GENEVA — Combining immunotherapy with checkpoint inhibitors with tyrosine kinase inhibitors (TKIs) in non–small cell lung cancer (NSCLC) has been called into question following two investigations in which encouraging responses were counterbalanced by high rates of adverse events.
The two studies were presented here at European Lung Cancer Conference (ELCC) 2016. Both assessed the combination of the investigational checkpoint inhibitor durvalumab (under development by AstraZeneca), a human IgG1 anti–programmed cell death ligand (PD-L) 1 antibody, with a tyrosine kinase inhibitor (TKI) in patients with endothelial growth factor receptor (EGFR) mutation- positive NSCLC, but the TKI was different in each case.
The hypothesis behind testing of the combination is that adding PD-inhibitor immunotherapy to the known benefits of TKI therapy would lead to a stronger and/or more durable response, inasmuch as previous studies have shown that PD-L1 is particularly upregulated in NSCLC tumors that are positive for EGFR mutations.
The first analysis looked at durvalumab plus the first-generation TKI gefitinib (Iressa, AstraZeneca Pharmaceuticals LP) in 20 patients with TKI-naive NSCLC. Although more than 75% of participants showed a response to treatment, there were high rates of adverse events of grade ≥3 and increases in serum levels of enzymes associated with liver damage.
Nevertheless, study presenter Don L. Gibbons, MD, PhD, assistant professor, Department of Thoracic/Head and Neck Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, said that the results "support potential future investigations of combined durvalumab/gefitinib treatment in NSCLC."
The second study was an analysis of 34 patients who received differing doses of durvalumab along with the third-generation TKI osimertinib (Tagrisso, AstraZeneca Pharmaceuticals LP). Again, although with the combination therapy, a large number of patients responded, there were also high rates of severe adverse events. Furthermore, interstitial lung disease (ILD) was reported as an adverse event in almost 40% of patients.
While highlighting the high overall response rates, lead researcher Myung-Ju Ahn, MD, PhD, professor, Division of Hemato-Oncology, Samsung Medical Center, Seoul, Republic of Korea, said that owing to the high incidence of ILD, recruitment to that arm of the trial has been put on hold while the etiology is investigated.
Better Efficacy, but More Toxicity
Discussing the studies, Johan F. Vansteenkiste, MD, PhD, Respiratory Oncology Unit, Department of Pulmonology, University Hospital Gasthuisberg, Leuven, Belgium, questioned the use of checkpoint inhibitors with TKIs, saying that it is "a challenging field, for different reasons."
One reason is that the TKIs are potent therapies, even when used on their own.
Dr Vansteekkiste emphasized that "if we combine treatments, we always need to look at the balance, because there are very little, if any, combinations in oncology that have less toxicity than single agents."
He continued: "This is quite obvious, so there will always somehow be some increase in toxicity, but the important thing is that the increase in toxicity is balanced out by a higher increase in benefit.
To assess whether that is the case with the new combination of PD inhibitor and TKI, he compared the results reported at the meeting with results for each drug used alone that were reported in previous studies of similar design and methodology.
This comparison showed that combination therapy resulted in a grade ≥3 treatment-related adverse event rate of 59%. That rate was driven by high rates of lung adverse events. By comparison, the rates were 13% for osimertinib alone and 8% for durvalumab alone in previous studies. In addition, the rate of discontinuation due to adverse events was 59% for the combination, vs 6% and 5%, respectively, for the two drugs used alone.
The comparison also showed that efficacy was improved. The combination achieved an overall response rate of 67% and a disease control rate of 95%, compared with 61% and 95%, respectively, for osimertinib alone in prior studies.
Referring to these percentages, Dr Vansteekkiste asked: "If you make this toxicity-benefit comparison, do you see what I see?"
Turning to the other presented study, he said that combination therapy resulted in a grade ≥3 treatment-related adverse event rate of 55%, largely owing to high rates of liver and lung adverse events. The rates were 28.7% and 8% for gefitinib and durvalumab, respectively, when used alone; the rates of discontinuation due to adverse events were 20% vs 6.9% and 5%, respectively.
But again, efficacy was improved. The combination achieved an overall response rate of 79%, and the disease control rate was 84%, vs 77% and 92%, respectively, for gefitinib used alone in previous studies.
Again, Dr Vansteenkiste asked the audience: "Do you see what I see?"
Study Details
The data on the durvalumab plus gefitinib combination comes from an an ongoing phase 1 studyinvolving 20 patients with TKI-nave EGFR mutation–positive NSCLC.
Ten patients received gefitinib 250 mg QD plus durvalumab 10 mg/kg every 2 weeks.
A further 10 patients were treated with gefitinib 250 mg QD for 4 weeks before receiving gefitinib 250 mg QD plus durvalumab 10 mg/kg every 2 weeks, for a maximum of 12 months.
After a follow-up of at least 3 months, one (5%) patient from the overall cohort had a complete response to therapy; 14 (74%) had a partial response. Furthermore, three (16%) patients had stable disease for at least 8 weeks, and one (5%) had stable disease lasting at least 24 weeks.
However, all patients experienced a treatment-related adverse event, with all-cause serious adverse events seen in four (20%) patients across the entire cohort.
Eight (40%) patients were found to have a grade 3/4 increase in alanine aminotransferase level; three (15%) had a grade 3/4 increase in aspartate animontransferase level. These were managed by dose interruption and/or use of steroids.
Nevertheless, Dr Gibbons, the lead researcher, said that the combination therapy was "generally well tolerated."
The second presentation discussed the osimertinib and durvalumab arm of the TATTON clinical trial, which is examining the safety and efficacy of osimertinib in combination with durvalumab, savolitinib, selumetinib, or tremelimumab in EGFR mutation–positive NSCLC.
Dr Ahn discussed the dose escalation phase of the study (part A), in which patients who experienced disease progression after prior TKI therapy were treated with osimertinib 80 mg QD plus durvalumab 3 mg/kg (n = 10) or 10 mg/kg (n = 13) IV every 2 weeks.
She also presented data on the dose expansion phase (part B), in which 10 treatment-naive patients were treated with osimertinib 80 mg QD plus durvalumab 10 mg/kg IV every 2 weeks.
Confirmed treatment responses were reported in four (40%) patients from the durvalumab 3 mg/kg cohort and in five (39%) patients from the durvalumab 10 mg/kg cohort of part A. Seven (70%) of the patients in part B had a confirmed response.
Interestingly, the rate of confirmed responses in part A was higher among patients who tested positive for the T790M gene mutation, which is associated with tumor progression, at 6/9 (67%) vs 3/14 (21%) among those without the mutation.
Serious adverse events were recorded in 13/34 (38%) patients overall, with one adverse event leading to death in the durvalumab 10 mg/kg cohort of part A. ILD developed in 13/34 (38%) patients, with a mean time to onset of 80 days and a median time to onset of 69 days.
Dr Ahn concluded: "An increase in ILD was reported with the combination of osimertinib and durvalumab compared to what would be expected with either drug alone."
This has resulted in a halt to the osimertinib and durvalumab arm of the trial, but recruitment continues in the other arms.
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