Promising findings across oncogenic targets

Amivantamab plus lazertinib in EGFR-positive lung cancer

The EGFR-MET bispecific antibody amivantamab is being assessed in combination with the third-generation EGFR tyrosine kinase inhibitor lazertinib in the multicohort CHRYSALIS-2 trial in patients with EGFR-mutant non–small-cell lung cancer (NSCLC). Results from the cohort receiving amivantamab/lazertinib in addition to carbo­platin/pemetrexed (n = 20) were presented at WCLC 2022 by Marmarelis et al. [1]. These patients had progressed on prior EGFR TKI treatment; 45 % and 70 % had received first/second-generation EGFR TKIs and osimertinib, respectively. In 25 %, platinum-based therapy had been administered. Safety constituted the primary endpoint.

The safety profile of the regimen was consistent with the profiles of the individual agents. Adverse events (AEs) were mostly grade 1 and 2. No cases of pneumonitis/interstitial lung disease (ILD) occurred. With respect to efficacy, the analysis yielded an overall response rate (ORR) of 50 % and a clinical benefit rate of 80 %. These results were identical in patients with baseline brain metastases (n = 10). Responses proved durable; after a median follow-up of 7.1 months, 15 patients remained on treatment. This included the 10 responders 3 of whom showed response duration of ≥ 6 months. Median duration of response, progression-free survival (PFS) and overall survival (OS) were not estimable at the time of the analysis. Amivantamab/lazertinib plus chemotherapy is currently being evaluated in the randomized, phase III MARIPOSA-2 trial in post-osimertinib settings (NCT04988295).

Likewise, amivantamab/lazertinib demonstrated clinically significant and durable antitumor activity in the untreated setting. In the CHRYSALIS study, all analyzed patients (n = 20) with advanced EGFR-mutated NSCLC (i.e., deletion 19 or L858R mutation) had partial responses after a median follow-up of 22.3 months [2]. Median duration of response and median PFS were not estimable. Seventy percent of patients were progression-free; in 2 additional cases, the treatment was ongoing beyond RECIST progression. No new safety signals occurred, and most AEs were graded as 1 or 2. One patient developed grade 3 pneumonitis/ILD (5 %). Cumulative grouped rash-related AEs (i.e., acneiform dermatitis, rash, folliculitis, erythematous rash, maculopapular rash) emerged in the entire group, with 2 grade ≥ 3 events (10 %).

The assessment included a ctDNA analysis according to which half of patients showed TP53 co-mutations. Activating EGFR mutations were found in 15 of 18 patients at baseline but were undetectable by day 1 of cycle 3. The ongoing phase III MARIPOSA trial is investigating frontline amivantamab/lazertinib compared to osimertinib in patients with EGFR-mutated NSCLC (NCT04487080).

VISION: analysis of Cohort C

The approval of the MET inhibitor tepotinib for the treatment of advanced lung cancer with MET exon 14 (METex14) skipping mutations was mainly based on the results obtained in Cohort A of the phase II VISION study [3]. At WCLC 2022, the primary analysis of the independent confirmatory Cohort C (n = 161) was reported [4]. Like Cohort A, these patients had received tepotinib 500 mg/d in the first, second, or third lines after central confirmation of ­METex14 skipping by liquid and/or tissue biopsy.

The data provided independent confirmation of the robust and durable efficacy of tepotinib, with comparable or improved outcomes across endpoints compared to Cohort A. ORR by independent review, which was defined as the primary endpoint, was 54.7 %, and disease control was achieved in 80.1 %. Median duration of response and median PFS were 20.8 and 13.8 months, thus exceeding the respective results observed in Cohort A (11.1 and 8.5 months). Median OS was 18.8 months. Treatment-naïve patients enrolled by tissue biopsy experienced particularly pronounced benefits, although the efficacy was also robust and durable in previously treated patients enrolled based on tissue biopsy (Table). For both Cohorts A and C, robust and durable clinical outcomes were observed in the first line as well as in later lines.

