OSIMETRINIB USE IN NSCLC

GENEVA ― New clinical data show that the novel third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib (Tagrisso, AstraZeneca Pharmaceuticals LP) is highly active when used up front in the treatment of EGFR-positive non–small cell lung cancer (NSCLC). However, an expert not involved with the studies wonders whether it is a good idea to use the drug before resistance has developed.

Osimertinib is an irreversible EGFR tyrosine kinase inhibitor (TKI) selective for the EGFR mutations at exons 19 and 20 and the T790 mutation, which is the cause of treatment resistance in up to 60% of NSCLC patients receiving EGFR TKIs. It was recently launched in the United States for the treatment of patients who had become resistant to previous EGFR therapy.

The new data, presented here at European Lung Cancer Conference (ELCC) 2016, show that when the drug is used up front, instead of in resistant patients, it elicits high response rates and yields extended progression-free survival (PFS).

When used as a first-line treatment in 60 patients with locally advanced or metastatic NSCLC, the drug achieved an overall response rate of 77% and a median PFS of 19.3 months, with few adverse events.

"The overall response rate was among the best reported for first-line therapy of EGFR-mutated NSCLC," commented study presenter Suresh S. Ramalingam, MD, professor of hematology and medical oncology at the Emory School of Medicine and deputy director of Winship Cancer Institute, Atlanta, Georgia, in a release.

"The PFS results are exciting, well exceeding the historical control rates of 10 to 13 months with first- or second-generation drugs," Dr Ramalingam said.

For some of the patients who did experience disease progression, T790M was not the mechanism of resistance, Dr Ramalingam noted, adding: "That tells us that we may be changing the biology of the disease with the use of first-line osimertinib."

The second study investigated the use of osimertinib as a second-line treatment in NSCLC. That study included two analyses of more than 450 patients who were T790M-positive and who had experienced disease progression following EGFR TKI therapy. These analyses revealed response rates of 71% and 66% and median PFS of 9.7 months and 11 months.

"We were able to show a high overall response rate, encouraging duration of response, and good tolerability profile," said James C. H. Yang, MD, PhD, director of the Department of Oncology and the Department of Medical Research, National Taiwan University Hospital, in Taipei, who presented the data.

"PFS was long compared to the 4 to 5 months seen with chemotherapy. This is good news for patients with EGFR mutations who have failed EGFR TKI, for whom osimertinib is now standard of care."

Discussing the two studies, Tony S. K. Mok, MD, chairman, Department of Clinical Oncology, Faculty of Medicine, the Chinese University of Hong Kong, said that although the PFS of 19.3 months with osimertinib is impressive, previous drugs have yielded decreases in PFS with further investigation. "So, more or less, we have to take about a 20% to 30% discount when we see data like that," he said.

As for the data on the use of osimertinib as a second-line therapy, Dr Mok noted that the findings represent "the largest cohort ever" of T790M-positive patients for any third-generation TKI. "It is trustworthy," he said. "The largest sample size ever assures us this observation is a true observation."

However, with these trials presenting osimertinib as both first- and second-line therapy, Dr Mok asked: "Who shall we believe? What should we do?"

He said that one basic question to consider concerns when a lung cancer tumor acquires the T790M mutation. Recent study has indicated that there are two pathways: either the mutation is preexisting, or it is a acquired following initial therapy, in which case the mutation is either T790M or something else.

Dr Mok warned that if osimertinib is given in cases of preexisting T790M and does not sufficiently enter the brain, there could be central nervous system progression of the lung cancer, along with possible small-cell transformation. Previous studies have shown that there is a reduction in the apoptotic response to TKIs with osimertinib.

If, on the other hand, osimertinib is given to patients with surviving lung cancer cells, those cells will go on to develop a mutation other than T790M, owing to the action of the drug. Recent investigations have indicated that these can be one of a whole range of mutations, including mutations associated with a poor prognosis.

"What worries me is that we will have caged the tiger but released a pack of wolves," Dr Mok said. "Which is better, the tiger or the wolf?"

He continued: "For all us to treat patients with osimertinib, collectively, I think we should do genetic sequencing to understand clinically what will happen to this mutation. Are we going to get better mutations or a worse scenario when you suppress T790M right from the beginning?"

