Summary

This phase II/III Lung-MAP trial compares the effect of combination immunotherapy with N-803 (ALT-803) and pembrolizumab versus usual treatment (docetaxel, gemcitabine, pemetrexed, or ramucirumab combined with docetaxel) in patients with non-small cell lung cancer (NSCLC) previously treated with anti-PD-1 or anti-PD-L1 immunotherapy and whose tumor has spread to other places in the body (advanced). N-803 (ALT-803) binds to and activates certain immune cells (natural killer cells and specific T cells). By doing this N-803 may increase tumor cell killing and decrease tumor growth. Chemotherapy drugs, such as docetaxel, gemcitabine, pemetrexed, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Ramucirumab is a monoclonal antibody that may prevent the growth of new blood vessels that tumors need to grow. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This study will help to understand whether combination immunotherapy with N-803 and pembrolizumab is better, the same, or worse than the usual approach in treating patients with recurrent NSCLC who previously received anti-PD-1 or anti-PD-L1 immunotherapy.

Objectives

PRIMARY OBJECTIVES:
I. To compare overall survival (OS) between participants randomized to nogapendekin alfa (N-803 [ALT-803]) + pembrolizumab versus standard of care therapy. (Primary Resistance Cohort)
II. To compare overall survival (OS) between participants randomized to N-803 (ALT-803) + pembrolizumab versus standard of care therapy. (Acquired Resistance Cohort)

SECONDARY OBJECTIVES:
I. To compare investigator assessed progression-free survival (IA-PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 between the treatment arms.
II. To compare the response rates between the arms.
III. To evaluate duration of response (DoR) among responders.
IV. To evaluate the frequency and severity of toxicities within each treatment arm.

TRANSLATIONAL MEDICINE OBJECTIVE:
I. To establish a blood repository to pursue future studies.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients may receive standard of care consisting of docetaxel intravenously (IV) over 30-60 minutes on day 1 of each cycle; gemcitabine IV over 30 minutes on days 1 and 8 of each cycle; pemetrexed IV over 10 minutes on day 1 of each cycle; or ramucirumab IV over 30-60 minutes and docetaxel IV over 30-60 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) or magnetic resonance imaging (MRI) and collection of blood samples throughout trial.

ARM B: Patients receive pembrolizumab IV over 30 minutes and nogapendekin alfa subcutaneously (SC) on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients then receive nogapendekin alfa SC on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI and collection of blood samples throughout trial.

After sub-study randomization, patients are followed up for 3 years or until death.

