PHARMA NEWS

November 2022 Pharma News Ariez

Osimertinib active as first-line treatment for advanced non-small-cell lung cancer patients with uncommon EGFR mutations

Based on the results of the pivotal FLAURA study, the 3rd generation EGFR inhibitor osimertinib became the preferred first line treatment for patients with advanced NSCLC harboring common EGFR mutations (i.e., exon 19 deletion or L858R allele).1 However, about 10% of EGFR mutations are ‘uncommon mutations’ (ucEGFRmut) and, compared to common EGFR mutations, these uncommon mutations are correlated with a lower response to 1st & 2nd generation EGFR inhibitors.2 As data on the efficacy of osimertinib in patients with ucEGFRmut are scarce, the retrospective UNICORN study was set up. In this study, a total of 62 patients NSCLC patients with an ucEGFRmut were enrolled, coming from 22 centers in 9 countries.3 The most frequent EGFR mutation in this cohort was G719X accounting for 29% of the cases, followed by L861Q (19%) and de novo T790M (16%). Compound EGFR mutations were found in 27 patients (44%). In this retrospective study, osimertinib proved to be active in patients with ucEGFRmut, reflected by an objective response rate (ORR) of 58% and a median duration of response of 17.4 months. The ORR was reported at 47%, 40% and 80% for patients with a G719X, T790M, or L861Q mutation, respectively. The median progression-free survival (PFS) in UNICORN was 9.5 months, with a median overall survival (OS) of 24.5 months. Of note, the outcome was somewhat worse for patients with only uncommon mutations compared to patients with uncommon + common mutations (median PFS: 8.4 vs. 30 months; median OS: 20.2 vs. 35.4 months). Interestingly, osimertinib also exhibited intracranial activity in this cohort of ucEGFRmut NSCLC patients, with an intracranial ORR of 46% (36% in patients with only ucEGFRmut).3

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References

  1. Ramalingam S, et al, N Engl J Med 2020;382:41-50.
  2. Passaro A, et al. J Thorac Oncol 2021;16(5):764-73.

Trodelvy® significantly prolongs the overall survival of pre-treated HR+/HER2-metastatic breast cancer patients

Trodelvy® (Sacituzumab govitecan) is a first-in-class Trop-2–directed antibody-drug conjugate (ADC) that is already approved for the treatment of patients with metastatic triple negative breast cancer who received at least 2 prior therapies (≥1 in the metastatic setting). TROPiCS- 02 study is a global, randomized phase III trial comparing Trodelvy® or physicians’ choice of chemotherapy (TPC: eribulin, capecitabine, gemcitabine or vinorelbine) in 543 previously treated patients with HR+/ HER2- metastatic breast cancer. In order to be eligible for this study, patients had to be previously treated with endocrine therapy, a CDK4/6 inhibitor and two to four lines of chemotherapy in the metastatic setting. At ASCO 2022, it was shown that TROPiCS-02 met its primary endpoint by demonstrating a significant improvement in progression-free survival (PFS) for patients treated with Trodelvy® (median PFS: 5.5 vs. 4.0 months; HR[95%CI]: 0.66[0.53-0.83]; p=0.0003; 12-months PFS rates: 21% vs. 7%).1 During ESMO 2022, it became clear that this delayed disease progression also translates into a significantly longer overall survival (OS). In fact, patients treated with Trodelvy® in this study had a median OS of 14.4 months, which is 3.2 months more than the 11.2 months median OS observed with chemotherapy, corresponding to a statistically significant 21% reduced death risk for patients treated with Trodelvy® (HR[95%CI]: 0.79[0.65-0.96]; p=0.02).2 At the 12-month landmark, 61% of patients treated with Trodelvy® were still alive as compared to 47% in the TPC arm.2 In addition to this, Trodelvy® also outperformed TPC in terms of overall response rate (21% vs. 14%), clinical benefit rate (34% vs. 22%) and median duration of response (8.1 vs. 5.6 months). Finally, Trodelvy® was found to significantly delay the time to a deterioration of Global Health Status and fatigue compared to TPC.2 In general, the safety profile of Trodelvy® in TROPiCS-02 was consistent with that of previous studies, without any new safety signals. With these TROPiCS-02 data, Trodelvy® has now demonstrated a survival benefit in the treatment of pre-treated patients with HR+/HER2- and triple negative metastatic breast cancer, two difficult-to-treat forms of breast cancer.

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References

  1. Rugo H, et al. Presented at ASCO 2022; Abstract LBA1001
  2. Rugo H, et al. Presented at ESMO 2022; Abstract LBA76

Selpercatinib (Retsevmo®) approved for the first-line treatment of patients with RET positive non-small-cell lung and medullary thyroid cancer

Earlier this year, the EMA approval of selpercatinib was extended to also include the first line treatment of patients with RET fusion-positive NSCLC. This extension is based on the results of the open-label, phase I-II LIBRETTO-001 trial in which 796 patients with RET-altered advanced or metastatic solid tumors were treated with selpercatinib. In total, 356 patients enrolled in this study were diagnosed with RET-fusion positive NSCLC. Among patients previously treated with platinum-based chemotherapy (N=247), an objective response rate (ORR) of 61.1% was reported, mounting to an impressive 84.2% in treatment-naïve patients (N=69). Despite a median follow-up of approximately two years in the pre-treated and treatment- naïve population, both the median duration of response (DoR) as the median progression-free survival (PFS) were still not mature. Nonetheless, the median DoR was estimated at 20.2 months for treatment- naïve patients, with an estimated median PFS of 22.0 months. Corresponding values for the platinum-chemotherapy pre-treated population were 28.6 and 24.9 months, respectively. In addition, meaningful clinical outcomes were reported in patients with difficult to treat brain metastases (ORR 84.6%).1,2 Since September 2022, selpercatinib monotherapy is also EMA approved for the treatment of patients (≥12 years) with advanced, RET mutant medullary thyroid cancer (MTC). Also this label extension was based on updated results of the LIBRETTO-001 study. Among the 142 vandetanib and cabozantinib naïve RET mutant MTC patients enrolled in this study, selpercatinib induced an ORR of 81%. Responses obtained to selpercatinib also proved to be durable with 91.9% and 83.7% of ongoing responses after 12 and 24 months, respectively. At the 24-month landmark, 81.1% of these treatment-naïve patients were still alive and free of progression.3

Selpercatinib was generally well-tolerated in the LIBRETTO- 001 trial. In the full safety population of this trial, the most common adverse reactions (≥25%) were oedema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache. The most common Grade 3 or 4 laboratory abnormalities (≥5%) consisted of a decreased lymphocyte count and elevations in ALT and/or AST levels.1-3

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References

  1. Drilon A, et al. Presented at ELCC 2022; Abstract 27P.
  2. Drilon A, et al. J Clin Oncol 2022; published online on Sept 19.
  3. Kroiss M, et all Presented at ESMO 2022; Abstract 1656P.
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