Published Trials

The PEARL study examined whether early referral for palliative care improved quality of life, cost effectiveness and quality of end-of-life care for adults who were newly diagnosed with an advanced thoracic cancer. Participants were randomly allocated (by chance) to receive either standard care referral to palliative care at the discretion of the treating oncologist, or to receive early referral to palliative care within 7 days of enrolling in this clinical trial. With the exception of the timing of the referral, the palliative care received by each group was as per standard care, with information and care provided by the palliative care team as required for each participant. Participants were asked to complete a number of questionnaires relating to quality of life and cancer symptoms at regular time points. Carers were asked to complete quality of life and death questionnaires and an interview at regular intervals.

14/001 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.

The NIVORAD trial was a randomised phase II study evaluating whether adding stereotactic ablative body radiotherapy (SABR) to nivolumab improves outcomes in patients with metastatic, immunotherapy-naïve non-small cell lung cancer (NSCLC) that had progressed after chemotherapy. Patients were randomised to receive nivolumab alone or nivolumab plus a single fraction of SABR to one metastatic site early in treatment. Key Findings: At a median follow-up of approximately two years, the addition of SABR to nivolumab did not significantly improve progression-free survival compared with nivolumab alone. Six-month PFS was similar between groups (49 % with SABR vs 44 % with nivolumab alone), and the hazard ratio suggested no statistically significant difference (HR 0.68; p = 0.23). Objective tumour response rates were comparable (about 24–25 %), and overall survival did not differ meaningfully between the treatment arms (HR 0.86; p = 0.69). Rates of serious adverse events (Grade 3–5) were also similar, and there was no apparent increase in toxicity with the addition of SABR. Overall, nivolumab plus single-fraction SABR exhibited similar efficacy and safety to nivolumab alone in this patient population.

BR.34 compared the overall survival following an immunotherapy treatment combination of both durvalumab plus tremelimumab with or without chemotherapy in metastatic NSCLC. Participants were allocated by chance to one of two treatment groups. Participants in both groups received durvalumab and tremelimumab every 28 days for 4 cycles followed by durvalumab every 28 days until disease progression. Participants in one group only also received one of two types of chemotherapy during durvalumab and tremelimumab treatment. Patients with squamous cell NSCLC received gemcitabine and cisplatin or carboplatin chemotherapy, and patients with non-squamous NSCLC received pemetrexed and cisplatin or carboplatin chemotherapy.

OSCILLATE measured the duration before progression when patients with EGFR-T790 mutation positive advanced NSCLC were treated with osimertinib and gefitinib. It was hypothesised that alternating therapy with the gefitinib and osimertinib would modulate the populations of EGFR-T790M positive and negative tumour clones, delaying the emergence of resistance to osimertinib. Sixty-eight percent of participants in OSCILLATE were able to complete 6 months of treatment without any delays or interruptions due to side effects, suggesting that the alternating approach was safe and feasible. The lung cancer was still under control 12 months after starting treatment in 38% of the participants, but this was not a statistically significant outcome. The side effects of treatment in OSCILLATE were similar to those seen in trials using either drug on its own. Accompanying translational research studies on samples obtained from patients have contributed to current understanding of resistance to EGFR tyrosine kinase inhibitor therapy.

The primary purpose of the ALKTERNATE clinical trial was to evaluate the efficacy, safety and feasibility of alternating lorlatinib and crizotinib for the treatment of ALK-rearranged advanced NSCLC, and to provide information on the potential to delay the emergence of drug resistance as compared to continuous lorlatinib therapy alone. The study found that alternating crizotinib and lorlatinib could be done safely and did not compromise the control of cancer compared to usual care. However, since the trial commenced, lorlatinib has become first line standard of care therapy for ALK+ NSCLC. Blood samples collected from patients during treatment on the ALKTERNATE clinical trial revealed that every ALK+ NSCLC patient is different, with no one clear mechanism identified for resistance to treatment.

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.

STIMULI investigated the efficacy and tolerability of the standard treatment (chemotherapy and radiotherapy) alone, compared with the standard treatment followed by nivolumab and ipilimumab (immunotherapy) in patients with limited stage SCLC. The results of STIMULI showed no significant difference between the immunotherapy and observation groups. Overall, there was no difference in the percentage of people with cancer progression at 12 and 24 months after starting immunotherapy or observation. There was also no difference in the percentage of people alive at 24 months, and the amount of tumour shrinkage was no different between the two groups. There was some data to suggest that immunotherapy after a more frequent radiotherapy schedule may be more effective, but this needs to be studied further.

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.

An observational cohort study to assess the clinical impact of CGP in metastatic lung cancer patients. The ASPiRATION study is investigating the clinical impact of comprehensive genomic profiling (CGP) on the management of metastatic NSCLC and assessing the feasibility of CGP implementation nationally. When the ASPiRATION study was open to recruitment, standard of care tumour testing for NSCLC patients could only identify changes in three genes: EGFR, ALK & ROS1. Patients enrolled on the ASPiRATION study also had their tumour tested using CGP, often referred to as molecular screening and/or profiling. This technique allows treating clinicians to look at changes in hundreds of genes in a single test. After a patient’s tumour was tested, a report was sent to the referring oncologist with information on (i) Any genetic biomarkers that were identified in the tumour and (ii) The types of treatment that may be suitable. It is hoped this research will determine whether additional molecular screening can be feasibly integrated into Australian clinical practice for patients with metastatic NSCLC. The ASPiRATION study is led by TOGA, in collaboration with Omico (Australian Genomic Cancer Medicine Centre) and the Sydney Clinical Trials Centre.

