Durvalumab and Tremelimumab for Adjuvant Therapy of Resected NSCLC

Lung cancer is the most common cancer and leading cause of cancer related death worldwide,
accounting for more than 1.3 million deaths annually. The 5 year survival of clinical stage
IIIA NSCLC, a technically curable lung cancer by surgery, chemotherapy +/- radiotherapy
delivered in the perioperative setting, remains a modest 15%, with systemic recurrence
occurring in the majority of patients. 5 year overall survival (OS) for patients with stage
IB and II disease is also modest at 53% and 25% respectively.

The FDA approvals of T-cell checkpoint inhibitors, targeting programmed cell death-1 (PD-1)
has changed the landscape of NSCLC. Although robust responses to anti-PD-1 can be observed,
it is a small subset of patients with durable benefit. In phase 3 trials, the response rate
to anti-PD- 1 is 19% with only ½ of these patients experiencing durable benefit. Even NSCLC
tumors with high levels of PD-L1 have only a 30% response rate and combination immunotherapy
has improved efficacy modestly.

Clinical trials in resectable lung cancer, have traditionally attempted to institute new
agents in the adjuvant setting. However clinical endpoints take years of follow-up to
ascertain. For example, The ANITA study was the most recent phase III study of adjuvant
chemotherapy in NSCLC. In this study, results were published 12 years after study
initiation. Thus, while OS remains the gold standard for assessment of benefit of adjuvant
therapy, studies that are 12 years long are slow, expensive, and may yield results that are
out of date by the time they are published. Thus the use of valid surrogate endpoints for OS
is a high priority in NSCLC.

The potential for durable benefit in the advanced NSCLC setting has, not unexpectably, led
to a foray with immune checkpoint blockade treatment into the adjuvant setting for
resectable NSCLC. Randomized trials with durvalumab, pembrolizumab, and nivolumab are all
underway.

However in the resected setting, adjuvant patients cannot be monitored radiologically for
treatment response due to the absence of measurable disease thus requiring innovative in
vitro and in vivo methods to study therapeutic response to immune checkpoint blockade.
Encouragingly, as proof of concept, single-agent ipilimumab has demonstrated improved
recurrence-free survival at 3 years in resected stage III melanoma compared to placebo
leading to FDA approval in this setting. Less encouragingly, the hazard ratio favored the
higher risk patients suggesting the benefit may be restricted to those tumors more apt to
have residual disease and may represent the subset where benefit is most realized.
Furthermore the data are not sufficiently mature to demonstrate an overall survival
advantage nor is it known if this data can be extrapolated to NSCLC where responses are
numerically lower.

Patients with resectable NSCLC will undergo surgical resection and bone marrow procurement
at the same time. Tumor will be dissociated into single cell suspension and separated into
viable cryopreserved tumor cells and tumor infiltrating lymphocytes will be expanded in
media and high dose IL-2. Post-operatively, after recovery from surgical resection, patients
will receive adjuvant treatment with chemotherapy as determined by the treating physician.
Subsequently patients will receive adjuvant durvalumab for 12 doses and tremelimumab for 4
doses. Serial PBMCs will be obtained every 4 weeks during therapy. Primary resected tumor
will undergo whole exome sequencing and RNA sequencing and clonal neoantigens will be
predicted with established algorithms. Neoantigen specific T cell reactivity will be tested
in autologous PBMCs with multimer (quantitative) and ICS (functional) assays.

Inclusion Criteria:

- Written informed consent and any locally-required authorization (e.g., HIPAA in the
USA, EU Data Privacy Directive in the EU) obtained from the subject prior to
performing any protocol-related procedures, including screening evaluations

- Adequate tissue must have been obtained from surgical intervention to satisfy
biospecimen requirements of study (collected under biospecimen collection protocols;
either AAAO5706 or AAAR1327).

- Histologically or cytologically confirmed squamous or non-squamous NSCLC.

- Stage IB-IIIA

- R0 or R1 resection

- Patients must have completed surgical resection and adjuvant chemotherapy (adjuvant
radiotherapy excluded) with no significant persisting treatment related toxicity
(grade 1 toxicity per CTCAE v4.0 allowed) as determined by the treating physician.

