Patient case: 48-year-old female with melanoma; genetic feature: tumor cells with >50% membranous PD-L1 expression

Clinical trial: MK-3475 in Melanoma and NSCLC Patients With Brain Metastases

Summary: The purpose of this trial is to study the activity of MK-3475 in untreated brain metastases from melanoma or non-small cell lung cancer.

Detailed description: While recent advances in the treatment of metastatic melanoma and NSCLC (non-small cell lung cancer) with agents targeting PD-1 are striking, there remains a significant need to develop therapies for patients with untreated brain metastases who were excluded from prior trials with MK-3475 and the majority of other studies in these diseases. The brain is a common site of disease spread in many solid tumors, most notably metastatic melanoma and NSCLC. 10-40% of patients with metastatic melanoma develop brain metastases during their lifetime and >75% have brain metastases at autopsy. Overall, historical melanoma patient cohorts have reported a median survival of patients with brain metastases in the order of 2.5 - 4 months despite use of whole brain radiation therapy (WBRT) and surgery. One older patient series showed a median survival of < 4 months in melanoma patients with brain metastases and a neurological death rate of >30% despite the treatment of intracranial metastases with whole brain radiation therapy (WBRT). Among those with NSCLC, 10% have brain metastases at presentation and another 30% develop them over the course of their disease. Survival after the development of brain metastases is as dismal in those with NSCLC as it is for melanoma. Multifocal disease is common in both of these diseases, with about half of patients with CNS disease presenting with more than one brain lesion.
  Patients with untreated brain metastases have been excluded from most clinical trials of systemic therapy for two reasons: (1) historically their prognosis has been poor (overall survival ≤ 4 months) and (2) experimental drugs are presumed to not penetrate the blood brain barrier (BBB) or BBB penetration is not well studied. In melanoma, for example, one phase III study evaluating ipilimumab excluded patients with untreated brain metastases and another study evaluating ipilimumab and dacarbazine excluded all patients with a history of brain metastases, regardless of prior treatment. A subsequent trial with ipilimumab for patients with untreated brain metastases indeed showed that the drug had some activity in treating CNS disease. In the initial vemurafenib studies, patients with progressing or unstable CNS metastases were excluded. The pivotal BRIM-3 trial excluded patients with brain metastases unless metastases had been definitively treated more than three months prior to trial enrollment. Both temodar and sorafenib cross the BBB. Initial studies with sorafenib alone and in combination with chemotherapy excluded patients with active brain metastases. A combination study of temodar and sorafenib in patients with or without brain metastases showed modest activity in patients without a history of prior temodar, and was thought to be favorable in part due to local therapies. Although a number of studies have been conducted for melanoma patients with untreated brain metastases using established therapies, most initial clinical trials with novel agents exclude these patients. A recent trial with dabrafenib, an inhibitor of mutated B-raf, is an exception to the long-standing paradigm. A phase I/II study of this agent included a subset of patients with untreated brain metastases. At the 2010 meeting of the European Society for Medical Oncology, Long et al reported that nine of the ten patients with untreated cerebral metastases enrolled in this trial had shrinkage of their brain lesions. This was the basis for a recent phase II trial of dabrafenib specific for patients with untreated brain metastases61. In NSCLC, a small number of trials have shown that combination chemotherapy regimens can induce a response in the CNS with untreated brain metastases with a median PFS up to 4 months. These studies demonstrate that asymptomatic brain metastases, similar to asymptomatic metastases in other sites, can be treated systemically on clinical trials, and that drug activity in the CNS is not necessarily different than in other metastatic locations.
  Current standard of care for brain metastases that require immediate local intervention (based on symptoms, location, size, or other concerning features) is craniotomy with resection or radiation therapy. As an adjunct to standard craniotomy, LITT is emerging as a new, minimally invasive local therapy to treat previously surgically inaccessible brain metastases. Not only is cell death instantaneous, thus decreasing the risk of delayed intra-tumoral hemorrhage, but another theoretical advantage of using LITT as part of management of brain metastases is that the hyperthermia breaks down the blood brain barrier at the edge of the coagulation region thereby possibly increasing access of chemotherapeutic agents into the lesion. In patients in whom either craniotomy or LITT are performed, biopsies of tumor and surrounding normal brain can also be obtained at the time of local therapy.
  The purpose of this trial is to study the activity of MK-3475 in untreated brain metastases from melanoma or NSCLC. Given the promising initial results of MK-3475 in these diseases but the lack of data in patients with untreated brain metastases thus far, this trial will study treatment in this patient population. Additionally, for patients with melanoma this trial requires local therapy with craniotomy or LITT to at least 1 brain lesion prior to systemic therapy, thereby allowing the acquisition of brain tumor tissue for correlative studies on biomarkers that may be predictive of clinical response in the CNS and systemically. We will also require a biopsy of an extra-cerebral metastasis when feasible, particularly when tissue from the brain lesion is not obtained in patients with NSCLC.

