Osimertinib in Elderly Patients with Epidermal Growth Factor Receptor T790M-Positive Non-Small-Cell Lung Cancer Who Progressed During Prior Treatment: A Phase II Trial.

LESSONS LEARNED: Non-small-cell lung cancer (NSCLC) represents 85% of lung cancer in elderly patients.In the present study performed in the 36 elderly subjects with epidermal growth factor receptor (EGFR) T790M mutation-positive NSCLC, osimertinib 80 mg demonstrated statistically significant improvement in the objective response rate, which was comparable to those in the nonelderly population.Osimertinib appears to be an effective and safe treatment option in elderly patients with advanced NSCLC with EGFR mutation; further research in larger scale is warranted.
BACKGROUND: Previous findings suggest the possibility of relatively safe use of osimertinib for patients with T790M-positive non-small-cell lung cancer (NSCLC), with few serious adverse events for the elderly in comparison with conventional endothelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and with an antitumor effect.
METHODS: This phase II study was performed to prospectively investigate the efficacy and safety of osimertinib for elderly patients aged ≥75 years with ineffective prior EGFR TKI treatment or with recurrence in T790M EGFR TKI resistance mutation-positive NSCLC.
RESULTS: A total of 36 patients were included in the analyses. Among the 36 subjects, 63.9% were female, with mean age of 79.9 years. The objective response rate (ORR) was 58.3% (95% confidence interval [CI], 42.2%-72.9%), demonstrating statistically significant efficacy of osimertinib (p = .0017). The median duration of response (DOR) was 27.9 weeks (95% CI, 21.1-82.0). Complete response (CR) and partial response (PR) were 2.8% and 55.6%, respectively. Disease control rate (DCR) was 97.2%. A waterfall plot revealed that 33 (91.6%) subjects exhibited tumor shrinkage during treatment, including 12 of 14 subjects who had stable disease (SD). All adverse events were not reason for discontinuation of the study drug.
CONCLUSION: Osimertinib may be an effective and safe treatment option in elderly patients with advanced NSCLC with EGFR mutation. © AlphaMed Press; the data published online to support this summary are the property of the authors.

Discussion

Lung cancer is the most common malignancy, accounting for 12.9% of all new cancer diagnoses, and the most common cause of cancer deaths [1]. Median age at diagnosis of lung cancer has been reported to be 63–70 years [2], [3], [4], [5], [6], and NSCLC represents 85% of lung cancer in elderly patients [7], [8], [9]. Treatment of elderly patients requires particular care for several reasons. Elderly patients typically have more comorbidities than younger patients, requiring concurrent management. Physiological functions decline with aging, such that some patients tolerate therapy more poorly. Furthermore, concurrent noncancer therapies may interfere with the metabolism of chemotherapeutic drugs. Afatinib, a second‐generation EGFR TKI, showed a proliferation‐inhibitory effect on a lung cancer cell strain that had T790M mutation [10]; however, as for safety in the elderly, the medical evidence is not yet clear, unlike that for the first‐generation EGFR TKI.

Osimertinib, a third‐generation EGFR TKI that irreversibly inhibits EGFR, demonstrates inhibitory activity against tumor cells harboring sensitizing EGFR mutations and also selective inhibitory activity against tumor cells harboring the TKI‐resistant mutation T790M [11], and is a first‐line treatment for EGFR mutation‐positive NSCLC [12]. The grade ≥3 adverse events reported in patients receiving osimertinib as a first‐line treatment in the AURA study [12], AURA extension study [13], and AURA2 study [14] were rash (2%, 1%, and 1%, respectively) and diarrhea (3%, 1%, and 1%, respectively). These results suggest the possibility of relatively safe use of osimertinib with few serious adverse events for the elderly in comparison with conventional EGFR TKIs.

Waterfall plot of maximum changes in tumor size (diameter) from baseline in individual patients during the treatment.

In the present study, which included 36 patients with EGFR T790M mutation‐positive NSCLC with ineffective prior EGFR TKI treatment or with recurrence, the ORR was 58.3% (95% CI, 42.2%–72.9%), the DOR was 27.9 weeks (95% CI, 21.1–82.0), and the DCR was 97.2% with osimertinib 80 mg administration. Because the lower limit of the estimated CI exceeded a threshold of 35%, a statistically significant improvement in the ORR was demonstrated. The ORR in the present study performed in elderly patients was comparable to that in the nonelderly population [13], [14], [15]. In addition, a waterfall plot revealed that 33 (91.6%) subjects exhibited tumor shrinkage during treatment, including 12 of 14 subjects who had SD.

There were no fatal events and no adverse events that required dose reduction or discontinuation of the study drug. The results of previous findings and the present study suggest that osimertinib may be an effective and safe treatment option in elderly patients with advanced NSCLC with EGFR mutation.

Trial Information

Lung cancer – NSCLC

Metastatic/advanced

More than two prior regimens

Phase II

Single arm

Overall response rate

Toxicity

Active and should be pursued further

Drug Information

Osimertinib

AstraZeneca

Small molecule

EGFR

Milligrams (mg) per flat dose

Oral (p.o.)

Osimertinib 80 mg OD tablet was orally administered until progressive disease occurred or a criterion for discontinuation was met.

