Encouraging clinical activity was demonstrated by the combination of osimertinib plus durvalumab in patients with advanced non-small-cell lung cancer (NSCLC) that had received prior treatment with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and also in EGFR-TKI naive patients that was offset by safety observations over the occurrence of interstitial lung disease (ILD) in some patients.
Dr. Myung-Ju Ahn, Department of Medicine, Section of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University, Seoul, Republic of Korea, presented results during the ‘Best Abstracts’ session at the European Lung Cancer Conference (ELCC), held in Geneva, Switzerland, 13 to 16 April, 2016 from the TATTON trial.
TATTON is a multi-arm phase Ib trial investigating osimertinib 80 mg in combination with durvalumab (anti-PD-L1 monoclonal antibody), savolitinib (MET inhibitor) or selumetinib (MEK 1/2 inhibitor) in patients with advanced EGFR-mutant lung cancer. The osimertinib and durvalumab combination is just one arm of the TATTON study, which has two parts: Part A was a dose escalation study in patients with advanced NSCLC that had received prior treatment with an EGFR-TKI. Part B was a dose expansion trial conducted in patients with advanced disease that were EGFR-TKI treatment-naive.
Osimertinib (AZD9291) is an oral, potent, irreversible, third-generation EGFR-TKI that selectively targets EGFR-mutated and T790M resistance mutations and durvalumab (MEDI4736) is a high-affinity human IgG1 monoclonal antibody that blocks PD-L1 binding to both PD-1 and CD80.
All patients had tumours with confirmed mutations
Dr. Ahn reported updated safety data from one arm of the TATTON study, the osimertinib plus durvalumab arm from 2 parts of TATTON study wherein all patients had EGFR-mutant NSCLC and no contraindication for immunotherapy; patients with a history of interstitial lung disease (ILD) were excluded.
Part A comprised patients with advanced NSCLC that had experienced radiologically documented disease progression after receiving EGFR-TKIs. Updated results from this treatment arm of the dose-expansion cohorts in part B were also reported from patients that were EGFR-TKI naive and were required to have had pre-study tumour biopsies for central determination of EGFR T790M status. In part A, osimertinib was administered at 80 mg orally once daily plus durvalumab at 3 mg/kg or 10 mg/kg i.v. two times weekly and patients received 80 mg daily of osimertinib plus 10 mg/kg by i.v. twice a week in part B.
The primary objectives of both study parts were safety and tolerability and the secondary objective was clinical activity of the combination.
Elevated rates of ILD were reported in both study arms
As of data cut-off, the osimertinib/durvalumab combination was administered to 23 patients in part A and to 11 patients in part B. The most commonly reported all-causality adverse events of any grade in part A were nausea, reported by 39% of patients, vomiting by 39%, anaemia by 35%, and diarrhoea, which was reported by 35% of patients. In part B, 55% of patients reported diarrhoea and 45% reported nausea.
ILD occurred in 6 (26%) patients in part A; of these, 2 cases were grades 3/4. ILD was reported by 7 (64%) patients in part B; of these, 3 cases were grades 3/4. No grade 5 cases of ILD occurred in either cohort and there were no fatalities; most patients were managed with corticosteroids. The median time from the beginning of treatment to ILD onset was 69 days.
Promising clinical activity demonstrated in patients with advanced disease
Data were evaluable for response in 21 part A patients receiving combination osimertinib plus durvalumab. Partial response (PR) was achieved by 12 patients and 9 patients had confirmed PR. Stable disease (SD) was achieved by 9 patients.
Of 10 patients with evaluable data from part B, 8 patients achieved PR, which was confirmed in 7 patients, and SD was observed in 2 patients.
In his discussant talk entitled ‘Combination therapies with checkpoint inhibitors: what are promising avenues’, Johan Vansteenkiste of the Respiratory Oncology Unit, University Hospital KU Leuven, Leuven, Belgium shared his perspective on why to combine the therapies, in which patients could we combine and how should we combine in term of modalities, concurrent or in sequence.
