...European Commission (EC) has approved a Type II variation for RYBREVANT®(amivantamab) in combination with chemotherapy (carboplatin and pemetrexed) for the first-line treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations.

...the U.S. Food and Drug Administration (FDA) has approved RYBREVANT® (amivantamab-vmjw) in combination with chemotherapy (carboplatin-pemetrexed) for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations as detected by an FDA-approved test...

The Janssen Pharmaceutical Companies of Johnson & Johnson announced today that Health Canada has issued a Notice of Compliance with Conditions (NOC/c) approving RYBREVANT® (amivantamab), a fully-human, bispecific antibody, for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating epidermal-growth factor receptor (EGFR) Exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy.

The Janssen Pharmaceutical Companies of Johnson & Johnson announced Conditional Marketing Authorisation (CMA) of RYBREVANT® (amivantamab) for the treatment of adult patients with advanced NSCLC with activating epidermal growth factor receptor (EGFR) exon 20 insertion mutations, after failure of platinum-based therapy

RYBREVANT is a bispecific EGF receptor-directed and MET receptordirected antibody indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, ] whose disease has progressed on or after platinum-based chemotherapy.

NON-SUPPORTIVE EVIDENCE: Amivantamab is not recommended, within its marketing authorisation, for treating locally advanced or metastatic non-small-cell lung cancer (NSCLC) after platinum-based chemotherapy in adults whose tumours have epidermal growth factor receptor (EGFR) exon 20 insertion mutations.

Amivantamab-vmjw and subsequent systemic therapy options (NSCL-K 4 of 5) added as treatment options following progression on mobocertinib. This is a category 2A recommendation….EGFR exon 20 insertion mutation positive…subsequent therapy...Amivantamab-vmjw

At a median follow up of 16.6 months, the median PFS for Asian pts was 11.5 months (95% CI, 9.8–13.7) for ami-chemo vs 5.6 months (95% CI, 4.9–7.0) for chemo (HR, 0.34; 95% CI, 0.23–0.49; P<0.001); this was comparable to the overall population. The 18-month PFS rate was 31% for ami-chemo vs 3% for chemo. ORR was 70% (95% CI, 60–79) for ami-chemo vs 51% (95% CI, 40–62) for chemo (odds ratio, 2.16; 95% CI, 1.19–3.93; P=0.012)....Ami-chemo demonstrated superior PFS vs chemo in Asian pts with a tolerable safety profile.

The use of amivantamab-chemotherapy resulted in superior efficacy as compared with chemotherapy alone as first-line treatment of patients with advanced NSCLC with EGFR exon 20 insertions.

The Janssen Pharmaceutical Companies of Johnson & Johnson today announced positive topline results from the Phase 3 PAPILLON study evaluating RYBREVANT® (amivantamab-vmjw) in combination with chemotherapy (carboplatin-pemetrexed) in patients with newly diagnosed advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations....Results showed the PAPILLON Phase 3 study met its primary endpoint with a statistically significant and clinically meaningful improvement in progression-free survival (PFS) in patients receiving RYBREVANT® plus chemotherapy versus chemotherapy alone.

The Janssen Pharmaceutical Companies of Johnson & Johnson announced today that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation for JNJ-61186372 (JNJ-6372) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) Exon 20 insertion mutations, whose disease has progressed on or after platinum-based chemotherapy. JNJ-6372 is an EGFR-mesenchymal epithelial transition factor (MET) bispecific antibody that targets activating and resistant EGFR and MET mutations and amplifications.

...- Has histologically or cytologically confirmed unresectable or metastatic non-small cell lung (NSCLC) cancer with an epidermal growth factor receptor (EGFR) exon 20 insertion (Exon20ins),...

...In participants diagnosed with mutations associated with de novo EGFR inhibitor resistance (for example, Exon 20 insertions), only previous treatment with combination platinum-based chemotherapy is required....

...In participants diagnosed with mutations associated with de novo EGFR inhibitor resistance (for example, Exon 20 insertions), only previous treatment with combination platinum-based chemotherapy is required....

...In participants diagnosed with mutations associated with de novo EGFR inhibitor resistance (for example, Exon 20 insertions), only previous treatment with combination platinum-based chemotherapy is required....