Moreover, the analyses revealed promising intracranial activity in patients with brain metastases. Across Cohorts A and C, 43 patients with brain lesions were evaluable. Fifteen had target lesions; here, the intracranial ORR was 66.7 %, and the intracranial median duration of response had not been reached yet. Tepotinib was generally well tolerated, with most AEs being mild to moderate. Peripheral edema was the most common AE (any grade, 66.5 %, grade ≥ 3, 10.9 %). Treatment-related AEs (TRAEs) led to permanent discontinuation in 14.7 %. They necessitated dose reductions and interruptions in 33.5 % and 42.5 %, respectively, although these patients were able to remain on treatment and continued to benefit.

Table Clinical outcomes obtained with tepotinib in METex14-positive lung cancer diagnosed by tissue biopsy

First data from CodeBreaK 100/101

The first-in-class KRASG12C inhibitor sotorasib is being used as monotherapy for patients with pretreated KRASG12C-mutated advanced NSCLC. In the animal model, sotorasib was shown to synergize with immune checkpoint inhibitors, inhibiting tumor growth and enhancing CD8+ T cell infiltration [5]. Therefore, the phase IB, multicenter, open-label CodeBreaK 100/101 study was designed to explore the combinations of sotorasib with either atezolizumab or pembrolizumab. Oral daily sotorasib doses of 120 mg, 240 mg, 360 mg, 720 mg, and 960 mg were tested. In one patient group, a lead-in regimen of sotorasib was administered for 21 or 42 days followed by the combination with atezolizumab (n = 10) or pembrolizumab (n = 19) Q3W. The concurrent treatment group, on the other hand, received sotorasib plus ate­zolizumab (n = 10) or pembrolizumab (n = 19) from the beginning. All patients had advanced KRASG12C-mutated NSCLC and had received or refused prior standard therapies. Prior anti-PD-(L)1 treatment had been administered in two thirds of patients. The primary endpoint was safety.

At WCLC 2022, Li et al. reported the first data for the lead-in and concurrent treatment groups after a median follow-up of 12.8 months [6]. Sotorasib plus ate­zolizumab or pembrolizumab gave rise to higher incidences of grade 3/4 TRAEs compared to the rates observed with either monotherapy [7-9]. Grade 3/4 TRAEs were mainly liver enzyme elevations. These showed an onset after a median of 50-73 days, which meant that 88 % occurred outside the dose-limiting toxicity window (i.e., 21 days following the initiation of combination treatment). Ninety-seven percent of grade 3/4 hepatotoxicity events resolved with corticosteroids, treatment modification, and/or discontinuation. The lead-in cohorts experienced lower incidences of grade 3/4 TRAEs and TRAEs prompting discontinuation than the concurrently treated cohorts; likewise, lower doses of sotorasib were associated with a trend towards less liver enzyme elevation. No fatal TRAEs occurred.

Across all cohorts, deep and durable responses were noted, which included treatment at low doses. Also, immunotherapy pretreatment did not affect clinical responses. The ORR was 29 %, and disease control was achieved in 83 %. Median duration of response was 17.9 months. In particular, lead-in sotorasib plus pembrolizumab induced deep responses. Median OS was 15.7 months for sotorasib plus any checkpoint in­hibitor. Based on these observations, low-dose sotorasib as a lead-in regimen followed by the combination with pembrolizumab will be further studied as first-line treatment in patients with advanced NSCLC.

