Oncogene-driven lung cancer: EGFR, METex14, ROS1, RET

NEOS: neoadjuvant osimertinib

The neoadjuvant potential of the third-generation EGFR TKI osimertinib was assessed in the multicenter, single-arm, phase II NEOS study that included patients with resectable, stage II-IIIB N2, EGFR-mutant (ex19del/L858R) adenocarcinoma of the lung. Forty patients received osimertinib 80 mg QD for 6 weeks prior to surgery. Among these, 38 completed treatment, and 32 underwent surgical resection. The interim analysis presented at the ASCO 2021 Congress already indicated that neoadjuvant osimertinib is effective and safe [1]. At ELCC 2022, Lyu et al. reported updated findings of the NEOS trial [2].

The objective response rate (ORR), which was defined as the primary endpoint, was 71.1 %. Disease control had been achieved by all patients. Three out of 28 pathologically evaluable individuals (11 %) experienced major pathological responses, which included one case of complete response (4 %). Almost half of all patients showed pathological responses of ≥ 50 %. R0 resections were performed in 94 %. Overall, the safety profile of neoadjuvant osimertinib remained consistent with previous reports. The most common adverse events (AEs) included rash (any grade, 50 %), diarrhea (30 %), and oral ulceration (30 %). Grade 3 treatment-related AEs (i.e., rash, hypertension, renal disease) were observed in 3 patients (7.5 %). No event led to treatment discontinuation.

As the authors noted in their conclusion, the NEOS study demonstrated promising efficacy and good tolerability of neoadjuvant osimertinib. Phase III trials enrolling larger numbers of patients are warranted to further validate this strategy. At present, the three-arm, randomized, NeoADAURA trial is assessing neoadjuvant osimertinib alone or together with chemotherapy vs. standard-of-care chemotherapy (NCT04351555).

First-line furmonertinib: FURLONG

Furmonertinib is a selective third-generation EGFR TKI that irreversibly inhibits both EGFR-sensitizing and T790M resistance mutations. The ran­domized, double-blind, multicenter, phase III FURLONG study investigated first-line treatment with furmonertinib 80 mg QD compared to gefitinib 250 mg QD in Chinese patients with locally advanced or metastatic, EGFR-mutated (ex19del/L858R) lung cancer [3]. Asymptomatic CNS metastases were allowed. The furmonertinib and gefitinib arms included 178 and 179 evaluable patients, respectively.

The primary endpoint was met, with patients treated in the experimental arm deriving significant PFS improvement compared to those in the control arm (20.8 vs. 11.1 months; HR, 0.44; p < 0.0001; Figure). Across subgroups, the PFS findings favored furmonertinib. No differences emerged between the study arms in terms of ORR (89 % vs. 84 %; p = 0.2078) or disease control rate (96 % vs. 93 %; p = 0.3551), although furmonertinib-treated patients experienced significantly longer duration of response (19.7 vs. 10.5 months; p < 0.0001) and time to progression (20.9 vs. 11.2 months; p < 0.0001). Median overall survival (OS) had not been reached yet.

Despite longer median duration of exposure in the experimental arm (18.3 vs. 11.2 months), furmonertinib showed a favorable safety profile, with relatively lower rates of grade ≥ 3 treatment-related AEs (TRAEs; 11 % vs. 18 %) as well as lower rates of abnormal liver function readings, diarrhea, and rash. Overall, these results suggest that furmonertinib, as compared to gefitinib, is a potentially preferred first-line regimen in patients with EGFR-mutant NSCLC.

Figure: Superior progression-free survival with furmonertinib vs. gefitinib in EGFR-mutated advanced lung cancer

Figure: Superior progression-free survival with furmonertinib vs. gefitinib in EGFR-mutated advanced lung cancer

Oritinib after progression

Oritinib, which is another selective, irreversible third-generation EGFR TKI, was tested in Chinese patients with locally advanced or metastatic NSCLC who had progressed on ≥ 1 first- and/or second-generation EGFR TKI [4]. This group was shown to harbor the EGFR T790M resistance mutation prior to inclusion. In this single-arm phase II study, 227 individuals received oritinib 200 mg OD. The ORR was defined as the primary endpoint.