Eligibility: Inclusion Criteria:
  1. Biopsy proven metastatic melanoma or NSCLC:
  1. Patients with metastatic melanoma must have at least two untreated brain metastases including:
  -  At least one cerebral metastasis that requires local intervention and is amenable to craniotomy or LITT therapy either due to symptoms, lesion size, location, edema or hemorrhage ("surgical lesion"). Alternatively, a patient may be eligible if one or more cerebral metastases was resected prior to enrollment and there is tumor tissue available for analysis.
  -  At least one ADDITIONAL cerebral metastasis that is at least 5 mm OR twice the MRI slice thickness, but less than 20 mm, that is asymptomatic and does not require local therapy at the time of enrollment ("clinically evaluable lesion(s)").
  OR
  2. Patients with stage IV NSCLC with at least one cerebral metastasis that is at least 5 mm OR twice the MRI slice thickness, but less than 20 mm, that is asymptomatic and does not require local therapy at the time of enrollment ("clinically evaluable lesion(s)").
  2. Age >18
  3. Adequate organ function
  4. ECOG performance status < 2
  5. Any number of previous treatments with the exception of previous inhibitors of PD-1; other prior systemic therapies must have been administered at least 2 weeks before administration of MK-3475
  6. Life expectancy of at least 3 months
  7. A history of radiotherapy for brain metastases is allowed, provided that at least 14 days have lapsed prior to initiation of MK-3475. Any lesion present at the time of WBRT or included in the stereotactic radiotherapy field will NOT be considered evaluable unless documented to have progressed since treatment.
  8. PD-L1 expression in at least 5% of cells from tumor tissue from any site is required for patients with NSCLC. PD-L1 expression is not required for patients with melanoma. Expression with determined by Merck using an in-house assay.
  9. Patients must have normal organ and marrow function:
  10. For women of childbearing potential, agreement to the use of two acceptable methods of contraception, including one barrier method, during the study and for 6 months after discontinuation of MK-3475.
  11. For men with female partners of childbearing potential, agreement to use a latex condom, and to advise their female partner to use an additional method of contraception during the study and for 6 months after discontinuation of MK-3475.
  12. Negative serum or urine pregnancy test within 7 days of commencement of treatment in premenopausal women.
  13. Patients must have the ability to understand and the willingness to sign a written informed consent document.
  Exclusion Criteria:
  1. Symptomatic brain metastases. Symptoms may be present from the surgical lesion prior to resection or LITT but must resolve following local therapy (ie symptoms should not be attributable to the clinically evaluable lesions)
  2. Radiotherapy or local therapy within 14 days of enrollment
  3. The use of corticosteroids to control cerebral edema or treat neurologic symptoms will not be allowed. Low-dose steroid use (≤10 mg of prednisone or equivalent) as corticosteroid replacement therapy is allowed
  4. Presence of leptomeningeal disease
  5. Presence of active autoimmune disease. Autoimmune thyroid disease will be allowed if thyroid function is within normal range
  6. Pregnancy or breast feeding.
  7. Patients may not be receiving any other investigational agents.
  8. Either a concurrent condition (including medical illness, such as active infection requiring treatment with intravenous antibiotics or the presence of laboratory abnormalities) or history of a prior condition that places the patient at unacceptable risk if he/she were treated with the study drug or a medical condition that confounds the ability to interpret data from the study.
  9. Concurrent, active malignancies (other than cutaneous squamous cell carcinoma or basal cell carcinoma)
  10. Any contraindication to MRI (i.e. patients with pacemakers or other metal implanted medical devices). An MRI safety questionnaire is required prior to MR imaging.
  11. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
  12. Evidence of interstitial lung disease.

Relevance to patient case: not relevant