Doublet and triplet therapy with Dato-DXd: TROPION-Lung02

Initial results for the TROP2-targeting antibody drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) in addition to pembrolizumab with or without platinum chemotherapy were presented by Levy et al. [10]. This was the first reported clinical experience of a TROP2 ADC combined with a checkpoint inhibitor ± platinum-based chemo­therapy. Patients with advanced or metastatic NSCLC participated in the phase IB TROPION-Lung02 study that contained 6 cohorts. Cohorts 1 and 2 tested the doublet approach, which was Dato-DXd 4 mg/kg or 6 mg/kg plus pembrolizumab Q3W, while Cohorts 3 to 6 were dedicated to the triplet regimens consisting of Dato-DXd 4 mg/kg or 6 mg/kg plus pembrolizumab and either carboplatin AUC5 (Cohorts 3 and 4) or carboplatin 75 mg/m2 (Cohorts 5 and 6). Overall, 40 and 48 patients received the doublet and triplet approaches, respectively. Pretreatment was allowed in the doublet group (median, 1 prior line), while the triplet group was treatment-naïve. Safety and tolerability represented the first endpoint.

After a median follow-up of 6.5 and 4.4 months for the doublet and triplet groups, respectively, the regimens showed a tolerable safety profile. The most frequent treatment-emergent AEs (TEAEs) were stomatitis with the doublets (any grade, 56 %) and nausea (any grade, 48 %) with the triplets (Figure). Most of the events were graded as 1 and 2. Grade ≥ 3 study treatment-related TEAEs occurred in 35 % and 54 %, respectively. TEAEs due to Dato-DXd led to discontinuation in 15 % and 10 %, respectively. Five percent of patients in the doublet group developed drug-related ILD grade 1/2; grade 3 events emerged in 3 % and 2 %, respectively.

Preliminary efficacy findings were encouraging. In the overall population, ORRs were 37 % and 41 % for the doublet and triplet therapy, respectively. Both groups had a 84 % disease control rate. In the first-line setting, doublets and triplets gave rise to ORRs of 62 % and 50 %, respectively, while 100 % and 90 % of patients, respectively, achieved disease control. Responses were obtained across all PD-L1 expression levels. As the authors noted in their summary, these results support further evaluation of Dato-DXd 6 mg/kg plus immunotherapy combination regimens. The phase III TROPION-Lung08 trial is evaluating Dato-DXd plus pembrolizumab vs. pembrolizumab alone as first-line therapy in patients with advanced or metastatic NSCLC and PD-L1 TPS > 50 % (NCT05215340).

Figure: Common adverse events with Dato-DXd plus pembrolizumab (doublet) and Dato-DXd plus pembrolizumab and platinum chemotherapy (triplet)

Figure: Common adverse events with Dato-DXd plus pembrolizumab (doublet) and Dato-DXd plus pembrolizumab and platinum chemotherapy (triplet)

REFERENCES

  1. Marmarelis M et al., Amivantamab and lazertinib in combination with platinum-based chemotherapy in relapsed/refractory EGFR-mutant NSCLC. WCLC 2022, MA07.04
  2. Cho BC et al., Amivantamab and lazertinib in treatment-naïve advanced EGFR-mutant non-small cell lung cancer. WCLC 2022, P1.16-01
  3. Paik PK, et al., Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations. N Engl J Med 2020; 383(10): 931-943
  4. Thomas M et al., Tepotinib in patients with MET exon 14 skipping NSCLC: primary analysis of the confirmatory VISION Cohort C. WCLC 2022, OA03.05
  5. Canon J et al., The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 2019; 575(7781): 217-223
  6. Li BT et al., CodeBreaK 100/101: first report of safety and efficacy of sotorasib in combination with pembrolizumab or atezolizumab in advanced KRAS p.G12C NSCLC. WCLC 2022, OA03.06
  7. Hong DS et al., KRAS G12C inhibition with sotorasib in advanced solid tumors. N Engl J Med 2020; 383(13): 1207-1217
  8. Mok TSK et al., Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 2019; 393(10183): 1819-1830
  9. Herbst RS et al., Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC. N Engl J Med 2020; 383(14): 1328-1329
  10. Levy B et al., TROPION-Lung02: initial results for datopotamab deruxtecan plus pembrolizumab and platinum chemotherapy in advanced NSCLC. WCLC 2022, MA13.07

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