), respectively, and a 6-month formulation delivering 22.5 mg triptorelin (in pamoate form) (Tradenames for triptorelin formulations include e.g. Decapeptyl, Trelstar, Pamorelin, Dipherelin). These formulations are provided as lyophilized powders that need to be suspended in an aqueous medium prior to intramuscular and/or subcutaneous injection. Also available are leuprolide acetate PLGA formulations 1, 3, 4 and 6 months, either in the form of microspheres (Lupron Depot) or of a liquid forming a depot after injection (Eligard). One-month formulations release either 3.75 mg, 7.5 mg, 11.25 mg or 15 mg leuprolide, 3-month formulations release 11.25 mg, 22.5 mg or 30 mg leuprolide, 4-month formulations release 30 mg leuprolide and 6 month formulations release 45 mg leuprolide. There are also implants of leuprolide acetate (Leuprorelin Sandoz) with a dose of 3.6 mg for one month and 5 mg for 3 months. “Suprefact Depot” formulations comprise buserelin acetate in PLGA. A two-month formulation contains the equivalent of 6.3 mg and a three-month formulation of 9.45 mg buserelin. These formulations are administered subcutaneously in a lateral abdominal region. “Vantas” and “Supprelin” contain 50 mg of histrelin (in acetate form) in a non-biodegradable hydrogel diffusion-controlled reservoir. These subcutaneous implants are intended for 12-month release of histrelin in a daily amount of 50-60 μg/day. “Zoladex” are PLGA-based implants of goserelin (present in acetate form), delivering 3.6 mg (one-month release) and 10.8 mg (three-month release) of goserelin, respectively. Synarvel is a nasal spray dispensing nafarelin (present as acetate). The spray delivers doses of 200 μg of nafarelin; the recommended dose is 400 μg per day.

[0042] Various formulations are available for different GnRH-At. In particular, non peptidic GnRH-At are administered orally (e.g. elagolix may be administered at 150 mg or 200 mg twice daily and relugolix may be administered at doses between 10 and 40 mg daily or between 80 and 160 mg daily) and peptidic GnRH-At are administered intramuscularly or subcutaneously. Degarelix formulations (“Firmagon”) are available as a sterile lyophilized powder for injection containing degarelix (as the acetate) and mannitol. For example, a starting dose comprises 240 mg given as two 3 mL subcutaneous injections of 120 mg each. Each vial of Firmagon 120 mg contains 120 mg degarelix and is to be reconstituted with a prefilled syringe containing 3 mL of Sterile Water for Injection to deliver 120 mg degarelix at a concentration of 40 mg/mL. A maintenance dose comprises 80 mg given as one 4 mL subcutaneous injection. Each vial of Firmagon 80 mg contains 80 mg degarelix that is to be reconstituted with a prefilled syringe containing 4.2 mL of Sterile Water for Injection—4 mL is withdrawn to deliver 80 mg degarelix at a concentration of 20 mg/mL. Maintenance doses are intended for monthly administrations. Available formulations of cetrorelix (“Cetrotide”) contain 0.25 mg or 3 mg cetrorelix (acetate) as a sterile lyophilized powder intended for subcutaneous injection after reconstitution with Sterile Water for Injection, that comes supplied in either a 1.0 mL (for 0.25 mg vial) or 3.0 mL (for 3 mg vial) pre-filled syringe. Each vial of Cetrotide 0.25 mg (multiple dose regimen, intended for daily administration) contains 0.26-0.27 mg cetrorelix acetate, equivalent to 0.25 mg cetrorelix, and 54.80 mg mannitol. Each vial of Cetrotide 3 mg (single dose regimen) contains 3.12-3.24 mg cetrorelix acetate, equivalent to 3 mg cetrorelix, and 164.40 mg mannitol. Ganirelix Acetate Injection is supplied as a colorless, sterile, ready-to-use, aqueous solution intended for subcutaneous administration. Each sterile, prefilled syringe contains 250 mcg/0.5 mL of Ganirelix Acetate, 0.1 mg glacial acetic acid, 23.5 mg mannitol, and water for injection adjusted to pH 5.0 with acetic acid, NF and/or sodium hydroxide, NF. Abarelix for injectable suspension (“Plenaxis”) is supplied as a white to off-white sterile dry powder, which, when mixed with the diluent, 0.9% Sodium Chloride Injection, USP, becomes a depot formulation intended for intramuscular injection. The single-dose vial contains 113 mg of anhydrous free base abarelix peptide (net) supplied in an abarelix Carboxymethylcellulose (CMC) complex. This complex contains 19.1 to 31 mg of CMC. After the vial is reconstituted with 2.2 mL of sodium chloride injection, 2 mL is administered to deliver a dose of 100 mg of abarelix (net) as the abarelix CMC complex at a pH of 5±1. Plenaxis may be administered intramuscularly on day 1, 15, 29 (week 4) and every 4 weeks thereafter.

