Leveraged Modalities are Leading to Improved Survival in EGFR+ NSCLC

Rao Mushtaq, MD

Improvements in survival are being seen across the spectrum of EGFR-mutant non–small cell lung cancer (NSCLC) in patients with resectable, oligometastatic, and metastatic disease with earlier utilization of osimertinib (Tagrisso), stereotactic body radiation therapy (SBRT), and VEGF/TKI combinations, explained Rao Mushtaq, MD.

For example, adjuvant osimertinib resulted in a statistically significant and clinically meaningful improvement in disease-free survival (DFS) in patients with stage IB/II/IIIA EGFR-mutated NSCLC in the phase 3 ADAURA trial.¹ Specifically, the third-generation EGFR TKI elicited a 79% reduction in the risk of disease recurrence or death vs placebo (HR, 0.21; 95% CI, 0.16-0.28; P < .0001). In October 2020, the FDA granted osimertinib a priority review designation to a supplemental new drug application for the adjuvant treatment of patients with early-stage EGFR-mutated NSCLC following complete tumor resection with curative intent.²

Moreover, the addition of SBRT to first-line treatment with a TKI––gefitinib (Iressa), erlotinib (Tarceva), or icotinib––led to an improvement in progression-free survival (PFS; HR, 0.618; 95% CI, 0.394-0.969; P < .001) and overall survival (OS; HR, 0.682; 95% CI, 0.456-1.001; P < .001) in patients with EGFR-mutant oligometastatic NSCLC in the phase 3 SINDAS trial (NCT02893332).³

Finally, the frontline combination of erlotinib and ramucirumab (Cyramza) led to a median PFS of 19.4 months vs 12.4 months with erlotinib alone in patients with EGFR-mutant metastatic NSCLC in the phase 3 RELAY trial (HR, 0.59; 95% CI, 0.46-0.76; P <.0001).⁴ In May 2020, the FDA approved the combination as a frontline treatment for patients with metastatic NSCLC whose tumors harbor EGFR exon 19 deletions or exon 21 substitution mutations.

“I will be closely monitoring the ADAURA trial because [adjuvant osimertinib] will be something I will use once we have survival data. The data regarding the use of SBRT for oligometastatic disease is pretty convincing, even if we exclude the exon 20 insertion imbalance in the patient distribution. That will definitely be something we will be doing more often,” said Mushtaq. “Additionally, VEGF inhibitors are now available if we want to use erlotinib up front as opposed to osimertinib.”

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on lung cancer, Mushtaq, an oncologist at National Jewish Health, provided perspective on these pivotal data in EGFR-mutant NSCLC.

OncLive^®: Could you shed light on the combination of erlotinib and ramucirumab as a frontline therapy for patients with newly diagnosed metastatic EGFR-mutant NSCLC?

Mushtaq: Findings from the RELAY trial led to the approval of erlotinib and ramucirumab. RELAY was a phase 3 study that included patients with untreated metastatic NSCLC with exon

19 deletion and L858R mutations without any CNS metastases. The combination was compared with erlotinib and showed a benefit in PFS and [a trend toward improved] OS.

We saw a higher incidence of high blood pressure in the treatment group compared with the placebo group. Proteinuria was also higher in the combination group, which is expected with VEGF inhibitors like ramucirumab, as well as diarrhea and paronychia.

Osimertinib is also approved as frontline therapy for patients with newly diagnosed metastatic EGFR-mutant NSCLC. Could the addition of gefitinib to osimertinib augment responses in patients with newly diagnosed metastatic EGFR-mutant NSCLC?

[First, I should say that] I would strongly recommend doing a repeat biopsy on progression to identify the mechanism of resistance because there are some data [to suggest] that we can add chemotherapy or additional TKIs depending on the mechanism of resistance.

