BMY today announced that an open-label, randomized Phase 3 study (CheckMate-017; NCT0164200) evaluating Opdivo vs docetaxel in previously treated patients with advanced, squamous NSCLC was stopped early because an assessment concluded that the study met its endpoint, demonstrating superior overall survival in patients receiving Opdivo.

CheckMate-017 is a Phase 3, open-label, randomized study. Patients who had failed prior platinum doublet-based chemotherapy received either nivolumab 3 mg/kg intravenously every two weeks or docetaxel 75 mg/m2 intravenously every three weeks (N = 272, randomized).

The primary endpoint is overall survival. Secondary endpoints include objective response rate and progression free survival. The initial time frame was 38 months from enrollment. The trial opened in 2012 and was scheduled for primary outcome measurement in January 2016, so this halt is a year early. An association between PD-L1 expression and efficacy measures (ORR, OS PFS) will be explored post hoc.

Arms	Assigned Interventions
Experimental: Arm A: Nivolumab Nivolumab 3 mg/kg solution intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends	Biological: Nivolumab Other Name: BMS-936558
Experimental: Arm B: Docetaxel Docetaxel 75 mg/m2 solution intravenously every 3 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends	Drug: Docetaxel Other Name: Taxotere®

Key Inclusion Criteria:

• Adult subjects with Stage IIIB/IV disease or with recurrent or progressive squamous cell NSCLC who present with disease following multimodal therapy (radiation therapy, surgical resection or definitive chemoradiation therapy for locally advanced disease)
• Disease recurrence or progression during/after one prior platinum doublet-based chemotherapy regimen for advanced or metastatic disease
• Evaluable by imaging (CT/MRI) per RECIST 1.1 criteria
• ECOG performance status ≤1
• Formalin fixed, paraffin-embedded tumor tissue block or unstained slides of tumor sample (archival or recent) available for biomarker evaluation. Biopsy is excisional, incisional or core needle.

Key Exclusion Criteria:

• Subjects with untreated central nervous system (CNS) metastases are excluded. Subjects are eligible if CNS metastases are treated and subjects are neurologically returned to baseline for at least 2 weeks prior to enrollment. In addition, subjects must be either off corticosteroids, or on a stable or decreasing dose of ≤10 mg daily prednisone (or equivalent)
• Subjects with active, known or suspected autoimmune disease (except for type I diabetes mellitus, hypothyroidism only requiring hormone replacement, vitiligo, psoriasis, or alopecia not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger).
• Subjects with a condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of randomization
• Prior therapy with anti- PD-1, anti-PD-L1, anti- PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
• Prior treatment with Docetaxel
• Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
• Treatment with any investigational agent within 14 days of first administration of study treatment

So stopping this trial early is great news. What can we anticipate in addition to the report of ORR, OS, PFS etc that we will likely get at ASCO? The answer lies in the details regarding the Checkmate-017 trial.

A few pointers:

1) there is no inclusion biomarker, ie., there is no specified use of PD-1 staining of biopsy tissue that puts patients into the trial. This is in line with the confusion surrounding use of PD-1 as a biomaker.

2) there is a requirement that pretreatment biopsy specimens be available, as these will be used retrospectively to associate response with expression of biomarkers, including PD-L1 (the PD-1 ligand). No doubt many other biomarkers will be explored.

3) if you have autoimmune disease or interstitial lung disease (a broad term) you are out of luck. So patients with RA, MS, IBD, lupus, and a whole host of other autoimmune diseases need not apply. If you have Type 1 Diabetes though, your good to go (which among other things reminds us just how damn puzzling T1D autoimmunity is).

4) you also cannot be immunosuppressed (corticosteroids) or have had prior treatment with with anti- PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4 antibody (including ipilimumab), or docetaxel. This last one excludes patients who may have gotten docetaxel as second line therapy, which is a setting in which it is commonly used. This tells us that the risk of toxicity in patients is deemed too high.

5) the study halt, being based on efficacy, does not mention toxicity, so we’ll have to wait and see.

Now back to the reading list. In the context of biomarker investigation this story has some resonance:

Day 2 – Immunotherapy: back to those biomarkers of response

Genetic Evolution of T-cell Resistance in the Course of Melanoma Progression

Sucker et al 2014. Clin Cancer Res; 20(24); 6593–604

This interesting paper outlines a technique for tracking the evolution of immune resistance, an essential part of the so-called immune editing process, using in vitro analysis of patient-derived (PDX) samples.

Three consecutive melanoma lesions obtained within one year of developing stage IV disease were analyzed for their recognition by autologous T cells.

One skin and two lymph node metastases were initially analyzed for T-cell infiltration. Then, melanoma cell lines established from the respective lesions. T-cell–stimulatory capacity, expression of cell surface molecules involved in T-cell activation, and specific genetic alterations affecting the tumor–T-cell interactions were identified.

Sampled skin lesions were infiltrated by T cells. The T cell infiltrate was diminished in the lymph node metastatic samples which were found to be HLA class I–negative due to an inactivating mutation in one allele of the beta-2-microglobulin (B2M) gene and concomitant loss of the other allele by a deletion on chromosome 15q. This is an impressive response to avoid immune detection.

The study reveals a progressive loss in melanoma immunogenicity during metastasis. Screening tumors for this and other genetic alterations  that cause acquired immune resistance will be clinically relevant in terms of predicting patient responses and designing combinatorial approaches to immunotherapy.

Day 2 – Immunotherapy: back to those tox issues: it’s hard to control ipilimumab-induced tox

In the trial above we noted two things: no current corticosteroid use and no prior ipilimumab. Turns out these don’t play well together either

http://clincancerres.aacrjournals.org/content/early/2014/12/23/1078-0432.CCR-14-2353.abstract