[0043] Preferred anti-PD-1 molecules are anti-PD-1 antibodies such as nivolumab or pembrolizumab and anti-PD-L1 antibodies such as atezolizumab, durvalumab or avelumab. Nivolumab is being distributed under the brand “Opdivo”. It comes as a 10mg/ml solution that comprises the nivolumab antibody, mannitol, pentetic acid, polysorbate 80, sodium chloride, sodium citrate dihydrate and water. For administration, it is diluted into 0.9% sodium chloride or 5% dextrose. Pembrolizumab is being distributed under the brand “Keytruda”. It is furnished as a solid composition comprising 50 mg antibody and inactive ingredients L-histidine, polysorbate-80 and sucrose. For administration, the composition is suspended in 0.9% sodium chloride. Atezolizumab is being distributed under the brand “Tecentriq”. It is furnished as a liquid composition comprising 1200 mg antibody in 20 mL solution. Durvalumab is being distributed under the brand “Imfinzi”. It is furnished as a liquid composition comprising 500 mg/10mL (50 mg/mL) solution in a single-dose vial or 120 mg/2.4mL (50 mg/mL) solution in a single-dose vial.

[0044] Suitable doses of immune checkpoint inhibitors are those currently used in clinical practice. A suitable dose of nivolumab is 3 mg/kg body weight or a 240 mg flat dose. This dose is administered by intravenous infusion during a period of 60 min. A suitable dose of pembrolizumab is 2 mg/kg body weight. This dose is administered by intravenous infusion during a period of 30 min. A flat dose of 200 mg can also be administered. These doses may be adapted in parallel with adaptations accepted in clinical practice. Dosing of nivolumab is typically repeated every two weeks, and that of pembrolizumab every three weeks.

[0045] The GnRH-A is administered preferably as a sustained release formulation. Various suitable sustained release formulations were described above. Preferred formulations are microparticle formulations releasing triptorelin over one month and comprising a biologically active and well tolerated dose, such as about 1 mg, 1.5 mg, 1.75 mg, 2 mg, 2.5 mg, 2.75 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 4.75 mg, 5 mg, 5.5 mg, 5.75 mg, 6 mg, 6.5 mg, 6.75 mg, 7 mg, 7.5 mg, 7.75 mg or 8 mg of triptorelin. Such formulations can be obtained using the same process of preparation as that of a commercial one-month triptorelin formulation, and simply adjusting the amount of microparticles to obtain the desired quantity/dose of triptorelin. For example, approximately 4% (w/w) of triptorelin pamoate is mixed with approximately 96% (w/w) PLGA 50/50 having a viscosity of about 0,50 dL/g, at room temperature. The given mixture is duly homogenized, subjected to progressive compression and simultaneously to a progressive heating, before extrusion at a temperature of approximately 110° C. The extrudate is cut into pellets and ground at a temperature of about —100° C. The microgranules obtained after grinding are sieved below 106 micrometers. The appropriate quantity of microgranules is filled in vials, which are then lyophilized and further sterilized with gamma irradiation. The latter microparticle formulations are re-suspended with water prior to intramuscular administration of the resulting aqueous suspension. Typically, they will be re-administered after one month, two months, three months, etc., (or after 4 weeks, 8 weeks, 12 weeks, etc,.) until the end of treatment. The formulations will cause a decrease of gonadotropins and a fall in plasma testosterone and estradiol to levels causing substantial immunological modifications (in particular, increasing TILs), which levels are maintained until the end of the treatment period. It is understood that the triptorelin formulations may be substituted with sustained release formulations of other GnRH-A as described above, which formulations are designed to similarly reduce sex hormones.