...In participants diagnosed with mutations associated with de novo EGFR inhibitor resistance (for example, Exon 20 insertions), only previous treatment with combination platinum-based chemotherapy is required....

...- Participant must have histologically or cytologically confirmed, locally advanced or metastatic, nonsquamous non-small cell lung cancer (NSCLC) with documented primary epidermal growth factor receptor (EGFR) Exon 20ins activating mutation...

...In participants diagnosed with mutations associated with de novo EGFR inhibitor resistance (for example, Exon 20 insertions), only previous treatment with combination platinum-based chemotherapy is required....

The weighted hazard ratio (HR) comparing mobocertinib to amivantamab was 0.74 (0.51-1.07) for IRC-assessed PFS, 0.92 (0.57-1.48) for OS, and 0.59 (0.30-1.18) for INV-assessed DoR….MAIC analysis showed that mobocertinib and amivantamab had similar efficacy in patients with NSCLC harboring EGFR ex20ins mutations whose disease progressed during or after platinum-based chemotherapy.

A total of 42 patients were analyzed, of which 16 patients were enrolled in the phase 1 study, and 26 patients received amivantamab through EAP. There were 14 (33%) patients with partial remission, 18 (43%) patients with stable disease, and 10 (24%) patients with disease progression. The objective response rate (ORR) was 33%, and the disease control rate (DCR) was 76%...The efficacy of amivantamab was confirmed for the real-world population for EGFR E20I-mutated NSCLC.

...the response rate ratio for the overall response was 2.14 (p = 0.0181), and the progression-free survival (PFS), time-to-next-treatment (TTNT) and overall survival (OS) hazard ratios (HRs) were 0.42 (p < 0.0001), 0.47 (p = 0.0063) and 0.48 (p = 0.0207), respectively. These analyses provide evidence of clinical and statistical benefits across multiple outcomes and adjustment methods, of amivantamab in platinum pre-treated patients with advanced NSCLC harboring EGFR Exon20ins.

In the absence of clinical evidence from randomized clinical trials, this study reflects the benefit of amivantamab after platinum-based chemotherapy for advanced non-small cell lung cancer patients harboring EGFR Exon 20ins, compared to current real-world therapies.

The results showed that aNSCLC patients with Exon20ins who received amivantamab had significantly improved TTNT and higher ORR than those who received current real-world therapies, while PFS and OS were numerically better.

This study estimates the relative effectiveness of amivantamab versus alternative anti-cancer treatments used in real-world settings for NSCLC with Ex20ins….Based on this adjusted treatment comparison, amivantamab provides significant benefits compared to alternative therapies used in real world practice.

Pts with EGFR Ex20ins advanced NSCLC whose disease progressed on platinum-based chemotherapy were recruited….Investigator-assessed overall response rate (ORR) was 37% (95% CI, 28–46)....Activity was observed across subgroups, including the elderly (ORR of 32% and 33% for age ≥65 and ≥75, respectively), heavily pretreated pts (ORR of 53% for >2 prior lines, 42% for prior immunotherapy, and 52% for prior EGFR TKI therapy), or those sensitive or resistant to prior platinum-based chemotherapy (ORR of 36% and 31%, respectively)....Ami demonstrated robust efficacy that was consistently observed across post-platinum patients with EGFR Ex20ins NSCLC, including the elderly, those with multiple prior lines, or those who were platinum sensitive or refractory.

ORR (INV) was 36.8% for amivantamab versus 17.0% for the adjusted EU + US cohort (response rate ratio [RR]: 2.16). Median OS, PFS (INV) and TTNT were 22.77 versus 12.52 months (hazard ratio [HR]: 0.47; p < 0.0001), 6.93 versus 4.17 months (HR: 0.55; p < 0.0001) and 12.42 versus 5.36 months (HR: 0.44; p < 0.0001) for amivantamab versus the adjusted EU + US cohort, respectively....Adjusted comparisons demonstrated significantly improved outcomes for amivantamab versus RWCP, highlighting the value of amivantamab in addressing unmet need in patients with advanced EGFR Exon20ins NSCLC...

