Patient case: 49-year-old female with lung cancer; genetic feature: ERBB2

Clinical trial: Neoadjuvant MPDL3280A, Nab-paclitaxel and Carboplatin (MAC) in NSCLC

Summary: This is a research study to test the effectiveness of nab-paclitaxel + carboplatin + MPDL3280A for treatment of non-small-cell lung carcinoma (NSCLC), which is a type of lung cancer. The study aims to determine if chemotherapy combined with immune-based therapy can lead to improvement in tumor response rates over historical response rates with chemotherapy alone.

Detailed description: Lung cancer is the most common cancer in both men and women worldwide, accounting for 13% of incident cancers. In 2015, it was estimated there would be 221,200 new lung cancers diagnosed in the United States, with 158,040 lung cancer deaths. Approximately 85% of all lung cancers are characterized as non-small cell lung cancer (NSCLC).
  Repeated studies have shown neoadjuvant cytotoxic chemotherapy to be safe prior to surgical resection of NSCLC with no difference in extent of surgical procedures performed, operative morbidity and mortality. The debate remains as to whether neoadjuvant or adjuvant chemotherapy is the best approach, with advantages and disadvantages to each.
  We propose that new therapies such as immune checkpoint inhibitors that demonstrate promising clinical activity in the advanced disease setting must be incorporated into the neoadjuvant setting, in order to maximize benefit early in a patient's treatment course, and with a suitable surrogate endpoint that can be used to establish a preliminary efficacy signal, prior to initiation of a large confirmatory study.

Eligibility: Inclusion Criteria:
  -  Patients must have pathologically confirmed non-small cell lung cancer, of either squamous or non-squamous histology.
  -  Stage IB-IIIA
  -  Deemed surgically resectable by a thoracic surgeon
  -  Age ≥ 18 years
  -  Radiologically measurable disease, as defined by response evaluation criteria in solid tumours (RECIST) v1.1
  -  Ability to understand and the willingness to sign a written informed consent document
  -  Females of child-bearing potential (defined as a sexually mature woman who (1) has not undergone hysterectomy [the surgical removal of the uterus] or bilateral oophorectomy [the surgical removal of both ovaries] or (2) has not been naturally postmenopausal for at least 24 consecutive months [i.e., has had menses at any time during the preceding 24 consecutive months]) must:
  -  Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis), or agree to use, and be able to comply with, effective contraception (</=1% failure rate annually) without interruption, 28 days prior to starting therapy (including dose interruptions), and while on study medication or for a period of 90 days following treatment completion. [Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception].
  -  Have a negative serum pregnancy test (β -hCG) result at screening and agree to ongoing pregnancy testing during the course of the study, and after the end of study therapy. This applies even if the subject practices true abstinence from heterosexual contact.
  -  Male subjects must practice true abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for 6 months following treatment discontinuation, even if he has undergone a successful vasectomy.
  -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
  -  Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (blocks are preferred) or at least 10 unstained slides, with an associated pathology report, for central testing of tumor PD-L1 expression
  -  Tumor tissue should be of good quality based on total and viable tumor content. Fine-needle aspiration, brushing, cell pellet from pleural effusion, and lavage samples are not acceptable. For core-needle biopsy specimens, at least three cores should be submitted for evaluation.
  -  Patients who do not have tissue specimens meeting eligibility requirements may undergo a biopsy during the screening period. Acceptable samples include core-needle biopsies for deep tumor tissue (minimum of three cores) or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions.
  -  Adequate organ and marrow function as defined below:
  -  Lymphocyte count ≥300/mcL
  -  Neutrophil count ≥1,500/mcL
  -  Hemoglobin ≥9.0g/dl
  -  Platelets ≥100,000/mcL
  -  Total bilirubin ≤1.5 x institutional upper limit of normal (ULN) (*Patients with Gilbert's disease: ≤3 x ULN)
  -  Aspartate aminotransferase (AST)(SGOT)/alanine aminotransferase (ALT)(SGPT) ≤2.5 × ULN
  -  Alkaline phosphatase ≤2.5 x ULN
  -  INR and aPTT ≤ 1.5 x ULN (*Unless the patient is on therapeutic anticoagulation)
  -  Serum creatinine ≤1.5 x ULN or
  -  Creatinine clearance ≥50 mL/min/1.73 m2 by Cockcoft-Gault estimation
  Exclusion Criteria:
  -  Any approved anticancer therapy, including chemotherapy, hormonal therapy, or radiotherapy, within 5 years prior to initiation of study treatment; however, the following are allowed:
  -  Hormone-replacement therapy or oral contraceptives
  -  Herbal therapy > 1 week prior to Cycle 1, Day 1 (herbal therapy intended as anticancer therapy must be discontinued at least 1 week prior to Cycle 1, Day 1)
  -  Malignancies other than the disease under study within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death and with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ treated surgically with curative intent) or undergoing active surveillance per standard-of-care management (e.g., chronic lymphocytic leukemia Rai Stage 0, prostate cancer with Gleason score ≤ 6, and prostate-specific antigen [PSA] ≤ 10 mg/mL, etc.)
  -  Patients who are receiving any other investigational agents concurrently.
  -  Patients with no smoking history
  -  History of allergic reactions attributed to compounds of similar chemical or biologic composition to MPDL3280A, carboplatin, or paclitaxel.
  -  Patients with active hepatitis B or C infections (defined as a positive Hepatitis B DNA or Hepatitis C RNA by PCR) or a history of HIV infection.
  -  Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible.
  -  Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
  -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection including TB, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  -  Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease
  -  Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
  -  History or risk of autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis
  -  Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible.
  -  Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible.
  -  Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:
  -  Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations
  -  Rash must cover less than 10% of body surface area (BSA)
  -  Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%)
  -  No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids)
  -  Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
  -  Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1 Received oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible
  -  Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of need for a major surgical procedure during the course of the study
  -  Patients must not have >/= Grade 2 pre-existing peripheral neuropathy (per CTCAE)
  -  Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or anticipation that such a live, attenuated vaccine will be required during the study
  -  Pregnant women are excluded from this study because MPDL3280A, and other members of the immune checkpoint blocking class of agents, have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with MPDL3280A, breastfeeding should be discontinued if the mother is treated with MPDL3280A.
  -  History of interstitial lung disease or pneumonitis of any cause
  Immunotherapy-Related Exclusion Criteria:
  -  Prior treatment with anti-PD-1, anti-CTLA-4, or anti-PD-L1 therapeutic antibody or pathway-targeting agents
  -  Treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1
  -  Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled.
  -  The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed.
  -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
  -  Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation.

Relevance to patient case: not relevant