Moreover, previous studies have shown that PFS is worse with T790M but that overall survival is largely unaffected. He therefore asked: "Why would we want to suppress T790M at the beginning?"

Stating that this will continue to be a controversial topic, Dr Mok proposed a two-stage, randomized study to provide some answers to these questions. He concluded that the best timing for the use of osimertinib remains to be defined.

Details of the First-Line Use

For the first presentation, Dr Ramalingam showed efficacy and safety results from two phase 1 expansion cohorts from the AURA study, in which EGFR mutation–positive NSCLC patients with locally advanced or metastatic disease received 80 mg or 160 mg osimertinib as first-line therapy.

Sixty patients were enrolled, of whom 40% had the EGFR exon 19 deletion, 42% had the L858Rmutation, and five (8%) were T790M-positive at baseline. At the analysis cutoff on January 4, 2016, the median follow-up was 16.6 months.

The confirmed overall objective response rate (ORR) was 77% ― 67% among patients receiving the 80-mg dose, and 87% for those given the 160-mg dose. The median duration of response had not been reached by the cutoff date.

The median PFS was 19.3 months; the median PFS was not reached by the cutoff date among the 80-mg group and was 19.3 months in the 160-mg group. At 18 months, the proportion of patients who were progression free was 55% overall ― 57% in the 80-mg group, and 53% in the 60-mg cohort.

The overall disease control rate was 97%. At baseline, all five T790M-positive patients had a partial response. The duration of response was not reached by the cutoff date in four patients.

Dose reduction due to the presence of adverse events was required in 10% of the patients receiving the 80-mg dose vs 47% of those receiving the 160-mg dose. The most common adverse events were rash, diarrhea, stomatitis, dry skin, and paronychia. There were seven adverse events of grade ≥3, six of which were in the 160-mg group.

Dr Ramalingam concluded, "In treatment-naive patients with EGFR mutation–positive locally advanced or metastatic NSCLC, osimertinib treatment results in high ORR, promising PFS, and a manageable tolerability profile."

Details of Second-Line Use

For the second presentation, Dr Yang presented data from the 80-mg expansion cohort of the AURA phase 1 study along with a preplanned pooled analysis of the AURA phase 2 extension study and the AURA2 study.

Using the same cutoff date of January 4, 2016, the team collected data on 63 patients from the 80-mg expansion cohort of the AURA phase 1 study and a total of 411 patients from the AURA phase 2 and AURA2 studies.

All patients had experienced disease progression following previous EGFR TKI therapy and were T790M-positive, as confirmed by tumor biopsy. They all had measurable disease, a World Heart Organization performance status of 0 or 1, and acceptable organ function. Stable brain metastases were allowed.

Analysis of the AURA phase 1 expansion study revealed that investigator-assessed ORR was 71%, the median duration of response was 9.6 months, and the median PFS was 9.7 months.

In the phase 2 pooled analysis, blinded, independent central review indicated that the ORR was 66%, the median duration of response was 12.5 months, and the median PFS 11.0 months. The proportion of patients who were progression free at 12 months was 47.5%.

The most common adverse events in both cohorts were rash, diarrhea, dry skin, and paronychia, with relatively few adverse events of grade ≥3.

Enriqueta Felip, MD, PhD, a medical oncologist at Vall d'Hebron University Hospital, in Barcelona, Spain, who did not take part in the study, commented in a release: "The study confirms the good results with osimertinib in this setting.

"Nowadays, in patients with EGFR mutation who progress after an EGFR TKI, there is a clear need for T790M testing, since we now have a highly active agent, osimertinib, for this situation."

Both studies were funded by AstraZeneca. Dr Ramalingam has received consultancy fees from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Genentech, Lilly, Merck, and Novartis. Dr Yang has served on the advisory board of Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, AstraZeneca, Astellas, Bayer, MSD, Merck Serono, Pfizer, Novartis, Clovis Oncology, and Celgene.

European Lung Cancer Conference (ELCC) 2016. Abstracts LBA1_PR and LBA2_PR, both presented on April 14, 2016.