Anti-PD-1/PD-L1 strategies are established in second-line NSCLC treatment with response rates of up to about 20%. Responses are durable, and translated in remarkable long-term survival. Toxicity is in overall less experienced than with chemotherapy treatment-related adverse events (50–69%), grade 3-4 treatment-related adverse events are present in 8–16% of cases, specific immune-related grade 3-4 adverse events in approximately 5% and adverse events leading to treatment discontinuation in approximately 5%. In term of defining expectations with single agent anti-PD-1/PD-L1, he reviewed the findings from the recent studies and said that PD-L1 immunohistochemistry shows likelihood of response to anti-PD-1/PD-L1 therapy. Furthermore, he reviewed the findings from dual checkpoint inhibition.
In terms of combination of checkpoint inhibitor and TKI, he said that it’s about challenging the field. There is a strong standard therapy, namely several generations of EGFR-TKIs. PD-L1 expression seems to be upregulated in early-stage EGFR mutation positive NSCLC. Clinical data in advanced disease, however, show lower response rates to anti-PD-1/ PD-L1 therapies in EGFR mutated tumours. Furthermore, overlapping toxicities may occur.
He concluded that in terms of immunotherapy combinations there is a clear rationale; in term of efficacy, it seems that oncology community needs to catch up with results for PD-L1 low/negative patients, but toxicity experience with treatment-related adverse events will be crucial. In terms of immunotherapy combinations with TKI, overall response rate is not obviously better than TKI alone – maybe more durable, but it is too early to say. In terms of toxicity there are points at “dangerous liaisons”– especially regarding lung, liver, skin, and gastrointestinal side effects. Regarding combinations of immunotherapy and chemotherapy, he said that the overall response rate is not obviously better than with chemotherapy alone and questioned if sequenced use should be preferred and if pemetrexed-based regimens are a better partner. However, in terms of toxicity there are no “dangerous liaisons”, but a sum of two different toxicity patterns.
- Current ongoing studies that combine immunotherapy with TKI are combinations of:
- durvalumab plus gefitinib in EGFR-mutated NSCLC
- durvalumab plus osimertinib in EGFR-mutated NSCLC
- nivolumab plus erlotinib in EGFR-mutated erlotinib failure setting
- nivolumab plus ceritinib in ALK-translocated crizotinib failure setting
- atezolizumab plus erlotinib in EGFR-mutated NSCLC
- atezolizumb plus alectinib in ALK translocated crizotinib failure setting
- pembrolizumab plus rociletinib in EGFR-mutated erlotinib failure setting
- pembrolizumab plus afatinib in EGFR-mutated pembrolizumab failure setting
- pembrolizumab plus crizotinib in ALK-translocated NSCLC
- and pamebrolizumab plus dabrafenib/trametinib in KRAS-mutated NSCLC
An increase in ILD was reported with the combination of osimertinib and durvalumab compared to what would be expected with either drug alone. Although the combined ILD rate of 38% with 5 cases of grades 3/4 reported for the combination was much greater than either sole agent, there was no apparent increase in the severity of ILD.
Tumour response rate suggests encouraging clinical activity of osimetinib plus durvalumab in EGFR-mutant NSCLC. Specifically, in patients with prior EGFR-TKI therapy, investigator-assessed overall response rate was 67% and 21% in those with T790M positive and T790M negative tumour status, and 70% in EGFR-mutant treatment-naive patients.
According to the authors, the tolerability and safety of combining these novel targeted therapies warrants further investigation. As a result, enrolment in the osimertinib plus durvalumab combination arm of the TATTON study has been suspended, in order to further characterise the combination. This has no impact on other arms of the TATTON study nor osimertinib and durvalumab as monotherapies, or in other combinations.
This trial was funded by AstraZeneca (NCT02143466)