[0046] Administration of GnRH-A is known to cause an initial increase in FSH and LH secretion, which results in an increased circulating testosterone (estrogen in women) level (the so-called “flare effect”). After about two to four weeks, a profound hypogonadal effect (i.e. decrease in testosterone and estrogen) is achieved through pituitary GnRH receptor downregulation by internalization of receptors followed by gonadal suppression. The treating physician may consider it beneficial to counteract this flare by co-administration of an androgen receptor antagonist for the period known to be required for the attainment of the sustained reduced levels of sex hormones causing substantial immunological modifications (in particular, increasing TILs), such as for example two to four weeks. A suitable androgen receptor antagonist is bicalutamide that is typically administered as a 50 mg/day oral dose. Alternatives are the older non-steroidal anti-androgens flutamide or nilutamide which are less potent, having lower affinities for androgen receptor as well as shorter half-lives than bicalutamide. Higher potency alternatives would include enzalutamide, apalutamide (ARN-509) or darolutamide (ODM-201). Yet other alternatives may be steroidal anti-androgens such as cyproterone acetate. Dosages for all mentioned anti-androgens are well known in the medical field.

[0047] The present disclosure relates to a method of treating human cancer patients with an anti-PD-1 molecule in association with a GnRH-A or GnRH-At. This method of treatment is suitable for all indications in which efficacy of an anti-PD-1 agent used as a single agent or in combination with another agent can be demonstrated. These indications can include all types of human cancer. In a particular embodiment, they include all types of human cancer except prostate cancer. In more particular embodiments, the indications are limited to melanoma, lung cancer, kidney cancer, bladder cancer, ovarian cancer, head and neck cancer, gastric cancer, colorectal cancer, triple-negative breast cancer, mesothelioma and Hodgkin's lymphoma.

[0048] The duration of combination treatment with an anti-PD-1 molecule, preferably an anti-PD-1 antibody such as nivolumab or pembrolizumab, in association with a GnRH-A or GnRH-At, preferably a triptorelin one-month sustained release formulation, will be determined by the treating physician based on the clinical benefit and tolerance.

[0049] Combination treatment of suitable cancers with an anti-PD-1 antibody such as nivolumab or pembrolizumab, in association with a GnRH-A such as triptorelin or a GnRH-At is expected to be more effective than treatment with the respective anti-PD-1 antibody alone. This is demonstrated in clinical experiments in which efficacy outcomes such as tumor response according to RECIST v. 1.1 (Eisenhauer, E. A., Eur. J. Cancer, 45: 228-47 (2009)), best overall response (BOR), duration of response, and objective response rate (ORR) are determined. Immune-related toxicities of the combination treatment are expected to be essentially the same as those resulting from treatment with the anti-PD-1 antibody alone.

[0050] The method of treatment disclosed herein involves administering by intravenous infusion 3 mg/kg body weight or a 240 mg flat dose of nivolumab (Opdivo) to a suitable cancer patient. The same dose is re-administered every two weeks. Dose amount and schedule of administration are as approved by regulatory agencies. Any modification of dose and schedule accepted by the medical community will also be applied to the presently described combination therapy. Another anti-PD-1 antibody may be used such as pembrolizumab (Keytruda). This antibody is also administered by infusion to a recommended dose of 2 mg/kg body weight or at a 200 mg flat dose. Re-dosing is every three weeks. Independently, the same patient is administered a sustained release formulation of a GnRH-A or a formulation of GnRH-At following the instructions of the manufacturer. From this formulation, GnRH-A or GnRH-At is released at a dose and/or rate sufficient to cause sex hormones to fall to levels causing substantial immunological modifications (in particular, increasing TILs) and to remain at these low levels to the end of the indicated period. A preferred slow-release GnRH-A formulation is a one-month triptorelin formulation, which formulation releases triptorelin at a rate sufficient to reduce sex hormones to levels causing substantial immunological modifications (in particular, increasing TILs). The formulation will be administered intramuscularly as a suspension comprising triptorelin-containing microparticles. Administration of triptorelin, GnRH-A or GnRH-At may be simultaneous with, prior to or subsequent to the administration of the anti-PD-1 antibody. It may be desirable that the first administration of GnRH-A sustained release formulation occurs considerably ahead of the anti-PD-1 antibody, for example by about three weeks, the time required for the sustained release formulation to reduce sex hormones to levels causing substantial immunological modifications (in particular, increasing TILs). Similarly, it may be desirable that the first administration of GnRH-At formulation occurs ahead of the anti-PD-1 antibody by the time required for the GnRH-At formulation to reduce sex hormones to levels causing substantial immunological modifications (in particular, increasing TILs). In addition or alternatively, the treating physician may opt to supplement the therapy with an anti-androgen to counteract the effect of the flare, for example during the two to four weeks starting before or following the initiation of GnRH-A. A preferred anti-androgen is bicalutamide (Casodex) that is typically given orally at 50 mg every day. Triptorelin one-month formulation may be re-administered after one month or 4 weeks.

