Optimal Sequence of EGFR TKI Therapy for NSCLC Under Investigation

Tetsuya Mitsudomi, MD, PhD

Recent positive clinical trial data have provided the oncology community with several sequencing strategies for patients with EGFR-mutant non-small cell lung cancer (NSCLC), according to Tetsuya Mitsudomi, MD, PhD, in a presentation during the 19th Annual International Lung Cancer Congress.

These approaches include a mix of tyrosine kinase and angiogenesis inhibitors, immunotherapy, and chemotherapy, explained Mitsudomi, vice director and chief of the Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine in Osaka, Japan.

Based on recent clinical data, Mitsudomi highlighted 3 potential sequencing strategies: 1) frontline dacomitinib or afatinib (Gilotrif), second-line osimertinib (Tagrisso) if the patient develops a T790M resistance mutation, followed by atezolizumab (Tecentriq)/bevacizumab (Avastin)/carboplatin/paclitaxel, or atezolizumab/bevacizumab/carboplatin/paclitaxel in the second-line setting; 2) frontline osimertinib, second-line gefitinib (Iressa) if the patient develops a C797S resistance mutation, followed by atezolizumab/bevacizumab/carboplatin/paclitaxel, or second-line atezolizumab/bevacizumab/carboplatin/paclitaxel; or 3) frontline osimertinib plus carboplatin/paclitaxel, second-line gefitinib if the patient develops a C797S resistance mutation, followed by docetaxel plus atezolizumab/bevacizumab in the third line, or second-line docetaxel plus atezolizumab/bevacizumab.

Single-Agent EGFR TKI Versus Chemotherapy

These emerging sequencing strategies stem from prior studies that have demonstrated benefit with EGFR tyrosine kinase inhibitors (TKIs) over chemotherapy, second- and third-line EGFR TKIs, immunotherapy, and novel combination regimens.In the past, clinical trials such as NEJ002, WJTOG3405, OPTIMAL, EURTAC, ENSURE, LUX-Lung 3, and LUX-Lung 6 have evaluated progression-free survival (PFS) and overall survival (OS) outcomes with EGFR TKIs compared with platinum-doublet chemotherapy. However, OS results demonstrated little benefit over chemotherapy.

For example, the phase III NEJ002 trial evaluated the first-generation EGFR inhibitor gefitinib with carboplatin/paclitaxel for patients with chemotherapy-naive NSCLC with sensitive EGFR gene mutations. Median PFS was 10.8 and 5.4 months with gefitinib and chemotherapy, respectively¹; median OS was 27.7 and 26.6 months.²

Erlotinib (Tarceva) was compared with carboplatin/paclitaxel in chemotherapy-naive patients with metastatic EGFR-mutant NSCLC in the phase III randomized OPTIMAL trial, the final OS and PFS results of which did not show a statistically significant difference at 22.8 versus 27.2 months and 13.7 versus 4.6 months with erlotinib and chemotherapy, respectively.³

Head-to-Head TKI Comparisons

In the open-label, randomized phase III LUX-Lung 6 trial, afatinib was evaluated versus cisplatin/gemcitabine for those with advanced EGFR-mutant NSCLC. Median OS was 23.1 months with afatinib and 23.5 months with chemotherapy.⁴More recent trials have compared the available and emerging EGFR TKIs head to head. Treatment with gefitinib, for example, was noninferior to erlotinib in patients with pretreated EGFR-mutant advanced lung adenocarcinoma in the phase III WJOG5108L trial. Data demonstrated a median PFS with gefitinib of 8.3 versus 10.0 months with erlotinib (HR, 1.093; 95% CI, 0.879-1.358; P = .424).⁵

Afatinib was compared with gefitinib in the phase IIb LUX-Lung 7 trial in patients with EGFR-mutant NSCLC, demonstrating similar median PFS outcomes of 11.0 and 10.9 months, respectively (HR, 0.73).⁶ An updated OS analysis did not demonstrate a significant difference between the TKIs; however, there was a trend towards improved OS with afatinib (not evaluable) over gefitinib (48.3 months) in patients who received subsequent osimertinib (HR 0.49; 95% CI, 0.20-1.19; P = .1070).⁷

More recent differences were observed in the phase III ARCHER 1050 trial, which explored the second-generation inhibitor dacomitinib versus gefitinib as a frontline treatment for patients with EGFR-mutant NSCLC. Initial findings presented showed a significant improvement in PFS with dacomitinib at 14.7 months versus 9.2 months with gefitinib (HR, 0.59; P <.0001).⁸

In April 2018, the FDA granted a priority review designation to dacomitinib for the frontline treatment of patients with EGFR-positive locally advanced or metastatic NSCLC based on these results.

The highly anticipated findings of the phase III FLAURA trial showed a nearly doubling of PFS with frontline osimertinib, a third-generation TKI, versus erlotinib or gefitinib at 18.9 months (95% CI, 15.2-21.4) and 10.2 months (95% CI, 9.6-11.1), respectively (HR, 0.46; 95% CI, 0.37-0.57; P <.001).⁹ Based on these data, the FDA approved osimertinib for first-line use in April 2018.

When compared with gefitinib or erlotinib, osimertinib demonstrated the best hazard ratio as first-line treatment, Mitsudomi said.

