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Takeda's Mobocertinib Moves Into Larger NSCLC Studies After Promising Efficacy in EGFR Exon 20 Insertions

NEW YORK – Takeda Pharmaceutical's mobocertinib has shown promising efficacy and safety in a Phase I/II trial in previously treated, advanced non-small cell lung cancer patients harboring EGFR exon 20 insertions. 

At the American Association for Cancer Research's Virtual Annual Meeting this week, Francois Gonzalvez, on behalf of Takeda, presented data showing that 43 percent of 28 mobocertinib-treated NSCLC patients with EGFR exon 20 insertions saw their tumors shrink and on average their tumors stopped progressing for around 7.3 months.

Takeda announced this week that based on the overall response rate and long-term benefit seen in patients in this Phase I/II trial, the US Food and Drug Administration has granted breakthrough therapy designation to mobocertinib. The safety and efficacy of this drug is now being evaluated further in NSCLC patients with EGFR exon 20 insertions in two larger global studies.

"There is still no approved effective treatment for [NSCLC patients with] EGFR exon 20 insertions. [Mobocertinib] is the first inhibitor to be specifically designed to address this unmet need," Gonzalvez said at the AACR meeting. "In the Phase I/II trial, [mobocertinib] has shown evidence of antitumor activity in previously treated patients with NSCLC harboring EGFR exon 20 insertions and has also shown a manageable safety profile."

In his presentation, Gonzalvez for the first time described how researchers designed mobocertinib from the start to specifically overcome the challenges of targeting EGFR exon 20 insertions, recognizing the unmet need in NSCLC patients with these rare mutations.

Approximately 20 percent of NSCLC patients harbor EGFR mutations. The most common driver mutations, EGFR exon 19 deletions and exon 21 L858R substitutions, can be targeted by first-generation tyrosine kinase inhibitors, erlotinib (Genentech's Tarceva) and gefitinib (AstraZeneca's Iressa); the second-generation inhibitor afatinib (Boehringer Ingelheim's Gilotrif); and the third-generation drug osimertinib (AstraZeneca's Tagrisso). There are more uncommon mutations that reside in EGFR exon 18 and exon 21, and those can also be targeted by afatinib.

However, the 2 percent of NSCLC patients with EGFR exon 20 insertions don't respond well to these existing drugs. Patients with these insertions have a median progression-free survival of around two months to first- and second-generation EGFR inhibitors. Comparatively, those with the common EGFR mutations on average see their disease stop progressing for around a year. Patients with EGFR exon 20 insertions also don't respond very well to checkpoint inhibitors.

However, developing a drug targeting EGFR exon 20 insertions has proven challenging since patients with these alterations are a heterogeneous group. There are multiple EGFR exon 20 insertion variants that can occur between amino acid positions 762 and 774 of the EGFR protein. The most common of these are EGFR exon 20 insFQEA (11 percent), insASV (20 percent), insSVD (20 percent), and insNPH (10 percent). There are a dozen other insertions that account for between 2 percent and 7 percent of EGFR exon 20 cases.

Patients with these insertions don't derive much benefit from existing EGFR inhibitors because they are not designed to select the mutant form of the EGFR protein, in this case EGFR exon 20 insertions, over wildtype EGFR. When the drugs hit wild-type EGFR, patients tend to have skin rashes and gastrointestinal toxicities, which hinder their ability to take them.

To balance the risk/benefit profile of the drug they were developing, researchers measured the target selectivity of first, second, and third generation inhibitors in clinical models and found that in order for an EGFR inhibitor to limit these skin and gastrointestinal toxicities, it must be more  potent in its ability to block mutant EGFR than wildtype EGFR. Resistance emerges with existing tyrosine kinase inhibitors in NSCLC patients with EGFR T790M or exon 20 insertions, Gonzalez observed, because first and second generation TKIs target these mutations less potently than wildtype EGFR. 

Unfortunately, the structure of certain EGFR exon 20 insertion proteins are very similar to the wildtype form of the protein, which further challenged researchers to design a drug that would have more affinity for binding to the mutant form over the wildtype form. As a starting point, researchers looked at the potency of different tyrosine kinase inhibitors and found that osimertinib had the best combination of potency and selectivity over wildtype EGFR. They then tweaked the chemical structure of osimertinib such that the resulting new drug could access a binding pocket to target EGFR exon 20 insertions but not wildtype EGFR.

Researchers then continued to tweak the chemical structure of the drug until it had the right balance of properties that ultimately resulted in mobocertinib. In preclinical models, the drug demonstrated its ability to inhibit all mutant EGFR variants, including EGFR exon 20 insertions, more potently than wildtype EGFR, "suggesting it has the right degree of selectivity to be efficacious in clinic," Gonzalvez said. In fact, mobocertinib has shown itself to be not just an EGFR inhibitor but also an inhibitor of HER2 exon 20 insertions and point mutations, he added. 

Gonzalvez's team eventually launched a Phase I/II dose escalation and expansion study for mobocertinib after it showed to be well tolerated and reduced tumors in xenograft models. In Phase I, researchers settled on moving the 160 mg/daily dose of the drug into Phase II studies.

In the Phase II setting, the trial splinters into seven cohorts exploring mobocertinib's efficacy in different patient subgroups, some of whom have EGFR exon 20 insertions, others with HER2 exon 20 insertions or point mutations, or those with EGFR T790M mutations. There is even an arm exploring the drug's efficacy in non-lung cancer tumor types with these mutations.

Gonzalvez presented data at the meeting only from cohort 1, which enrolled 28 NSCLC patients with EGFR 20 insertions and brain metastases who were refractory to other treatments. In this cohort, the overall response rate was 43 percent and median progression-free survival was 7.3 months. Mobocertinib shrank tumors in patients with a range of EGFR exon 20 variants, including two out of five patients harboring the insASV variant; two out of four patients with the insNPH variant (who were predicted to be more resistant to therapy based on preclinical data); six out of 15 patients with other exon 20 insertions; and two out of four patients whose exact exon 20 insertion variants were not known.

The safety data suggests the drug is well tolerated with most treatment-related events being grade 1/2 and reversible. Gastrointestinal events were the most common adverse events but Gonzalvez said that these were manageable with changes to patients' diet.

Mobocertinib is currently being investigated in a global extension cohort, called EXCLAIM, which is fully enrolled and includes 91 locally advanced or metastatic NSCLC patients, who may or may not have metastasis to the brain, who were previously treated with chemotherapy, and harbor exon 20 insertions. The primary endpoint in this study is overall response rate, and secondary endpoints are duration of response, as well as survival and quality of life endpoints.

A separate clinical trial, EXCLAIM-2, is currently enrolling treatment naïve, recurrent or metastatic NSCLC patients who will be randomized to mobocertinib or platinum chemotherapy. Researchers are aiming to enroll more than 300 patients with EGFR exon 20 insertions globally in this trial.

Given the unmet need in this subset of NSCLC patients, several drug companies are working on treatments targeting EGFR exon 20 insertions. At the AACR meeting, researchers provided more details on the efficacy of Spectrum Pharmaceuticals' poziotinib, which failed to meet its pre-specified primary endpoint in a Phase II cohort, yielding an overall response rate of 14.8 percent. However, the drug demonstrated activity in terms of median progression-free survival (4.2 months) and duration of response (7.4 months), based on which Spectrum has decided to continue studying the drug after making some changes to the trial design. Black Diamond Therapeutics is also advancing BDTX-189 in this same setting.