[With that said], osimertinib is a treatment for patients who have a T790M mutation, which usually develops if somebody is on gefitinib. When someone is on osimertinib, they develop a C797S mutation, which is a resistance mechanism to osimertinib. Therefore, the thought was to combine the two TKIs, osimertinib and gefitinib. The investigators found that at two weeks, the circulating DNA was cleared in 88% of patients, which is really amazing compared with the FLAURA trial, which showed a rate of only 45% after 3 weeks. What we don’t know right now is how much that information will translate into OS with the clearance of circulating DNA at 2 weeks.

How are treatment approaches for patients with oligometastatic disease evolving?

A study evaluated first-line TKI of physician’s choice with or without SBRT for patients with oligometastatic disease. The investigators included patients with NSCLC and an EGFR mutation, exon 19 deletion and L858R with 5 or less metastases. Patients could not have had more than 2 metastases in 1 organ.

Patients’ baseline characteristics were pretty well matched [between arms]. Though, there were slightly more patients with exon 20 insertions in the TKI-alone arm, who we know do not respond to standard-of-care TKIs. The median PFS was 20.5 months in the TKI/SBRT group vs 12.5 months in the TKI-alone group. The median OS was also improved with the addition of SBRT, at 25 months.

Turning to the adjuvant setting, could you discuss the significance of the ADAURA trial?

The phase 3 ADAURA trial, which was presented at the 2020 ASCO Virtual Scientific Program, evaluated the use of adjuvant osimertinib in patients with stage IB to IIIA EGFR-mutated NSCLC after complete resection. These patients have an early risk of recurrence. The 5-year risk of recurrence is about 45% for patients with stage IB disease, which goes up to 62% in stage II disease and 76% in stage III disease. With that, the investigators gave patients 80 mg of adjuvant osimertinib for 3 years.

The patient characteristics were pretty well matched between the 2 arms. About 45% patient in each arm did not get adjuvant chemotherapy, which is a standard of care. The results showed an improvement in DFS in patients with stage II and IIIA disease. The 2-year DFS rate was close to 90%. The secondary end point, which was DFS in the overall population, including the stage IB/II patients, the 2-year DFS rate was around 89%.

However, the RADIANT, the SELECT, and the Chinese adjuvant trials did not show that the DFS [benefit] will translate into an OS benefit, which is one reason why people want to wait and see until we have some OS data from ADAURA before changing our practice.

What other updates came out of recent medical meetings?

A phase 2 study was presented with osimertinib with or without bevacizumab (Avastin) in patients who had an EGFR T790M mutation. In these patients, osimertinib is effective. We didn’t see a median PFS benefit, but we did see a higher overall response rate [ORR] close to 72% compared with osimertinib alone at 55%.

Another study, which was presented at the 2020 ESMO Virtual Congress evaluated the combination of apatinib and gefitinib, which are 2 TKIs, vs gefitinib alone. The results showed that the combination led a median PFS benefit, better ORR, and also longer duration of response vs gefitinib alone.

References

1. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients (pts) with stage IB-IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(suppl 15):LBA5. doi:10.1200/JCO.2020.38.18_suppl.LBA5
2. Tagrisso granted priority review in the US for the adjuvant treatment of patients with early-stage EGFR-mutated lung cancer. News release. AstraZeneca. October 20, 2020. Accessed November 5, 2020. https://bit.ly/35ggsDR.
3. Wang XS. First-line tyrosine kinas inhibitor with or without aggressive upfront local radiation therapy in patients with EGFRm oligometastatic non-small-cell lung cancer: interim results of a randomized phase III, open-label clinical trial (SINDAS) (NCT02893332). J Clin Oncol. 2020;38(suppl 15):9508. doi:10.1200/JCO.2020.38.15_suppl.9508
4. Lilly's Cyramza (ramucirumab) receives FDA approval as first-line treatment for metastatic EGFR-mutated non-small cell lung cancer. News release. Lilly. May 29, 2020. Accessed November 5, 2020. https://bit.ly/36V9G7f.