Although FLAURA does not yet have OS data with osimertinib available, investigators have reported a trend toward OS improvement with the third-generation TKI (HR, 0.63; 95% CI, 0.45-0.88; P = .0068).

"The OS [trend] looks very nice...but at this point we cannot say if there is prolongation of OS," explained Mitsudomi. "It's promising, but it's not significant at this moment."

Meanwhile, OS findings of ARCHER 1050 were reported at the 2018 ASCO Annual Meeting; the median OS was 34.1 months in patients treated with dacomitinib versus 26.8 months with gefitinib (HR, 0.76; P = .0438).¹⁰

"As you can see, ARCHER 1050 was able to show prolongation of OS," said Mitsudomi. "This may have some meaning."

However, an analysis of FLAURA showed a clinical meaningful delay in time to second-line therapy or death with osimertinib,¹¹ which could be a factor for physicians in determining therapeutic sequence and further establishing osimertinib as the frontline standard of care, explained Mitsudomi.

The most common second-line therapy in the osimertinib arm was platinum-based chemotherapy, while those in the standard arm most frequently received subsequent osimertinib. The median PFS2 was not reached for those receiving frontline osimertinib (95% CI, 23.7-not calculable [NC]) versus 20.0 months in patients receiving standard chemotherapy (95% CI, 18.2-NC). This led to a 42% reduction in the risk of progression on second-line therapy or death (HR, 0.58; 95% CI, 0.44-0.78; P <.001).

Mitsudomi explored other factors from the analysis in helping physicians decide on an optimal sequence of agents.

From the same analysis, the median time to first subsequent therapy or death was 23.5 months in the osimertinib group (95% CI, 22.0-NC) versus 13.8 months (95% CI, 12.3-15.7) for those receiving standard chemotherapy (HR, 0.51; 95% CI, 0.40-0.64; P <.0001). Median time to second subsequent therapy or death was also prolonged in the osimertinib group (25.9 months in the standard arm and not reached in the osimertinib group; HR, 0.60; 95% CI, 0.45-0.80).

Potential Role for Immunotherapy

With osimertinib, the median time to discontinuation of study treatment or death was 20.8 months (95% CI, 17.2-24.1) compared with 11.5 months (95% CI, 10.3-12.8) with chemotherapy. The median time to discontinuation of any EGFR TKI or death was 23.0 months (95% CI, 19.5-NC) with osimertinib and 16.0 months with chemotherapy (95% CI, 14.8-18.6).Checkpoint inhibitors have shown little benefit in patients with EGFR mutations. However, in the phase III IMpower150 study, which investigated the combination of atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) in patients with advanced wild-type nonsquamous NSCLC, the regimen reduced the risk of death by 22% versus bevacizumab and chemotherapy (BCP).^12,13

First-Line Combinations

For patients enrolled on the trial who had EGFR/ALK-altered disease, there was a 46% reduction in the risk of death with ABCP. Median PFS was 9.7 months (95% CI, 6.9-15.2) and 6.1 months (95% CI, 5.7-8.4) for ABCP and BCP, respectively (HR, 0.59; 95% CI, 0.37-0.94). Median OS in patients with EGFR/ALK alterations only was not evaluable with ABCP compared with 17.5 months for BCP (HR, 0.54; 95% CI, 0.29-1.03).Combinations with standard TKIs are another approach being actively studied to overcome resistance, Mitsudomi said. These include EGFR TKIs with chemotherapy, angiogenesis inhibition, and small molecule inhibitors.

Results of the phase III NEJ009 trial, which investigated the combination of gefitinib and platinum-doublet chemotherapy in treatment-naive patients with advanced EGFR-mutant NSCLC, failed to demonstrate superiority in PFS2, but investigators noted that it may increase long-term survivors.¹⁴

The possible OS advantage with gefitinib plus carboplatin/pemetrexed over gefitinib alone may be due to the high rate of chemotherapy used to cope with various co-driver mutations, he explained.

Survival follow-up data from the JO25567 trial, looking at erlotinib plus bevacizumab compared with erlotinib, were recently reported. The results of the study showed a median PFS of 16.4 versus 9.8 months for the combination versus erlotinib monotherapy, respectively (HR, 0.52; 95% CI, 0.35-0.76; P = .0005). There was a slight trend in OS improvement, but it was not of statistical significance.¹⁵

The combination was also evaluated in the phase III NEJ026 trial of patients with treatment-naive EGFR-mutant NSCLC, with a median PFS of 16.9 versus 13.3 months (HR, 0.605; 95% CI, 0.417-0.877; P = .01573).¹⁶

Resistance to osimertinib in the form of T790M loss, however, is a poor prognostic factor, Mitsudomi said.

There are a number of ongoing clinical trials investigating combination regimens to address resistance mechanisms: a phase I/II trial of BGB324, an AXL inhibitor, with erlotinib in patients with stage IIIb/IV NSCLC (NCT02424617); osimertinib plus dasatinib (Sprycel) in advanced EGFR-mutant NSCLC (NCT02954523), and osimertinib plus bevacizumab as a second-line treatment for patients with stage IIIb/IVb EGFR-mutant NSCLC.

References

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