Erasca: New Focus After Restructuring, But Need More Differentiation

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Erasca has streamlined its pipeline, now focusing on a phase 3 trial for Naporafenib targeting NRAS-mutant melanoma, showing preliminary antitumor activity and manageable safety.Naporafenib, combined ...

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I am happy to see that the pipeline is now much more focused, and there's now a phase 3 trial ongoing. This follows from a restructuring effort they undertook in May, abandoning or licensing out old programs and acquiring some new ones. Background Erasca develops cancer drugs that target the well-recognized RAS/MAPK pathway. This is a critical cell signaling pathway whose genetic mutations cause cancer. RAS proteins like KRAS transmit signals from the cell surface to the nucleus, where the MAPK pathway, which includes proteins like BRAF and MEK, are activated. Some of these MAPK kinases cause gene expressions within the cellular nucleus to induce cell proliferation and survival. The lead molecule is Naporafenib, a BRAF/CRAF inhibitor targeting NRASm melanoma, in a phase 3 trial called SEACRAFT-2. This trial was started in June, and it has a two stage design. Stage 1 will produce a “randomized data readout of naporafenib plus trametinib against single agent trametinib in 2025 and will inform the randomized Phase 2 dose (RP2D) for the combination.” The two primary endpoints of Stage 2 will be PFS and OS. The same molecule is also in a phase 1 trial called SEACRAFT-1 targeting Pan-RAS Q61X tissue agnostic solid tumors. All other assets are preclinical. This is in striking contrast with what we saw last year when four other assets were in the clinic. Erasca acquired Naporafenib from Novartis (NVS), where it was run through a number of trials. I discussed one such trial in advanced/metastatic KRAS- or BRAF-mutant non–small-cell lung cancer or NRAS-mutant melanoma. The trial produced some positive to confusing efficacy data, but the safety profile was very poor. Erasca has continued with the 2nd indication here, NRAS mutant melanoma, so I will be essaying to isolate that earlier data for NRASm melanoma patients and see how they fared. The ASCO data Last year at ASCO, the company summed up the NRASm melanoma data, saying they were able to show preliminary antitumor activity as well as a manageable safety profile for naporafenib. This was administered as a combination with trametinib to patients with NRAS-mutant melanoma who have progressed on prior standard treatment. The study authors noted that while NRAS mutation occurs in 15%-20% of melanomas, there are no approved treatments. MEK inhibition has been studied in NRASm melanoma, however the best outcome from a treatment of 7 NRASm melanoma patients has been stable disease in two patients who were treated with trametinib. In this Novartis trial, there were six NRASm melanoma patients in the escalation cohort and 30 in the expansion cohort. In the second cohort, “all 30 patients experienced ≥1 AE, including rash (80%, n = 24), diarrhea (40%, n = 12), and anemia, blood creatine phosphokinase increased, and constipation (37%, n = 11 each).” The efficacy data was: The ORR was 46.7% (95% CI, 21.3 to 73.4; n = 7) in patients treated with naporafenib 200 mg twice a day plus trametinib 1 mg once daily and 13.3% (95% CI, 1.7 to 40.5; n = 2) in patients treated with naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily (Table 2). Overall, nine patients (30%) reported a PR, and 13 patients (43%) reported SD. No patients reported a CR (Figs 2B and 2C). The median (95% CI) DOR was 3.75 (1.97 to not estimable [NE]) months for patients treated with naporafenib 200 mg twice a day plus trametinib 1 mg once daily, and 3.75 (2.04 to NE) for patients treated with naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. The overall median (95% CI) PFS was 5.03 (3.42 to 5.62) months (5.52 months in patients treated with naporafenib 200 mg twice a day plus trametinib 1 mg once daily, and 4.21 months in patients treated with naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily; Fig 2D). Surprisingly, increasing naporafenib and reducing trametinib decreased the ORR drastically, although there was no change in duration of response. There was a slight improvement in median PFS for the former group than the latter. This does not bode well for naporafenib. However, the ORR data wasn’t too bad, with