Early results from a phase I trial of durvalumab plus gefitinib demonstrated tolerability and encouraging anti-tumour activity in tyrosine kinase inhibitor (TKI)-naive patients with non-small cell lung cancer (NSCLC) and EGFR mutations. Durvalumab is a human IgG1 monoclonal antibody that selectively blocks interaction of programmed death ligand-1 (PD-L1) with PD-1 and CD-80, and gefitinib is an EGFR-TKI that is used in NSCLC.
Dr. Donald Gibbons of the Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA, presented results during the ‘Best Abstracts’ session at the European Lung Cancer Conference (ELCC), held in Geneva, Switzerland, 13 to 16 April 2016.
Dr. Gibbons reported updated dose-expansion phase data from this ongoing phase I open-label multi-centre study evaluating the safety and tolerability of combined therapy with durvalumab plus gefitinib in TKI-naive patients with NSCLC and sensitising EGFR mutations. Exon 19 deletion was detected in 11 patients and 8 patients had exon 21 L858R mutation.
Treatment arms have 10 patients each: patients in arm 1 receive concurrent durvalumab at 10 mg/kg every 2 weeks plus gefitinib at 250 mg once-daily and arm 2 patients received 4 weeks of priming gefitinib monotherapy followed by concurrent durvalumab plus gefitinib at the same dose as arm 1. Patient characteristics and demographics were balanced across both arms.
The trial’s primary endpoints were safety and tolerability and the secondary endpoints included tumour response by RECIST 1.1, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity.
Treatment with combined gefitinib and durvalumab was well tolerated
The results show that the primary endpoints of tolerability and safety were met. The gefitinib/durvalumab combination was tolerable in most patients. The most frequently reported treatment-related adverse events of any grade occurring in 4 or more patients included diarrhoea, which was reported by 80% and 60% of patients in arms 1 and 2, respectively. In arm 1, 70% of patients reported increased ALT and 60% of patients had rash. In arm 2, 60% of patients reported increased ALT or pruritis.
Elevated AST/ALT (asymptomatic) was seen in both arms with higher incidence/severity in arm 2. Increased ALT/AST is managed by dose interruption/steroid use; patients were able to continue on treatment in arm 1 (concurrent durvalumab and gefitinib).
Trial discontinuation due to treatment-related CTC grade 3/4 adverse events was reported only in arm 2 wherein 3 patients discontinued treatment due to increased ALT and/or AST, and one patient discontinued due to pneumonitis.
Promising response observed with gefitinib and durvalumab
Efficacy was assessed at ≥8 weeks for 19 patients; 9 patients in arm 1 and 10 patients in arm 2 had evaluable data. The investigator-determined best objective response rate (ORR) in arm 1 was 77.8% with 7 of 9 patients demonstrating response. The best ORR in arm 2 was 80.0% where 8 of 10 patients showed response. One (11.1%) patient in arm 1 achieved complete response. Partial response was achieved in 6 (66.7%) and 8 (80.0%) of patients in arms 1 and 2, respectively. Stable disease lasting 8 weeks or longer was observed in 2 (22.2%) and 1 (10.0) patient(s) in arms 1 and 2, respectively. Stable disease lasting 24 weeks or longer was observed in 1 patient (10%) in arm 2.
PK profiles showed similarity to monotherapy; complete inhibition of soluble PD-L1 and absence of anti-drug antibody activity was observed.
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
Conclusions
The authors decided to bring the 10 mg/kg durvalumab plus gefitinib at 250 mg dose regimen forward since it was generally well-tolerated. They concluded that the encouraging activity observed with this regimen in TKI naive patients with NSCLC and sensitising EGFR mutations supports continued evaluation and potential future investigations of combined durvalumab/gefitinib treatment in NSCLC. Additional exploratory biomarker analyses in pre/post-treatment tumour biopsies (e.g. pEGFR, PD-L1) and whole blood samples are in progress to further elucidate the mechanism of action of EGFR-TKIs in combination with immunotherapies.
Disclosure
This trial (NCT02088112) was funded by MedImmune, the global biologics R&D arm of AstraZeneca
Reference
57O. Efficacy, safety and tolerability of MEDI4736 (durvalumab [D]), a human IgG1 anti-programmed cell death-ligand-1 (PD-L1) antibody, combined with gefitinib (G): A phase I expansion in TKI-naïve patients (pts) with EGFR mutant NSCLC