Indeed, oritinib demonstrated potential clinical benefit, with an ORR of 60.4 % and a disease control rate of 92.5 %. Most patients experienced decreases in target lesion size. Responses lasted for a median of 12.5 months, and median PFS was 12.6 months. The new EGFR TKI showed a favorable safety profile. Diarrhea represented the most common TRAE (any grade, 41.9 %), followed by increases in blood creatine phosphokinase levels (23.8 %). Among grade ≥ 3 AEs, creatine phosphokinase elevations were observed most frequently (4.0 %). The rates of TRAEs leading to dose reduction or discontinuation were low at 1.3 % and 1.8 %, respectively. Four patients died due to TRAEs (1.8 %). A randomized, controlled, double-blind, phase III trial is currently comparing oritinib with gefitinib in the first-line treatment of patients with advanced NSCLC harboring EGFR-sensitizing mutations (NCT04239833).

Savolitinib in METex14-mutated tumors

The highly selective oral MET TKI savolitinib has demonstrated clinically meaningful ORR in patients with unresectable or metastatic, METex14-mutated pulmonary sarcomatoid carcinoma (PSC) and other NSCLCs in a single-arm, phase II study [5]. Within the full analysis set of 70 patients, 28 were treatment-naïve but unfit for chemotherapy, while 42 were chemotherapy-pretreated. Twenty-five had been diagnosed as PSC and 45 as other NSCLCs. Savolitinib was administered according to body weight, with patients ≥ 50 kg receiving 600 mg and those < 50 kg receiving 400 mg OD. Fifteen individuals had CNS metastases. Lu et al. presented the final OS results of the study as well as subgroup analyses at the ELCC 2022 [6].

In the full analysis set, median PFS was 6.9 months, with a 15-month PFS rate of 25 %. Both treatment-naïve and previously treated patients showed a median PFS of 6.9 months; likewise, the PFS results did not differ for the PSC vs. other NSCLCs cohorts (5.5 and 7.0 months, respectively) and groups with and without brain metastases (7.0 and 6.2 months, respectively). Median OS in the full analysis set amounted to 12.5 months; at 24 months, 31 % of patients were alive. Pretreated patients fared better regarding OS than the treatment-naïve population (19.4 vs. 10.9 months), although this should be interpreted with caution due to differences in patient characteristics. The group with PSC had shorter OS than the one with other NSCLCs (10.6 vs. 17.3 months), which was presumably due to the poor prognosis of this lung cancer type. Median OS in patients with brain metastases was 17.7 months; this further confirms the efficacy of savolitinib with respect to CNS affliction.

With prolonged follow-up, the AE rates were similar to previously reported data. Peripheral edema, nausea, and hypoalbuminemia were noted as the most common any-grade AEs. Grade ≥ 3 AEs primarily included transaminase elevations. According to the authors, the updated findings of this phase II trial corroborate the benefit and acceptable safety profile of savolitinib in patients with METex14-mutated NSCLC.

ROS1-positive disease: unecritinib

Unecritinib (TQ-B3101) has been designed to target receptor tyrosine kinases including ALK, ROS1, and MET. Phase I data have revealed favorable tolerability and preliminary antitumor activity of this agent in pretreated patients with advanced ALK-positive, ROS1-positive, or MET-amplified tumors [7]. In the phase II trial conducted at 29 sites in China, unecritinib was assessed at a dose of 300 mg BID in 111 patients with locally advanced or metastatic, ROS1-positive NSCLC after ≤ 2 chemotherapy regimens [8]. Fifty-nine percent were treatment-naïve, while 31 % and 10 % had received 1 and 2 prior treatment lines, respectively. Almost 30 % showed brain metastases at baseline.

Objective responses, which constituted the primary outcome, occurred in 78.4 %. The disease control rate was 87.4 % and the median duration of response 20.3 months. Almost all subgroups benefited from the treatment. Median PFS was 15.6 months, and median OS had not been reached yet at the time of the analysis. At 24 months, 88.1 % of patients were alive.