Patient Characteristics

13

23

IIIB: 1, IV: 25, Postoperative recurrence: 10

Median (range): 79.9 years

Median (range): Not collected

0 — 8

1 — 28

2 — 0

3 — 0

Unknown — 0

Adenocarcinoma, 35; Combined SCLC with adenocarcinoma, 1

Primary Assessment Method

ORR

36

36

36

RECIST 1.1

n = 1

n = 20

n = 14

n = 1

n = 0

The ORR was 58.3% (95% CI, 42.2%–72.9%), demonstrating statistically significant efficacy of osimertinib (p = 0.0017). The median of the DOR was 27.9 weeks (95% CI, 21.1–82.0). CR and PR were 2.8% and 55.6%, respectively. DCR was 97.2%. The waterfall plot shows that 33 (91.6%) subjects exhibited tumor shrinkage during treatment, including 12 of 14 subjects who had SD. DpR ≥50% was achieved in 11 (30.5%) subjects and ≥30% in 26 (72.2%) subjects.

Adverse Events

Adverse events reported in 10% or more cases were fatigue (38.9%), decreased appetite (38.9%), diarrhea (36.1%), rash (33.3%), paronychia (33.3%), pruritus (22.2%), oral mucositis (11.1%), nausea (11.1%), and fever (11.1%).

Assessment, Analysis, and Discussion

Study completed

Active and should be pursued further

To the authors’ knowledge, this is the first prospective study to examine the efficacy and safety of osimertinib in elderly patients with epidermal growth factor receptor (EGFR) mutation T790M‐positive non‐small‐cell lung cancer (NSCLC) with disease progression on prior treatment. In the AURA phase II extension study performed in patients with EGFR mutation T790M‐positive advanced NSCLC and progression after EGFR tyrosine kinase inhibitor (TKI) treatment [13], the objective response rate (ORR) was 62% (95% confidence interval [CI], 54%–68%), and in the AURA 2 phase II and AURA 3 phase III studies in patients after NSCLC progression on frontline EGFR TKI, ORR was 51%–71% [14], [15]. In comparison, the ORR of docetaxel, which is the standard treatment for elderly patients in Japanese guidelines, has been reported to be 22.7% in a controlled study with vinorelbine and 41.2% in a study of combined carboplatin and pemetrexed in elderly Japanese patients [17], [18]. Based on these findings, the expected response rate and threshold response rate are estimated to be 60% and 35%, respectively. Assuming a two‐sided significance level of 5% and a power of 80%, 31 subjects were required. Considering dropouts, 35 subjects were to be enrolled in the study. In the present study, ORR was 58.3% (95% CI, 42.2%–72.9%), duration of response was 27.9 weeks (95% CI, 21.1–82.0), and the disease control rate was 97.2% with osimertinib 80 mg administration in 36 elderly subjects with EGFR T790M‐positive NSCLC. Because the lower limit of the estimated CI exceeded a threshold of 35%, statistically significant improvement in the ORR was demonstrated. The ORR in the present study performed in elderly patients was comparable to those in the nonelderly population. In addition, waterfall plot revealed that 33 (91.6%) subjects exhibited tumor shrinkage during treatment, including 12 of 14 subjects who had stable disease.

The most common side effects observed in the AURA phases I–II and AURA 2 studies were gastrointestinal symptoms (diarrhea, 47%; nausea, 22%; and decreased appetite, 21%), followed by dermatologic side effects (rash, 40%; dry skin; and pruritus), and a fatal event was reported as being possibly drug‐related. Hyperglycemia and QT prolongation were seen in 2% and 4%, respectively, which required no dose reduction [19]. In the present study, as for the gastrointestinal symptoms, decreased appetite was observed in more patients compared with those in the AURA studies (38.9% vs. 21%); however, diarrhea (36.1% vs. 47%) and nausea (11.1% vs. 22%) were less frequent. Among these, grade ≥3 events were decreased appetite (11.1%) and diarrhea (2.8%). The most frequent dermatological symptom, rash, was less frequent in the present study versus that of the AURA studies (33.3% vs. 40%), followed by paronychia in 33.3%, but neither of these was grade ≥3. There were no fatal events and no adverse events that required dose reduction or discontinuation of the study drug.

A recently conducted retrospective study compared the frequency of adverse events associated with osimertinib between elderly (aged ≥75 years) and nonelderly (aged <75 years) patients with advanced NSCLC with EGFR T790M mutation [20]. Comparison was also performed between the initial EGFR TKI treatment before osimertinib administration in the same patient cohort. The results showed that the only grade ≥2 event that was significantly more frequent in the elderly group compared with the nonelderly group was paronychia (16.6% vs. 1.6%; p = .04), and the maximum grade of EGFR TKI‐related adverse events associated with osimertinib in the elderly group was significantly lower than that of the initial EGFR TKI treatment (p = .03).

To obtain conclusive results, further studies in a larger elderly population is warranted.

Taking together the results of previous findings and the present study, osimertinib appears to be an effective and safe treatment option in elderly patients with advanced NSCLC with EGFR mutation.

Kaplan‐Meier curve shows the duration of response, defined as the time from the achievement of a response to progression, among 26 responders. The median of the duration of response was 27.9 weeks (95% confidence interval, 21.1–82.0 weeks).

Abbreviation: NC/NA, No change from baseline/no adverse event.