[0051] The patients to whom the combination therapy disclosed herein is administered preferably are naïve patients, i.e., none of them will have received a therapy involving administration of an anti-PD-1 molecule. In another aspect, the combination therapy can be given to patients who failed or became resistant to therapy with an anti-PD-1 molecule (given either in monotherapy or in combination with (an) agent(s) different from GnRH-A or GnRH-At).

[0052] In other embodiments, the present disclosure also encompasses combinations of GnRH-A with other immune checkpoint inhibitors such as anti-CTLA-4 molecules.

EXAMPLES

Example 1: Phase I Study Debio 8200-IMM-101

[0053] To evaluate a combination therapy according to the present disclosure, a clinical trial is designed as an open label, single arm phase I study of the safety and efficacy of the combination of triptorelin and nivolumab (Debio 8200-IMM-101). The study population is male adult patients with refractory/relapsing locally advanced or metastatic histologically confirmed melanoma who progressed under anti-PD-1/PD-L1 (antibody)-containing regimens. Potentially evaluable patients are screened.

[0054] Fifteen evaluable patients are planned to be enrolled in the study. If any patient becomes unevaluable during the study, he is replaced.

[0055] The study involves 3 to 12 treatment cycles (depending on individual responses) of 28 days each. Patients receive triptorelin embonate (pamoate) 3.75 mg one-month formulation i.m. on day 1 of each 28-day cycle and nivolumab (Opdivo®) at 3 mg/kg body weight i.v. (1-hour infusion) on days 1 and 15 of each cycle. On day 1 of each cycle, triptorelin is administered prior to nivolumab. In addition, patients take bicalutamide 50 mg p.o. once daily for 28 days throughout cycle 1 only, to counteract the initial testosterone “flare” induced by triptorelin.

[0056] Tumor biopsies are taken prior to the beginning of dosing and at the end of three treatment cycles. The investigator then decides upon treatment continuation in the best interest of the patient, mainly based on the patient's clinical status and the tumor size assessment according to RECIST v1.1 at week 11 or 12, but the patient's overall disease evolution since diagnosis and initiation of anti-PD-1/PD-L1 treatment is also taken into account. Patients demonstrating benefit, i.e. complete response (CR), partial response (PR) or stable disease (SD) after 3 cycles, continue treatment for up to 12 cycles until disease progression, unacceptable toxicity (by investigator judgment), withdrawal of consent, or premature termination of the study, whichever comes first. In the absence of disease progression, patients undergo regular reevaluation of response every 3 cycles. Patients with disease progression after 3 cycles are reassessed 7-8 weeks later, i.e. at week 19 or 20. If disease progression is confirmed, they discontinue study treatment; otherwise they may continue treatment for up to 12 cycles at the discretion of the treating physician, as stated above.

[0057] Tumors are assessed according to RECIST version 1.1 guidelines by physical examination and photography with caliper, or CT scan (Computed Tomography) or MRI (Magnetic Resonance Imaging), performed as per site standard but whenever possible using contrast agent, at screening and during treatment at cycle 3 (week 11 or 12) and then every 3 cycles for up to 12 cycles (weeks 23, 35, and 49) until disease progression/end of treatment.

[0058] The primary endpoint is the incidence and severity of treatment-emergent adverse events/serious adverse events (AEs/SAEs), graded according to NCI-CTCAE version 4.03 criteria (as published on Jun. 14, 2010 by the U.S. Department of Health and Human Services, National Institutes of Health and National Cancer Institute) throughout the study. The most important secondary efficacy endpoints are (1) tumor response according to RECIST v1.1, (2) best overall response (BOR), (3) duration of response, and (4) objective response rate (ORR).

