POSEIDON Phase III post-hoc exploratory analyses presented at WCLC 2022

Late-breaking post-hoc exploratory results from the POSEIDON Phase III trial suggest a trend for improved overall survival (OS) with a limited course of five cycles of tremelimumab added to AstraZeneca’s IMFINZI® (durvalumab) plus platinum chemotherapy, in the 1st-line treatment of patients with STK11, KEAP1 or KRAS-mutated Stage IV (metastatic) non-small cell lung cancer (mNSCLC).

These results will be presented on 9 August 2022 at the International Association for the Study of Lung Cancer (IASLC) 2022 World Conference on Lung Cancer (WCLC) (Abstract #OA15.04).

NSCLC tumors with STK11 and KEAP1 mutations are often associated with a poor prognosis and frequently classified as immunologically “cold”, with immune T-cells missing from the  tumor.1,2 KRAS-mutated NSCLC is typically responsive to immunotherapy, unless associated with STK11 or KEAP1 co-mutations where outcomes are often poor.1,2 KRAS mutations are the most common tumor growth driver in NSCLC representing approximately 25% of patients; while an estimated 6-15% of NSCLC is KEAP1-mutated and approximately 15% of NSCLC is KRAS-driven and STK11-mutated.1,3-6

A trend for OS improvement was observed in the POSEIDON Phase III trial for patients with these mutations when treated with a limited course of tremelimumab added to IMFINZI (durvalumab) plus platinum chemotherapy compared to chemotherapy. The exploratory analysis reported a hazard ratio (HR) of 0.56 (95% CI 0.30-1.03) for STK11-mutated non-squamous NSCLC, an HR of 0.43 (95% CI 0.16-1.25) for KEAP1-mutated NSCLC, and 0.56 (95% CI 0.36-0.88) for KRAS-mutated non-squamous NSCLC.

Median OS and two-year survival rates across all mutational subgroups also increased with the immunotherapy combination compared to chemotherapy. The STK11 and KRAS subgroup analyses were presented for patients with non-squamous histology; while the KEAP1 subgroup analysis was presented for all mutation-evaluable patients irrespective of tumor histology, due to a small sample size. These subgroup analyses should be interpreted with caution as they are post hoc, exploratory and of smaller sample sizes.

Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca, said: “These exploratory analyses for POSEIDON presented at WCLC are an encouraging sign for a group of metastatic lung cancer patients whose prognosis is particularly poor. We are eager to continue following the science to fully understand how patients with these specific mutations and with PD-L1 negative lung cancer respond to immunotherapy combinations including CTLA-4 inhibitors. These initial survival associations warrant further study.”

Also at WCLC, additional exploratory analyses from the POSEIDON Phase III trial evaluated outcomes in patient subgroups whose tumors were PD-L1-negative (tumor cell [TC] expression <1%) versus patients whose tumors expressed PD-L1 (TC≥1%), and further subdivisions based on histology (squamous and non-squamous). While this analysis was exploratory, the data suggest the addition of tremelimumab to IMFINZI and chemotherapy may extend clinical benefit to PD-L1-negative patients across both squamous and non-squamous histologies.

The POSEIDON trial met key endpoints of PFS in 2019 and OS in 2021, reducing the risk of disease progression or death by 28% and the risk of death by 23% in patients with mNSCLC treated with 1st-line tremelimumab, IMFINZI and chemotherapy compared to chemotherapy alone. The combination delivered a broadly similar safety profile to the IMFINZI and chemotherapy combination and addition of tremelimumab did not lead to increased treatment discontinuation. These results were presented at the IASLC 2021 World Conference on Lung Cancer.

Tremelimumab is under review by global regulatory authorities in combination with IMFINZI and chemotherapy in 1st-line mNSCLC based on the results of the POSEIDON trial.

IMPORTANT SAFETY INFORMATION

There are no contraindications for IMFINZI® (durvalumab).

