Management of NSCLC After Progression on EGFR TKIs Remains a Challenge

Despite several strategies to overcome resistance to EGFR tyrosine kinase inhibitors (TKIs) being investigated in an effort to improve outcomes in patients with non-small-cell lung cancer (NSCLC) after progression, diverse results from some studies have been presented at ESMO Virtual Congress 2020.

“Preclinical and clinical evidence suggests that EGFR TKIs may work synergistically with VEGF inhibitors,” says Prof. Martin Reck, LungenClinic Grosshansdorf, Grosshandorf, Germany, commenting on one such strategy, “and there have been some positive data when first-generation EGFR TKIs have been combined with bevacizumab in untreated patients.” Here, disappointing data have been reported from a phase II study for the third-generation EGFR TKI, osimertinib, plus the VEGF inhibitor, bevacizumab in 81 EGFR-mutated T790M-positive patients who had progressed after EGFR-TKI therapy (Abstract 1259O). In this trial, while objective response rates (ORR) were higher with osimertinib plus bevacizumab than osimertinib monotherapy (72% versus 55%), progression-free survival (PFS) was shorter with the combination (9.4 versus 13.5 months). Reck highlights, “Although these data are not promising in this limited number of pre-treated patients with a resistance-mediating mutation, further investigations combining anti-angiogenic agents with more modern EGFR TKIs as frontline therapy are warranted.”

More promising data were reported in the Late-Breaking presentation of the phase II RAIN-701 study, although further confirmation is required (Abstract LBA61). Tarloxotinib, a hypoxia-activated prodrug of a pan-ErbB kinase inhibitor showed some signs of efficacy in patients with advanced NSCLC who progressed on/after platinum-based chemotherapy and an HER2-activating mutation. Included patients had NSCLC and an EGFR Exon20 insertion (cohort A), NSCLC and an HER2-activating mutation (cohort B) or any solid tumour and an NRG1, EGFR, HER2 or HER4 gene fusion (cohort C). In 11 evaluable patients with an EGFR Exon20 insertion, the best response was stable disease in 6 patients. Of 9 evaluable patients with an HER2-activating mutation, 2 had a confirmed partial response and 4 had stable disease; 3 patients were treated beyond 6 months. Only 1 patient had been enrolled in cohort C. “These are difficult-to-treat, fast-progressing tumour types and the results in patients with an EGFR Exon20 insertion were not particularly promising,” says Reck pointing out that over one-fifth of patients required a reduction of the dose of tarloxotinib due to toxicities. “In addition to the typical EGFR inhibitor adverse events affecting the skin and gastrointestinal tract, QT elongation was observed in over half of patients. Close monitoring is needed to define the toxicity profile of tarloxotinib.”

In a third study presented, targeting HER3 expression with patritumab deruxtecan showed to be a potentially useful approach (Abstract LBA62). “There is evidence that HER3 expression may be associated with resistance to EGFR TKIs,” says Reck, explaining the rationale for a phase I trial of the HER3-directed antibody–drug conjugate, patritumab deruxtecan, in EGFR-mutated NSCLC following EGFR TKI and platinum-based chemotherapy. Late-Breaking results revealed an ORR of 25% in 56 enrolled patients, with preliminary data indicating a complete response in 2% of patients, a partial response in 23% and stable disease in 45% of patients. Reck warns, “It is hard to generate any signal of clinical efficacy in such a heavily pre-treated population, but the response rate suggests that targeting HER3 expression with patritumab deruxtecan may be a potentially useful approach. It must be cautioned that these are very early data and the duration of response and PFS need to be known before conclusions can be made. It will also be interesting to assess whether HER3 expression correlates with efficacy.” He adds, “Combining patritumab deruxtecan with an EGFR TKI in earlier settings is a strategy worth exploring to help address tumour resistance.”

Abstracts and sessions details

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