(1) Tumor response is assessed according to RECIST version 1.1. Complete responses (CR) and partial responses (PR) must be demonstrated by objective tumor assessment (CT scan or MRI) while disease progression may be determined clinically, based on the investigator's assessment.
(2) BOR is the best response (CR, PR, stable disease or disease progression) recorded from the start of study treatment until disease progression/recurrence is documented, a new systemic therapy is started or analysis cut-off, whichever occurs first.
(3) Duration of response is the time from documentation of tumor response to first documented evidence of disease progression.
(4) ORR is derived as any PR or CR recorded from the start of study treatment until disease progression/recurrence is documented or confirmed, a new systemic therapy is started or analysis cut-off, whichever occurs first.

[0059] Per protocol, to exclude pseudo-progressions, any disease progression observed according to RECIST v1.1 is confirmed as per iRECIST criteria (Seymour, L., et al., iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol, 2017. 18(3): p. e143-e152) between 4 weeks and 8 weeks after first observation.

[0060] The study is expected to show that the incidence and severity of treatment-emergent AEs/SAEs produced by the combination treatment is not worse than that observed for single therapy with nivolumab in terms of immune-related toxicity. Furthermore, the study is expected to show evidence of efficacy for the combination treatment by the measures of efficacy defined above.

Example 2: Results of Combination Therapy on Patient A

[0061] A 71-year-old (at screening on 23 May 2018) male patient of White race had been operated on 26 Sep. 2016 for left lung lobectomy for melanoma metastasis of unknown origin. On 21 Aug. 2017, biopsy of PET-CT (Positron emission tomography—computed tomography) detected a new melanoma metastasis in the pancreas. From 27 Sep. 2017 until 13 Mar. 2018 (last administration at Cycle 9) he was treated with anti-PD-1 molecule pembrolizumab. On 12 Dec. 2017 a Partial Response (PR) was objectivized. However, on 30 Mar. 2018 PET-CT showed progression (PD) of the metastasis. On 23 May 2018, the size of this unique pancreatic metastasis was 34 mm on CT-scan.

[0062] On 12 Jun. 2018 the patient was enrolled in the protocol Debio 8200-IMM-101 and received the first injections of triptorelin -anti-androgen bicalutamide was added for 28 days- and anti-PD-1 molecule nivolumab.

[0063] As expected due to triptorelin treatment, the serum testosterone levels of the patient decreased from a baseline (Day 1) level of 15.7 nmol/L on 12 Jun. 2018 to a very low castrate level of 0.6 nmol/L four weeks later 10 Jul. 2018 (Day 29), and have remained in the castrate range (i.e. <1.735 nmol/L) until the last value available to date of 0.69 nmol/L on 29 Oct. 2018 (Day 141).

[0064] On 21 Aug. 2018, the tumor was stable at 31 mm on CT-scan. On 13 Nov. 2018, that is 5 months after treatment initiation, new CT-scan objectivized PR with 61% reduction of the tumor mass to 13 mm (compared to baseline of 34 mm). The PR was further confirmed by CT-scan on 12 Dec. 2018.

[0065] Immunohistochemistry on biopsy taken on 31 Aug. 2018 compared with baseline biopsy taken on 19 Apr. 2018 (i.e. 16 days after last pembrolizumab administration, end of cycle 9), demonstrated a 5-fold increase in number of CD8+TILs from 55/mm.sup.2 to 300/mm.sup.2.

[0066] Thus, the chemical castration with GnRH-A triptorelin associated with anti-PD-1 molecule nivolumab allowed the patient to develop an immunological boost translating into a local increase in number of TILs. The objective response obtained strongly suggests that the combination therapy of the present invention has rendered the patient responsive again to anti-PD-1 treatment, thus improving the patient outcome.

[0067] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein.

[0068] The description herein of any aspect or embodiment of the invention using terms such as reference to an element or elements is intended to provide support for a similar aspect or embodiment of the invention that “consists of”,” “consists essentially of” or “substantially comprises” that particular element or elements, unless otherwise stated or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood as also describing a composition consisting of that element, unless otherwise stated or clearly contradicted by context).

[0069] This invention includes all modifications and equivalents of the subject matter recited in the aspects or claims presented herein to the maximum extent permitted by applicable law.