a number of PRs and SD, although there were no CRs. However, the better ORR at the higher trametinib dose confused things for naporafenib. In an announcement in June cited above, the company states: A pooled analysis of the Phase 1b and Phase 2 trials of patients with NRASm melanoma dosed with naporafenib in combination with trametinib showed a median OS (MOS') of 13.0 and 14.1 months and a median PFS (mPFS) of 5.1 and 4.9 months at two doses of the combination, respectively. The pooled dataset at each dose compares favorably relative to historical benchmarks. From what I saw, the historical data highlights this data in a positive light:  ...the phase II trial of binimetinib showed encouraging activity in 30 NRAS-mutant melanoma patients with an ORR of 20% and a median PFS of 3.7 months. Taking into account these results, a randomized Phase III trial (NEMO trial) was undergone in 402 NRAS mutated melanoma patients. Binimetinib significantly increased ORR (7% vs 15%) and PFS (1.5 vs 2.8 months; Hazard Ratio 0.62) compared to dacarbazine. However, no differences in terms of OS were observed. Based on these results, binimetinib monotherapy did not received approval for the treatment of NRAS-mutant melanoma. Other MEKi such as pimasertib (AS703026) or RO498765541 have also been tested for efficacy. Pimasertib was evaluated in a randomized phase II trial with 194 NRAS-mutant patients versus Dacarbazine. A significant benefit for pimasertib was observed, with a mPFS of 13.0 weeks (vs 6.9 weeks) and a DCR of 37.7% (vs 26.6%). Once more, no differences in OS were observed (8.9 vs 10.6 months).40 RO4987655 (CH4987655) has also been tested in a phase I trial enrolling 8 patients with NRAS-mutant melanoma. ORR was 13% with partial response (PR') as best responses.  As we can see here, the PFS is much better in the naporafenib trial. As for trametinib’s own past data, a phase 1 study only managed to have stable disease in 29% of patients, and was abandoned. So combining it with naporafenib does a much better job here. The indication NRASm melanoma is an aggressive form of melanoma, with some 75,000 patients annually affected with the disease. Lack of approved therapies and ineffective current standards of care make it a disease with high morbidity. Moreover, this type of melanoma has a higher chance of brain metastasis. Currently, immunotherapies with checkpoint inhibitors using anti-PD-1 antibodies like Pembrolizumab (Keytruda) and Nivolumab (Opdivo) are used with mixed results, especially due to increasing drug resistance. Ipilimumab (Yervoy), an anti-CTLA-4 antibody, is also used in combination with the above two. Binimetinib, developed by Array Biopharma, now owned by Pfizer (PFE), has been tested in various trials targeting NRASm melanoma. It has shown a PFS of between 2.8 and 3.7 months and OS of 11 months. Pimasertib, being developed by Day One Biopharmaceuticals (DAWN), has shown PFS of 13 weeks. Fosun Pharma’s FCN-159 is also being studied in phase 1 studies. Tunlametinib (HL-085) has been approved in China as the first targeted therapy for patients with NRAS-mutated melanoma. It ran a phase 2b trial with mPFS of 4.2 months and a median overall survival of 13.7 months. It was developed by KeChow Pharma. Among other drugs, Selumetinib developed by AstraZeneca (AZN) and Merck (MRK) has also been studied in a phase 2 trial, with “mPFS of 2.2 months in the high March 2009pAKT cohort and 7.1 months in September 2013 the low pAKT cohort.” Financials ERAS has a market cap of $755mn and a cash balance of $460mn. R&D expenses were $33.0 million for the quarter ended June 30, 2024, while G&A expenses were $12.3 million. At that rate, they have a cash balance of 8–9 quarters. Risks The target market is a difficult to treat indication with poor data in historical studies. The data we see here is better, but only marginally so. For example, there's a 3-month improvement in both PFS and OS, which may or may not be significant. Erasca has a history of abandoning programs and restructuring. Bottom line I checked out ERAS because of its decent market cap and cash balance and its focus on late-stage trials. However, what I see here does not give me a lot of clarity as to the value of the asset they have in phase 3. I will continue to watch this from the sidelines.  Editor's Note: This article discusses one or more securities that do not trade on a major U.S. exchange. 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