- Study treatment must begin within 30 days of surgical resection or adjuvant
treatment. This timeline may be extended if further time for recovery from treatment
related toxicities is required.

- Age ≥18 years; as no dosing or adverse event data are currently available on the use
of durvalumab-tremelimumab in patients <18 years of age, children are excluded from
this study, but will be eligible for future pediatric trials.

- ECOG performance status ≤1 (Karnofsky ≥70%).

- Patients must have normal organ and marrow function as defined below:

- Hemoglobin >or = 9.0 g/dL

- Absolute neutrophil count ≥1.5 x 109/L

- Platelets ≥100 x 109/L

- Total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal

- Serum creatinine CL > or = 40 mL/min by the Cockcroft-Gault formula (Cockcroft
and Gault 1976) or by 24-hour urine collection for determination of creatinine
clearance.

- The effects of durvalumab-tremelimumab on the developing human fetus are unknown. For
this reason, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry, for the duration of study participation, and 6 months after completion
of durvalumab + tremelimumab administration or 90 days after the last dose of
durvalumab monotherapy, whichever is the longer time period. Should a woman become
pregnant or suspect she is pregnant while she or her partner is participating in this
study, she should inform her treating physician immediately. Men treated or enrolled
on this protocol must also agree to use adequate contraception prior to the study,
for the duration of study participation, and 6 months after completion of durvalumab
+ tremelimumab administration or 90 days after the last dose of durvalumab
monotherapy, whichever is the longer time period.

- Ability to understand and the willingness to sign a written informed consent
document.

- Female subjects must either be of non-reproductive potential (ie, post-menopausal by
history: ≥60 years old and no menses for ≥1 year without an alternative medical
cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history
of bilateral oophorectomy) or must have a negative serum pregnancy test upon study
entry.

- Subject is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up.

Exclusion Criteria:

- Pre- or post-operative radiotherapy.

- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site).

- Participation in another clinical study with an investigational product during the
last 4 weeks

- Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an
anti-CTLA4, including tremelimumab

- Mean QT interval corrected for heart rate (QTc) ≥ 470 ms calculated from 3
electrocardiograms (ECGs) using Fredericia's Correction

- Current or prior use of immunosuppressive medication within 28 days before the first
dose of durvalumab or tremelimumab, with the exceptions of intranasal and inhaled
corticosteroids or systemic corticosteroids at physiological doses, which are not to
exceed 10 mg/day of prednisone, or an equivalent corticosteroid

- Any unresolved toxicity ( > CTCAE grade 2) from previous anti-cancer therapy.

- Any prior Grade ≥ 3 immune-related adverse event (irAE) while receiving any previous
immunotherapy agent, or any unresolved irAE >Grade 1

- Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects
with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within
the past 2 years) are not excluded.

- Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
ulcerative colitis)

- Active hepatitis B or C (defined as positive Hepatitis B surface antigen, hepatitis C
antibody)

- History of HIV infection

- History of interstitial lung disease/pneumonitis from any cause

- Never-smokers if EGFR/ALK testing results are unknown

- Patients with NSCLC that harbors an ALK rearrangement, or sensitizing EGFR mutation.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Pregnant women are excluded from this study because durvalumab-tremelimumab are
investigational agents with 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 durvalumab-tremelimumab, breastfeeding
should be discontinued if the mother is treated with these agents.

- History of allogeneic organ transplant

- History of hypersensitivity to durvalumab or any excipient

- History of hypersensitivity to the combination or comparator agent

- Known history of active tuberculosis

- Receipt of live attenuated vaccination within 30 days prior to study entry or within
30 days of receiving durvalumab or tremelimumab

- Female subjects who are pregnant, breast-feeding or male or female patients of
reproductive potential who are not employing an effective method of birth control

- Any condition that, in the opinion of the investigator, would interfere with
evaluation of study treatment or interpretation of patient safety or study results

- Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ effective birth control from
screening to 180 days after the last dose of durvalumab + tremelimumab combination
therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the
longer time period