Immune-Mediated Adverse Reactions

Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment or after discontinuation. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue IMFINZI depending on severity. See Dosing and Administration for specific details. In general, if IMFINZI requires interruption or discontinuation, administer systemic corticosteroid therapy (1 mg to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

IMFINZI can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients who did not receive recent prior radiation, the incidence of immune-mediated pneumonitis was 2.4% (34/1414), including fatal (<0.1%), and Grade 3-4 (0.4%) adverse reactions. In patients who received recent prior radiation, the incidence of pneumonitis (including radiation pneumonitis) in patients with unresectable Stage III NSCLC following definitive chemoradiation within 42 days prior to initiation of IMFINZI in PACIFIC was 18.3% (87/475) in patients receiving IMFINZI and 12.8% (30/234) in patients receiving placebo. Of the patients who received IMFINZI (475), 1.1% were fatal and 2.7% were Grade 3 adverse reactions. The frequency and severity of immune-mediated pneumonitis in patients who did not receive definitive chemoradiation prior to IMFINZI were similar in patients who received IMFINZI as a single agent or with ES-SCLC when in combination with chemotherapy.

Immune-Mediated Colitis

IMFINZI can cause immune-mediated colitis that is frequently associated with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 2% (37/1889) of patients receiving IMFINZI, including Grade 4 (<0.1%) and Grade 3 (0.4%) adverse reactions. 

Immune-Mediated Hepatitis

IMFINZI can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 2.8% (52/1889) of patients receiving IMFINZI, including fatal (0.2%), Grade 4 (0.3%) and Grade 3 (1.4%) adverse reactions. 

Immune-Mediated Endocrinopathies

  • Adrenal Insufficiency: IMFINZI can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Immune-mediated adrenal insufficiency occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions. 
  • Hypophysitis: IMFINZI can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement as clinically indicated. Grade 3 hypophysitis/hypopituitarism occurred in <0.1% (1/1889) of patients who received IMFINZI. 
  • Thyroid Disorders: IMFINZI can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated.
  • Thyroiditis: Immune-mediated thyroiditis occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions.  
  • Hyperthyroidism: Immune-mediated hyperthyroidism occurred in 2.1% (39/1889) of patients receiving IMFINZI. 
  • Hypothyroidism: Immune-mediated hypothyroidism occurred in 8.3% (156/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions.  
  • Type 1 Diabetes Mellitus, which can present with diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Grade 3 immune-mediated type 1 diabetes mellitus occurred in <0.1% (1/1889) of patients receiving IMFINZI. 

Immune-Mediated Nephritis with Renal Dysfunction

IMFINZI can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.5% (10/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions. 

Immune-Mediated Dermatology Reactions 

IMFINZI can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), have occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Immune-mediated rash or dermatitis occurred in 1.8% (34/1889) of patients receiving IMFINZI, including Grade 3 (0.4%) adverse reactions. 

Other Immune-Mediated Adverse Reactions

The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in patients who received IMFINZI or were reported with the use of other PD-1/PD-L1 blocking antibodies. 

  • Cardiac/vascular: Myocarditis, pericarditis, vasculitis.  
  • Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.
  • Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.
  • Gastrointestinal: Pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis.
  • Musculoskeletal and connective tissue disorders: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic. 
  • Endocrine: Hypoparathyroidism 
  • Other (hematologic/immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection.

Infusion-Related Reactions

IMFINZI can cause severe or life-threatening infusion-related reactions. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue IMFINZI based on the severity. See Dosing and Administration for specific details. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses. Infusion-related reactions occurred in 2.2% (42/1889) of patients receiving IMFINZI, including Grade 3 (0.3%) adverse reactions.

Complications of Allogeneic HSCT after IMFINZI

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/L-1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/L-1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/L-1 blocking antibody prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMFINZI and for at least 3 months after the last dose of IMFINZI.

Lactation

There is no information regarding the presence of IMFINZI in human milk; however, because of the potential for adverse reactions in breastfed infants from IMFINZI, advise women not to breastfeed during treatment and for at least 3 months after the last dose.

Adverse Reactions

  • In patients with Stage III NSCLC in the PACIFIC study receiving IMFINZI (n=475), the most common adverse reactions (≥20%) were cough (40%), fatigue (34%), pneumonitis or radiation pneumonitis (34%), upper respiratory tract infections (26%), dyspnea (25%), and rash (23%). The most common Grade 3 or 4 adverse reactions (≥3%) were pneumonitis/radiation pneumonitis (3.4%) and pneumonia (7%) 
  • In patients with Stage III NSCLC in the PACIFIC study receiving IMFINZI (n=475), discontinuation due to adverse reactions occurred in 15% of patients in the IMFINZI arm. Serious adverse reactions occurred in 29% of patients receiving IMFINZI. The most frequent serious adverse reactions (≥2%) were pneumonitis or radiation pneumonitis (7%) and pneumonia (6%). Fatal pneumonitis or radiation pneumonitis and fatal pneumonia occurred in <2% of patients and were similar across arms 
  • In patients with extensive-stage SCLC in the CASPIAN study receiving IMFINZI plus chemotherapy (n=265), the most common adverse reactions (≥20%) were nausea (34%), fatigue/asthenia (32%), and alopecia (31%). The most common Grade 3 or 4 adverse reaction (≥3%) was fatigue/asthenia (3.4%) 
  • In patients with extensive-stage SCLC in the CASPIAN study receiving IMFINZI plus chemotherapy (n=265), IMFINZI was discontinued due to adverse reactions in 7% of the patients receiving IMFINZI plus chemotherapy. Serious adverse reactions occurred in 31% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 1% of patients were febrile neutropenia (4.5%), pneumonia (2.3%), anemia (1.9%), pancytopenia (1.5%), pneumonitis (1.1%), and COPD (1.1%). Fatal adverse reactions occurred in 4.9% of patients receiving IMFINZI plus chemotherapy 

The safety and effectiveness of IMFINZI have not been established in pediatric patients.

Indications:

IMFINZI is indicated for the treatment of adult patients with unresectable Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.

IMFINZI, in combination with etoposide and either carboplatin or cisplatin, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC).

Please see complete Prescribing Information, including Medication Guide.

Notes

Stage IV NSCLC
Lung cancer is the leading cause of cancer death accounting for about one-fifth of all cancer deaths.5 Patients are commonly diagnosed at Stage IV, when the tumor has spread outside of the lung.6

 

Lung cancer is broadly split into NSCLC and small cell lung cancer (SCLC), with 80-85% classified as NSCLC.6-8 Within NSCLC, patients are classified as squamous, representing 25-30% of patients, or non-squamous, the most common type representing approximately 70-75% of NSCLC patients.6 Stage IV is the most advanced form of lung cancer and is often referred to as metastatic disease.9

POSEIDON
The POSEIDON trial was a randomized, open-label, multi-center, global, Phase III trial of IMFINZI plus platinum-based chemotherapy or IMFINZI, tremelimumab and chemotherapy versus chemotherapy alone in the 1st-line treatment of 1,013 patients with metastatic NSCLC. The trial population included patients with either non-squamous or squamous disease and the full range of PD-L1 expression levels. POSEIDON excluded patients with certain epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions.

In the experimental arms, patients were treated with a flat dose of 1,500mg of IMFINZI, or IMFINZI and 75mg of tremelimumab with up to four cycles of chemotherapy every three weeks, followed by maintenance treatment with IMFINZI once every four weeks, or IMFINZI and a fifth dose of 75mg of tremelimumab given at week 16. In comparison, the control arm allowed up to six cycles of chemotherapy. Pemetrexed maintenance treatment was allowed in all arms in patients with non-squamous disease if given during the induction phase. Nearly all patients with non-squamous disease (95.5%) had pemetrexed and platinum, while the majority of patients with squamous disease receiving chemotherapy (88.3%) received gemcitabine and platinum.

Primary endpoints included PFS and OS for the IMFINZI plus chemotherapy arm. Key secondary endpoints included PFS and OS in the IMFINZI plus tremelimumab and chemotherapy arm. As both PFS endpoints were met for IMFINZI plus chemotherapy and IMFINZI, tremelimumab and chemotherapy, the prespecified statistical analysis plan allowed for testing OS in the IMFINZI plus tremelimumab and chemotherapy arm. The trial was conducted in more than 150 centers across 18 countries, including the US, Europe, South America, Asia and South Africa.

IMFINZI®
IMFINZI (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics and releasing the inhibition of immune responses.

IMFINZI is the only approved immunotherapy in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) in patients whose disease has not progressed after chemoradiotherapy, and is the global standard of care in this setting based on the PACIFIC Phase III trial.

IMFINZI is also approved in the US, EU, Japan, China and many other countries around the world for the treatment of extensive-stage small cell lung cancer (ES-SCLC) based on the CASPIAN Phase III trial. In 2021, updated results from the CASPIAN trial showed IMFINZI plus chemotherapy tripled patient survival at three years versus chemotherapy alone.

IMFINZI is also approved for previously treated patients with advanced bladder cancer in several countries.

Since the first approval in May 2017, more than 100,000 patients have been treated with IMFINZI.