Of the 148 EGFR E20i pts, 94 pts were selected as EC pts. Compared to DOC in EC pts (n=67), amivantamab-treated pts (n=115) had risk reduction in PFS (HR: 0.81 [95%CI: 0.57-1.16]; median: 6.7 vs 6.2 months) and OS (HR: 0.67 [0.43-1.04], 19.9 vs 16.6 months), and higher ORR (41.7% vs 26.0%, p=0.012). Compared to TKIs in EC pts (n=45), amivantamab-treated pts had risk reduction in PFS (HR: 0.39 [0.26-0.59], 6.7 vs 2.8 months) and OS (HR: 0.43 [0.26-0.71], 19.9 vs 10.4 months), and higher ORR (41.7% vs 11.5%, p<0.001). Compared to IO in EC pts (n=59), amivantamab-treated pts had risk reduction in PFS (HR: 0.44 [0.30-0.66], 6.7 vs 3.5 months) and OS (HR: 0.63 [0.41-0.99], 19.9 vs 14.6 months), and higher ORR (41.7% vs 8.3%, p<0.001)....Amivantamab-treated pts had better clinical benefits compared to DOC, TKIs and IO. Amivantamab should be considered a standard therapy after platinum-based chemotherapy for EGFR E20i aNSCLC pts.

...amivantamab was significantly superior to RWCP across all endpoints and methods….These findings suggest that amivantamab is an effective treatment option associated with significantly better OS, PFS, and TTNT for EGFR ex20ins advanced NSCLC compared with current clinical practice in France.

Amivantamab-treated patients had significantly longer PFS, TTNT and OS, and significantly higher ORR than patients treated with RW therapies in the post-plt chemotherapy setting in Japan. This reflects the benefit of amivantamab after plt chemotherapy for aNSCLC E20i patients...

Adjusted comparisons demonstrate significant improvements for amivantamab vs European RW SoC, as previously reported versus a US RWE cohort, highlighting the potential for amivantamab to address unmet medical need in pts with advanced exon20ins NSCLC.

Real-world patient data from Europe and the US were obtained from chart reviews (retrospective) and registries (retrospective and prospective) for patients with EGFR Exon20ins NSCLC following platinum-based therapy….Adjusted comparisons demonstrate a statistically significant clinical benefit for amivantamab versus RWCP...

We aimed to assess the activity/safety of amivantamab in a RWD-cohort of patients with Ex20ins aNSCLC from an Expanded Access Program (EAP)....ORR was 30% (all partial responses) and DCR was 70%; 1 patient had progressive disease (PD) as best response....Our preliminary RWD-data shows clinical activity consistent with previously reported in EGFR ex20ins, including some durable responses.

Among pts alive at week 12 (n¼107), 42 (39%) had PR+, 52 (49%) had SD,and 13 (12%) had PD. Among pts with PR+ and SD, the median PFS was 12.2 mo and7.0 mo, respectively. A corresponding improvement in OS was observed in pts who achieved PR+ (median not reached; HR vs PD¼0.21 [95% CI: 0.08e0.54]) and SD(median 23.0 mo; HR vs PD¼0.33 [95% CI: 0.14e0.77]), relative to those with PD(median 14.0 mo). Treatment benefit with amivantamab was observed in pts who achieved SD, in addition to those achieving PR+ as best response, with a 67% and 79%reduction in risk rate of death, respectively, compared to those with PD. These data demonstrate the value of disease control, regardless of depth of response, with amivantamab.

Key inclusion criteria were diagnosis of EGFR ex20ins advanced NSCLC...Amivantamab-treated patients had longer progression-free survival (median 8.3 vs 2.9 months; hazard ratio [HR; 95% CI]: 0.47 [0.34-0.65]), time to next therapy (median 14.8 vs 4.8 months; HR [95% CI]: 0.40 [0.28-0.57]), and overall survival (median 22.8 vs 12.8 months; HR [95% CI]: 0.49 [0.31-0.77]) than external controls....Among post-platinum patients with EGFR ex20ins advanced NSCLC, those treated with amivantamab had improved outcomes, including 10-month longer overall survival, versus external controls.