Eligibility

1. Participants must have been assigned to S1800D (this treatment subprotocol) by the Southwest Oncology Group (SWOG) Statistics and Data Management Center (SDMC). Assignment to S1800D is determined by the LUNGMAP (NCT03851445) or S1400 protocol (NCT02154490)
2. Participants must have measurable or non-measurable disease documented by CT or MRI. Measurable disease must be assessed within 28 days prior to randomization. Non-measurable disease must be assessed within 42 days prior to randomization. The CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic quality. All known sites of disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1)
3. Participants must have a CT or MRI scan of the brain to evaluate for central nervous system (CNS) disease within 42 days prior to sub-study randomization
4. Participants with spinal cord compression or brain metastases must have received local treatment to these metastases and remained clinically controlled and asymptomatic for at least 7 days following stereotactic radiation and/or 14 days following whole brain radiation, and prior to sub-study randomization
5. Participants with spinal cord compression or brain metastases must not have residual neurological dysfunction, unless no further recovery is expected, and the participant has been stable on weaning doses of corticosteroids (=< 10 mg daily prednisone or equivalent) prior to sub-study randomization
6. Participants must not have leptomeningeal disease that requires CNS-specific treatment prior to registration and must not be planning to receive the CNS-specific treatment through the first cycle of the protocol therapy
7. Participants must not have experienced the following: * Any grade 3 or worse immune-related adverse event (irAE). Exception: asymptomatic nonbullous/nonexfoliative rash * Any unresolved grade 2 irAE * Any toxicity that led to permanent discontinuation of prior anti-PD-1/PD-L1 immunotherapy * Exception to the above: Toxicities of any grade that requires replacement therapy and has stabilized on therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) are allowed
8. Participants must not have any history of organ transplant that requires use of immunosuppressives
9. Participants must not have history of (non-infectious) pneumonitis that required steroids or current pneumonitis/interstitial lung disease
10. Participants must not have any known allergy or reaction to any component of the investigational formulations. If there is a known allergy or reaction to standard of care formulations, participants must be able to safely receive at least one of the standard of care options
11. Participants must not have any grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., participants with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, and myocardial infarction within 6 months prior to sub-study randomization, or serious uncontrolled cardiac arrhythmia
12. Participants must not have experienced any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to sub-study randomization
13. Participants must not have an active or uncontrolled infection in the opinion of the treating investigator
14. Participants must not have a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen
15. Participants must not have any of following: * Cirrhosis at a level of Child-Pugh B (or worse) * Cirrhosis (any degree) and a history of hepatic encephalopathy * Or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis
16. Participants must not have any family or personal history of long or short QT syndrome, Brugada syndrome or known history of corrected QT (QTc) prolongation, or Torsade de Pointes or risk factors for Torsade de Pointes including heart failure of hypokalemia
17. Participants must have progressed (in the opinion of the treating investigator) following the most recent line of therapy for NSCLC
18. Participants with a known sensitizing mutation for which an Food and Drug Administration (FDA)-approved targeted therapy for NSCLC exists (e.g. EGFR, ALK gene fusions, ROS1, BRAF, RET, NTRK, and MET sensitizing mutations), must have previously received at least one of the approved therapy(s)
19. Participants must have received exactly one line of anti-PD-1 or anti-PD-L1 therapy for advanced disease (stage IV or recurrent, or stage III in certain circumstances outlined below) given alone or in combination with platinum-based chemotherapy. Participants must have experienced disease progression during or after this regimen * Continuing the same agent(s) after progression counts as a single line of therapy. However, a change or addition in agent(s) after progression (e.g. the addition of chemotherapy to anti-PD-1 monotherapy after progression) counts as a subsequent line of therapy and would exclude the participant * For participants who received consolidation anti-PD-1 or anti-PD-L1 therapy following concurrent chemoradiation for stage III disease as their only line of anti-PD-1 or anti-PD-L1 therapy: ** If they experienced disease progression less than (<) 365 days from the first date of anti-PD-1 or anti-PD-L1 therapy, this counts as the single line of anti-PD-1 or anti-PD-L1 therapy for advanced disease ** If they experienced disease progression more than or equal to (>=) 365 days from the first date of anti-PD-1 or anti-PD-L1 therapy, this is not considered a line of anti-PD-1 or anti-PD-L1 therapy for advanced disease
20. Participants must have recovered (=< grade 1) from any side effects of prior therapy, except for alopecia
21. Participants must not have received anti-CTLA4 therapy (e.g. ipilimumab, tremelimumab), or other immune-modulatory therapy (e.g. anti-TIM-3, anti-LAG-3, anti-GITR, IL-2, IL-15)
22. Participants must not have received any prior systemic therapy (systemic chemotherapy, immunotherapy or investigational drug) within 21 days prior to sub-study randomization
23. Participants must not have received any radiation therapy within 14 days prior to sub-study randomization
24. Participants must not have received nitrosoureas or mitomycin-c within 42 days prior to sub-study randomization
25. Participants must not have received systemic treatment with corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 7 days prior to sub-study randomization. Inhaled or topical steroids, and adrenal replacement doses =< 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease
26. Participants must not have received a live attenuated vaccination within 28 days prior to sub-study randomization. All coronavirus disease 2019 (COVID-19) vaccines that have received FDA approval or FDA emergency use authorization are acceptable
27. Participants must not be planning to receive any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment while receiving treatment on this study
28. Participants must not have had a major surgery within 14 days prior to sub-study randomization. Participant must have fully recovered from the effects of prior surgery in the opinion of the treating investigator
29. Participants must be able to safely receive at least one of the investigator’s choice of standard of care regimens, per the current FDA-approved package insert
30. Absolute neutrophil count (ANC) >= 1.5 x 10^3/uL (obtained within 28 days prior to sub-study randomization)
31. Platelet count >= 100 x 10^3/uL(obtained within 28 days prior to sub-study randomization)
32. Hemoglobin >= 9 g/dL (obtained within 28 days prior to sub-study randomization)
33. Serum bilirubin =< institutional upper limit of normal (IULN) (within 28 days prior to sub-study randomization). For participants with liver metastases, bilirubin must be =< 5 x IULN
34. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2 x IULN (within 28 days prior to sub-study randomization). For participants with liver metastases, ALT and AST must be =< 5 x IULN
35. Serum creatinine =< the IULN or calculated creatinine clearance >= 50 mL/min using Cockcroft-Gault formula. This specimen must have been drawn and processed within 28 days prior to sub-study randomization
36. Participants’ most recent Zubrod performance status must be 0-1 and be documented within 28 days prior to sub-study randomization
37. Participants must have history and physical exam must be obtained within 28 days prior to sub-study randomization
38. Participants with known human immunodeficiency virus (HIV) infection must be receiving anti-retroviral therapy and have an undetectable viral load at their most recent viral load test within 6 months prior to sub-study randomization
39. Participants must have an electrocardiogram (ECG) performed, with a Fridericia's correction formula (QTcF) =< 470 msec, within 28 days prior to sub-study randomization
40. Participants must not have an active autoimmune disease that has required systemic treatment within two years prior to sub-study randomization (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
41. Participants must not have any history of primary immunodeficiency
42. Participants must not be pregnant or nursing. Women/men of reproductive potential must have agreed to use an effective contraceptive method during the study and 4 months after completion of study treatment. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate participant chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures during the study and 4 months after study completion
43. Participants must also be offered participation in banking and in the correlative studies for collection and future use of specimens
44. Note: As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system * Participants must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines