20/008 Met Exon 14 ASPiRATION SUBSTUDY

Metastatic spread of cancer from its primary site to distant organs is the commonest cause of death from cancer. The term oligometastases describes an intermediate metastatic state, in which cancer exists as a limited number of metastases at first, before cells acquire the ability to metastasise more widely. For the large majority of solid cancers, once metastatic disease has been diagnosed the chances of cure are small. There are several situations where this is not the case, but it is not known if stereotactic body radiotherapy (SBRT) for oligometastatic disease will alter outcomes or whether the toxicity burden of this treatment is justified. SBRT is targeted radiotherapy which destroys cancer cells in the area of the body it is aimed at however low dose radiation may be received by surrounding tissue. It is difficult to quantify incidence of patients with multiple primary cancers developing at intervals that are representative of oligometastatic stage IV disease, (defined for the purposes of this trial as ≤ 3 metastatic sites). However an increase in the use of surveillance imaging, together with improved diagnostic sensitivity has led to the diagnosis of patients with asymptomatic oligometastatic relapse becoming a more common clinical occurrence. The CORE study is a randomized controlled clinical trial that will be conducted in patients with cancer in one of three primary sites where oligometastatic disease relapse is a common clinical scenario: breast, prostate and non-small cell lung cancer (NSCLC). The clinical trial will evaluate the use of SBRT in this patient population. Eligible patients who consent to participate in this clinical trial will be randomized to receive standard care or standard care plus SBRT.

20-40% of patients with NSCLC will develop brain metastases at some point during their course of the disease. Osimertinib has demonstrated intracranial activity in EFGR mutated NSCLC with leptomeningeal disease in the phase 1 BLOOM study. Stereotactic radiosurgery (SRS) is one of the standard local treatment for patients with limited number of brain metastases. Currently, it is unclear whether adding SRS to Osimertinib will result in superior intracranial disease control in patients with EGFR mutated NSCLC with brain metastases diagnosed de novo or developed while on first line EGFR tyrosine kinase inhibitors (TKIs) such as Erlotinib and Gefinitib. The aim of this clinical trial is to compare the effects of Osimertinib alone versus Osimertinib plus SRS on intra-cranial disease control in EGFR mutated NSCLC with brain metastases diagnosed or developed while on first line EGFR tyrosine kinase inhibitors.

CHEST RT is investigating the safety and effectiveness of combining chemotherapy and immunotherapy with chest radiation therapy for the treatment of extensive stage small cell lung cancer (ES-SCLC). For over 20 years, a combination of chemotherapy using etoposide with either cisplatin or carboplatin had been used to treat ES-SCLC. Adding immunotherapy to the chemotherapy combination has been shown to help boosts the body’s natural defences to fight cancer, improving response to treatment. This combination of chemotherapy with immunotherapy is now the standard of care treatment. The immunotherapy used in this study is called durvalumab (IMFINZI). Durvalumab is approved by the Therapeutic Goods Administration (TGA) in Australia as the first-line treatment of patients with ES-SCLC, in combination with etoposide and either cisplatin or carboplatin. Research has shown that radiation therapy also improves the ability of the immune system to recognise tumours. The researchers would like to investigate whether combining radiation therapy with the standard chemo/immunotherapy may further improve patients response to treatment.

BR.31 examined whether durvalumab after surgery (and possibly chemotherapy) for Stage IB-IIIA PDL1-positive NSCLC prolonged disease-free survival. This type of treatment after surgery is known as adjuvant immunotherapy (or chemoimmunotherapy) treatment. Participants were randomly allocated (2:1 randomisation) to receive either durvalumab or placebo and followed up for a maximum of 10 years to assess overall survival and disease-free survival.

ILLUMINATE evaluated the efficacy and tolerability of immunotherapy (durvalumab and tremelimumab) with platinum-pemetrexed chemotherapy in patients with metastatic EGFR-mutant NSCLC (T790M+ve or T790M-ve) who had progressed following prior EGFR TKI therapy. At the time the ILLUMINATE study commenced, the role of immunotherapy for patients with EGFR+ NSCLC that had progressed on a third generation TKI was unclear. Various studies suggested benefit, but differed in whether immunotherapy was delivered as monotherapy, as a dual immunotherapy combination or together with chemotherapy.

DREAM3R is determining the effectiveness of adding immunotherapy to standard first line chemotherapy with cisplatin and pemetrexed in advanced malignant pleural mesothelioma and identifying potential and prognostic biomarkers from blood and tissue. Durvalumab is a type of immunotherapy that works by blocking a body substance called Programmed Death-Ligand 1 (PD-L1). Blocking PD-L1 helps the body’s immune system attack cancer cells. Initially participants were randomised to durvalumab and chemotherapy or the control arm of chemotherapy alone. However, when the dual immunotherapy combination of ipilimumab and nivolumab became standard of care, DREAM3R was amended so participants randomised to the control arm could choose, in consultation with their treating clinician, the ipilimumab and nivolumab combination immunotherapy treatment or chemotherapy.

A single arm, open label, phase II trial of alectinib in patients with advanced tumours harbouring ALK gene alterations detected by comprehensive genomic profiling (CGP) (MoST 14).

The HER2 ASPiRATION substudy intends to demonstrate activity of trastuzumab emtansine in advanced HER2+ metastatic NSCLC. Trastuzumab emtansine is a drug known as an antibody drug conjugate (ADC) consisting of a monoclonal antibody trastuzumab, to target the tumour, that is covalently linked to the cytotoxic agent DM1. This drug has demonstrated efficacy in HER2+ breast cancer.