Recap: Mobocertinib for Pretreated Patients With EGFR Exon 20 Insertion–Positive Metastatic NSCLC

In a Between the Lines presentation hosted by CancerNetwork^®, Gregory J. Riely, MD, PhD, and Tarek M. Mekhail, MD, MSc, discussed the efficacy and safety of mobocertinib (Exkivity) in a phase 1/2 trial (NCT02716116) that is investigating treatment outcomes in patients with EGFR exon 20 insertion–positive metastatic non–small cell lung cancer (NSCLC) pretreated with platinum therapy.¹ Both are among the trial’s investigators.

Riely and Mekhail explained that limited therapeutic options exist for patients with NSCLC harboring EGFR exon 20 insertions, which are found in only about 4% to 12% of all EGFR-mutated NSCLCs.²

“We typically see this mutation in the same kind of patients [in whom] we see other sensitizing mutations. But if you don’t look for it, you will not find it
[because] it is quite uncommon,” explained Mekhail, medical director of the Thoracic Cancer Program at Advent Health Cancer Institute.

“If we can get more specific [drugs to treat] EGFR exon 20 insertions, it’s likely that we’ll be able to have a better therapeutic window, leading to better outcomes for our patients,” added Riely, who is vice chair of clinical research in the Department of Medicine at Memorial Sloan Kettering Cancer Center.

Mobocertinib for Platinum-Pretreated Patients With NSCLC

The dose-escalation phase 1 trial used a standard 3 + 3 design, with the current analysis focused on 2 groups: the platinum-pretreated patients (PPP; n = 114); and the EXCLAIM cohort (n = 96), which was composed of patients previously treated with 1 or 2 systemic therapies, only 10 of whom had not been treated with platinum. There was overlap in the 2 cohorts, with
86 patients in the PPP cohort being evaluated in EXCLAIM, as well as those from the dose-escalation part (n = 6) and expansion cohort 1 (n = 22). The study enrolled further cohorts when determining the recommended phase 2 dose. All patients in the current analysis received mobocertinib at 160 mg once daily.

Mekhail said “10 patients on the EXCLAIM cohort did not have prior platinum, but the other 86 patients [did receive prior platinum therapy], so you’ll find similarities in the results [for the PPP and EXCLAIM cohorts].”

To be eligible, patients needed to be 18 years or older and have measurable disease by RECIST 1.1 criteria, an ECOG performance score of 0 or 1, a normal QT interval, and adequate kidney, hepatic, and bone marrow function.

The PPP cohort was composed of patients receiving mobocertinib 160 mg once daily from the dose-escalation (n = 6), dose-expansion (n = 22), and EXCLAIM (n = 86) cohorts.

The primary end point for these cohorts was objective response rate by
independent review committee. Secondary end points included objective response rate (ORR) by investigator assessment, duration of response, progression-free survival (PFS), overall survival (OS), and safety.

As Mekhail explained, the overall population was relatively young, comparable with real-world populations, with a median age of 60 years (range, 27-84) in the PPP cohort and 59 years (range, 27-80) in the EXCLAIM cohort. In both cohorts, most patients were female (66% in PPP and 65% in EXCLAIM), Asian (60% vs 69%, respectively), had adenocarcinoma histology (98% vs 99%), and had an ECOG performance score of 1 (75% vs 71%).

ORR by independent review committee in the PPP cohort was 28% (95 % CI, 20%-37%) compared with 25% (95% CI, 17%-35%) in the EXCLAIM cohort. Partial responses were observed in 28% and 25% of patients, respectively. The remaining patients achieved stable disease (50% vs 51%) or were not evaluable for response (11% vs 10%).

When examining the secondary end points, Riely emphasized that the median OS of 24.0 months (95% CI, 14.6-28.8) for patients in the PPP cohort was striking given what this group normally experienced. Median OS in the EXCLAIM cohort was not reached (NR; 95% CI, 13.1 months to NR) with a median follow-up of 13.0 months.

The PPP cohort “had a range of prior therapies, so it’s not as though this is a standard second-line cohort,” Riely explained, crediting Mekhail for highlighting the variable. “This is a group of people who had up to 3 prior therapies, so that median OS of 24 months is impressive given prior treatments.”

Regarding the disease control rate, Riely emphasized that most patients had some degree of tumor shrinkage. Because the trial population represented a large number of exon 20 insertion variants, the experts could not discern a particular variant for which mobocertinib is most active.

“It’s intellectually disappointing that we couldn’t find the particular variant that benefited,” Riely explained. “The fact is that these response rates are relatively low, but the vast majority of patients have some tumor shrinkage, [and] it is certainly reassuring that the treatment leads to disease control for most.”

Managing Diarrhea and Other Adverse Effects

Regarding toxicity with mobocertinib, both Mekhail and Riely were primarily concerned with diarrhea, which was a common any-grade adverse effect (AE) in both the PPP (91%) and EXCLAIM cohorts (93%). Grade 3 or higher diarrhea was found in 21% and 16% of patients in those cohorts, respectively.

Developing strategies to manage diarrhea is very necessary, Mekhail explained, but dose reductions are not something he sees as beneficial.
“I try not to reduce the dose. I try aggressively to manage the diarrhea because there are some hints in the paper that the response [rates] in patients for whom the dose was reduced were numerically lower than if you didn’t reduce the dose, [in the range of] 20% vs 31%,” Mekhail emphasized, specifying that these response rates include a small sample size.

Other common any-grade AEs for patients in the PPP and EXCLAIM cohorts, respectively, included rash (45% vs 45%), paronychia (38% vs 39%),
decreased appetite (35% vs 32%), nausea (34% vs 30%), dry skin (31% vs 31%), and vomiting (30% vs 26%). No grade 3 or higher AEs other than diarrhea were observed in more than 4% of patients.

Overall, Riely summed up the tolerability of mobocertinib in this patient population, suggesting that “what you see is a relatively narrow window where patients tolerate the drug and it’s effective.”

Looking Ahead With Mobocertinib for EGFR Exon 20 Insertions

Looking ahead, Mekhail and Riely are intrigued by the potential of another therapeutic option to treat patients with EGFR exon 20 insertion–positive metastatic NSCLC.

“We didn’t have a good therapy in the past,” Mekhail explained. “We’ve tried many things that were certainly supported by some small studies [that looked at] doubling the dose of osimertinib, but now we have a targeted drug and it’s not the only one.”

Mekhail and Riely agreed that these data provide supporting evidence for mobocertinib in this patient population, and Riely explained that the potential to improve outcomes and toxicities may exist beyond this first generation of agents.

“We’ve seen, [as] with the development of new ALK inhibitors and EGFR inhibitors, that the first generation is not always the best,” Riely noted. “We have a drug establishing that this is a group of patients who can benefit from this strategy, but with the second and third generations of these [kinds of] drugs, we can often significantly improve upon both the efficacy and the tolerance.”

References

1. Zhou C, Ramalingam SS, Kim TM, et al. Treatment outcomes and safety of mobocertinib in platinum-pretreated patients with EGFR exon 20 insertion–positive metastatic non–small cell lung cancer: a phase 1/2 open-label nonrandomized clinical trial. JAMA Oncol. 2021;7(12):e214761. doi:10.1001/jamaoncol.2021.4761
2. Fang W, Huang Y, Hong S, et al. EGFR exon 20 insertion mutations and response to osimertinib in non-small-cell lung cancer. BMC Cancer. 2019;19(1):595. doi:10.1186/s12885-019-5820-0