MAIC estimates of relative efficacy for amivantamab vs. mobocertinib were: PFS: HR=1.09 [95%CI: 0.69, 1.71]; OS: HR=0.70 [0.39, 1.24]); ORR: RRR=1.73 [0.84, 3.58]...The MAIC suggests that amivantamab has similar efficacy and more favorable safety profile in comparison with mobocertinib in EGFR Exon20ins NSCLC.

The Janssen Pharmaceutical Companies of Johnson & Johnson announced today that the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a conditional marketing authorisation for the medicinal product amivantamab, intended for the treatment of adult patients with advanced NSCLC with activating epidermal growth factor receptor (EGFR) exon 20 insertion mutations...European marketing authorisation application (MAA) is based on results from the Phase 1 CHRYSALIS study...

...EGFR Exon20ins NSCLC population treated at the recommended phase II dose of 1,050 mg amivantamab...The overall response rate was 40% (95% CI, 29 to 51), including three complete responses, with a median duration of response of 11.1 months...Amivantamab, via its novel mechanism of action, yielded robust and durable responses with tolerable safety in patients with EGFR Exon20ins mutations after progression on platinum-based chemotherapy.

The amivantamab-treated population (N = 81) included post-platinum pts with EGFR Exon20ins NSCLC treated at the recommended phase 2 dose….Median overall survival (OS) among amivantamab pts was 22.8 months and EC pts was 13.1 months (HR = 0.53 [95% CI, 0.33, 0.86])...amivantamab pts had longer progression-free survival (8.3 vs 2.9 months; HR = 0.46 [95% CI, 0.33, 0.63]) and time to next treatment (14.8 vs 4.8 months; HR = 0.42 [95% CI, 0.29, 0.6]) compared to the EC pts. Confirmed overall response rate was 40% among amivantamab pts and 10% for the EC pts...

Amivantamab treatment led to promising efficacy with durable responses in patients with EGFR Exon20ins NSCLC post-platinum doublet and continues to demonstrate a manageable safety profile in over 250 patients treated at the RP2D.

Fifty patients with EGFR Exon 20 insertion-mutated NSCLC received the recommended Phase 2 dose (RP2D) of amivantamab. Among these 50 patients, 39 were evaluable for response with 13 distinct EGFR Exon 20 insertion mutations identified.

Importantly, in vivo efficacy of amivantamab was superior to cetuximab or poziotinib, an experimental Exon20ins targeted-TKI. Amivantamab produced robust tumor responses in two Exon20ins patients, highlighting the important translational nature of this preclinical work.

This study was conducted to evaluate the effectiveness and tolerance of Amivantamab in NSCLC patients with EGFR/MET gene abnormalities....The overall response rate (ORR) and disease control rate (DCR) were 28.6% (2/7) and 100.0% (7/7) in seven patients with EGFR exon 20 insertion, respectively. The ORR and DCR were 40.0% (2/5) and 100.0% (5/5) in five post-osimertinib EGFR-mutant patients, respectively....Amivantamab was effective in Chinese NSCLC patients with EGFR exon 20 insertion and post-Osimertinib EGFR-mutant patients...

Pts received JNJ-372 (140–1400 mg) IV weekly for the first 28-day cycle and biweekly thereafter...s of 17 Jan 2019, 116 enrolled pts with NSCLC were treated...6/20 pts with Exon20ins had best timepoint response of PR (3 confirmed).

Our case report manifests a deep, fast and clinical benefit of amivantamab over a patient with NSCLC EGFR ex20ins. Furthermore, amivantamab seems to have activity over symptomatic pleural effusion, which add more value to amivantamab in this setting.

This case report confirms the efficacy of second-line treatment with Amivantamab in EGFR ex20insertion NSCLC, even at the level of brain lesions. The treatment resulted in a prolonged survival with a good quality of life for the patient.

JNJ-372 drives antitumor activity in preclinical models of EGFR ex20ins, which have no therapeutic options in clinic, by decreasing EGFR and cMet receptor levels, inhibiting downstream signaling cascades, activating apoptotic signaling as well as ADCC. These results provide a promising therapeutic option to patients with EGFR ex20ins mutations and an understanding of the activity of JNJ-372 being observed in the first-in-human study.