In the past year, IMFINZI combinations have resulted in positive Phase III trials in multiple additional cancer settings with positive Phase III trials in unresectable advanced liver cancer (HIMALAYA), biliary tract cancer (TOPAZ-1) and resectable non-small cell lung cancer (AEGEAN). The data from HIMALAYA and TOPAZ-1 are under review with global health authorities.

As part of a broad development program, IMFINZI is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, several GI cancers, ovarian cancer, endometrial cancer and other solid tumors. 

Tremelimumab
Tremelimumab is a human monoclonal antibody and potential new medicine that targets the activity of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Tremelimumab blocks the activity of CTLA-4, contributing to T-cell activation, priming the immune response to cancer and fostering cancer cell death.

Beyond POSEIDON, tremelimumab is being tested in combination with IMFINZI across multiple tumor types including in bladder cancer (VOLGA and NILE), locoregional HCC (EMERALD-3) and SCLC (ADRIATIC).

Tremelimumab is also under review by global regulatory authorities in combination with IMFINZI in unresectable advanced liver cancer based on the results of the HIMALAYA Phase III trial.

AstraZeneca in lung cancer
AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in the resistant and advanced settings. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most.

The Company’s comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations including osimertinib; durvalumab and tremelimumab; fam-trastuzumab deruxtecan-nxki and datopotamab deruxtecan in collaboration with Daiichi Sankyo; savolitinib in collaboration with HUTCHMED; as well as a pipeline of potential new medicines and combinations across diverse mechanisms of action.

AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer, including and beyond treatment.

AstraZeneca in immunotherapy
Immunotherapy is a therapeutic approach designed to stimulate the body’s immune system to attack tumors. The Company’s Immuno-Oncology (IO) portfolio is anchored in immunotherapies that have been designed to overcome evasion of the anti-tumor immune response. AstraZeneca is invested in using IO approaches that deliver long-term survival for new groups of patients across tumor types.

The Company is pursuing a comprehensive clinical-trial program that includes IMFINZI as a single treatment and in combination with tremelimumab and other novel antibodies in multiple tumor types, stages of disease, and lines of treatment, and where relevant using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient.

In addition, the ability to combine the IO portfolio with radiation, chemotherapy, and targeted small molecules from across AstraZeneca’s oncology pipeline, and from research partners, may provide new treatment options across a broad range of tumors.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

About AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialization of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.

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References

1.     Skoulidis F, et al. STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma. Cancer Discov. 2018 July; 8(7): 822–835.

2.     Papillon-Cavanagh S, et al. STK11 and KEAP1 mutations as prognostic biomarkers in an observational real-world lung adenocarcinoma cohort. ESMO Open 2020;5:e000706.

3.     Donnelly L, et al. Functional assessment of somatic STK11 variants identified in primary human non-small cell lung cancers. Carcinogenesis, Volume 42, Issue 12, December 2021, Pages 1428–1438.

4.     Peters S, et al. Association Between KRAS/STK11/KEAP1 Mutations and Outcomes in POSEIDON: Durvalumab ± Tremelimumab + Chemotherapy in mNSCLC. Presented at IASLC 2022 World Conference on Lung Cancer.

5.     Frank R, et al. Clinical and Pathological Characteristics of KEAP1- and NFE2L2-Mutated Non-Small Cell Lung Carcinoma (NSCLC). Clin Cancer Res. 2018 Jul 1;24(13):3087-3096.

6.     Chen X, et al. Pan-cancer analysis of KEAP1 mutations as biomarkers for immunotherapy outcomes. Annals Of Translational Medicine. 2019 8(4), 141.

7.     World Health Organization. International Agency for Research on Cancer. Lung Fact Sheet. Available at: http://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf. Accessed August 2022.

8.     Abernethy AP, et al. Real-world first-line treatment and overall survival in non-small cell lung cancer without known EGFR mutations or ALK rearrangements in US community oncology setting. PLoS ONE. 2017;12(6):e0178420.

9.     Cheema PK, et al. Perspectives on treatment advances for stage III locally advanced unresectable non-small-cell lung cancer. Curr Oncol. 2019;26(1):37-42. 

10.  Cancer.net. Lung Cancer - Non-Small Cell: Introduction. Available at: https://www.cancer.net/cancer-types/lung-cancer-non-small-cell/introduction. Accessed August 2022.

11.  American Lung Association. Lung Cancer Staging. Available at: https://www.lung.org/lung-health-diseases/lung-disease-lookup/lung-cancer/symptoms-diagnosis/lung-cancer-staging. Accessed August 2022.

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