TRAEs mainly comprised transaminase elevations, vomiting, neutrophil and leukocyte count decreases, sinus bradycardia, diarrhea, and elevated serum creatine phosphokinase levels. Grade ≥ 3 TRAEs occurred in 45.1 %. Among AEs of interest, any-grade ocular organ diseases were observed in 26.1 % but were restricted to grade 1 and 2. Overall, TRAEs led to dose disruption and discontinuation in 35.1 % and 16.2 %, respectively. The authors noted that unecritinib exhibited promising efficacy with a manageable safety profile, thus offering a new first-line strategy for patients with locally advanced or metastatic ROS1-positive NSCLC.

Lasting effects of selpercatinib in LIBRETTO-001

The first-in-class, highly selective and potent RET inhibitor selpercatinib has shown durable responses in patients with RET-fusion–positive NSCLC in the ongoing, global, phase I/II LIBRETTO-001 study [9]. At ELCC 2022, Drilon et al. reported an update for 316 patients 69 of whom were treatment-naïve while 247 had previously been treated with platinum-based chemotherapy [10]. Selpercatinib continued to demonstrate robust and durable efficacy. ORRs were 84.1 % and 61.1 % for the treatment-naïve and pretreated groups, respectively, and median PFS was 22.0 and 24.9 months, respectively. The 3-year OS rates amounted to 57.1 % and 58.5 %, respectively.

Moreover, selpercatinib showed considerable CNS activity. Measurable CNS metastases had been present at baseline in 26 patients. In this group, 22 (84.6 %) experienced complete or partial remission in the CNS (Table). The median CNS PFS was 19.4 months at a median follow-up of 22.1 months. No new safety signals occurred during the extended follow-up. While LIBRETTO-001 is still enrolling patients with RET-altered solid tumors, recruitment has started for the global, randomized, phase III LIBRETTO-431 trial that will compare selper­catinib to standard frontline chemotherapy in treatment-naïve patients with RET-fusion–positive advanced or metastatic NSCLC (NCT04194944).

Table LIBRETTO-001: CNS response to selpercatinib in patients with RET-fusion–positive NSCLC (n = 26)


  1. Lyu C et al., Osimertinib as neoadjuvant treatment for resectable stage II-IIIB EGFR mutant lung adenocarcinoma (NEOS). J Clin Oncol 39, 2021 (suppl 15; abstr 8524)
  2. Lyu C et al., Osimertinib as neoadjuvant therapy in patients with EGFR mutated resectable stage II-IIIB lung adenocarcinoma (NEOS): updated results. ELCC 2022, abstract 81M0
  3. Shi Y et al., Furmonertinib versus gefitinib in treatment-naïve EGFR mutated non-small cell lung cancer: a randomized, double-blind, multi-center, phase III study (FURLONG). ELCC 2022, abstract 1O
  4. Zhou C et al., Oritinib (SH-1028), a third-generation EGFR tyrosine kinase inhibitor in locally advanced or metastatic NSCLC patients with positive EGFR T790M mutation: results of a single-arm phase II trial. ELCC 2022, abstract 7M0
  5. Lu S et al., Once-daily savolitinib in Chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: a multicentre, single-arm, open-label, phase 2 study. Lancet Respir Med 2021; 9(10): 1154-1164
  6. Lu S et al., Final results and subgroup analysis of savolitinib in patients with MET exon 14 skipping mutations (METex14+) NSCLC. ELCC 2022, abstract 2M0
  7. Fang Y et al., A phase I study to evaluate safety, tolerability, pharmacokinetics, and preliminary antitumor activity of TQ-B3101. J Clin Oncol 38: 2020 (suppl; abstr e21705)
  8. Lu S et al., The phase II study of unecritinib (TQ-B3101) monotherapy in the first line treatment in patients with ROS1 positive non-small cell lung cancer. ELCC 2022, abstract 8M0
  9. Drilon A et al., Efficacy of selpercatinib in RET fusion-positive non-small-cell lung cancer. N Engl J Med 2020; 383(9): 813-824
  10. Drilon A et al., Durability of efficacy and safety with selpercatinib in patients with RET fusion+ non-small-cell lung cancer: LIBRETTO-001. ELCC 2022, abstract 27P

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