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.

Single arm, open label, phase II trial of vemurafenib and cobimetinib in patients with advanced tumours harbouring BRAF V600 mutations detected by CGP (MoST 12).

A single-arm, open-label, phase II trial of entrectinib in patients with advanced tumours harbouring NTRK fusions or ROS1 gene rearrangements detected by CGP (MoST 13)

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).

OCEANiC will investigate whether, following surgery for local or locally advanced EGFR+ NSCLC, patients with tumours containing certain types of genetic signatures can achieve the same disease-free survival with osimertinib treatment alone, as has previously been achieved with osimertinib and chemotherapy. Standard of care treatment is evolving to include osimertinib in addition to chemotherapy, but the OCEANiC trial may provide evidence for similar benefits for using the drug alone, with less toxicity, improved quality of life and reduced health care costs.

A single-arm, open-label, signal-seeking, phase II trial of tepotinib in patients with advanced non-small cell lung cancer harbouring MET Exon 14 skipping mutations detected by comprehensive genomic profiling (MoST 17).

SHERLOCK will examine whether sotorasib used in first line treatment of advanced KRAS G12C+ NSCLC, in combination with two chemotherapy drugs (called carboplatin and pemetrexed) and bevacizumab (which improves anti-cancer drug delivery) improves the response of the tumour to treatment. Sotorasib is available on the PBS as monotherapy in 2^nd or later lines of treatment. Patients with advanced KRAS G12C+ NSCLC usually undergo initial treatment with chemotherapy, immunotherapy or a combination of the two treatments.

The ADOPT-Lung study will examine disease free status (DFS) following 12 months of adjuvant durvalumab in addition to neoadjuvant chemotherapy and durvalumab in NSCLC patients who do not achieve a complete pathological response following surgery. ‘Operable’ patients will be given 3-4 cycles of neoadjuvant durvalumab and chemotherapy every 3 weeks, and provided the tumour is satisfactorily removed by surgery (R0 or R1), the patients will be randomised to 12 months of durvalumab given every 4 weeks, or observation. Participants will have CT scans every 12 weeks in the first year, and every 6 months in years 2 and 3. Blood will be collected at the scan visit to measure correlation of DFS with ctDNA clearance.

ASPiRATION 2 Liquid (ASPiRATION-2L) will establish a national framework for precision medicine in lung cancer through the implementation of using serial blood-based ctDNA testing (called “liquid biopsy’) to guide treatments following progression on targeted therapies. ctDNA results will be reviewed by an expert tumour molecular board to inform clinical decision making on next line treatment. The option for further ctDNA sampling and review is available for participants should progression recur, which will enable treatment to be tailored based on the tumour’s changing molecular profile.

DEFIANT aims to determine whether Dato-DXd can provide meaningful and tolerable disease control for patients with EGFR exon 20 insertion NSCLC after progression on targeted therapy and chemotherapy, including prior amivantimab. The primary endpoint is  objective tumour response rate (RECIST 1.1), with ctDNA dynamics and clearance to be examined in correlative studies. Patients with untreated and asymptomatic brain metastases can be included in the study. Due to open to recruitment in 2027.

PHARAOH-A will determine the efficacy and tolerability of the combination of savolitinib and osimertinib in patients with EGFR-mutated, MET-overexpressed and/or amplified advanced NSCLC following disease progression on first- or second-line osimertinib. The primary endpoint is  objective tumour response rate (RECIST 1.1), with ctDNA dynamics and clearance to be examined in correlative studies. Patients with untreated and asymptomatic brain metastases can be included in the study. The study will also open to recruitment in Taiwan with first patient in expected in 2027.

The trial shows that the combination of durvalumab and standard chemotherapy was safe and has promising effects against mesothelioma. Tumour imaging by CT showed that 31 of 54 patients (57%) were alive and progression free at 6 months, which was higher than the expected outcomes with chemotherapy alone. The combination of durvalumab, cisplatin and pemetrexed showed promising activity and an accepted safety profile.

Participants in this trial were randomly allocated to one of two groups. Both groups underwent 6 x 3 week treatment cycles of standard chemotherapy determined by their doctor. In addition, participants in group one received nitroglycerin administered as a 25mg patch for 12 hours each day for 2 days before, the day of, and for two days after each chemotherapy injection. The primary endpoint was progression-free survival. The final results showed that adding nitroglycerin to chemotherapy was no better than chemotherapy alone, and nitroglycerin had no major side effects. This trial has conclusively shown that adding nitroglycerin to standard chemotherapy for advanced NSCLC provides no benefit and further research on this treatment combination is not recommended.