Nadler Reviews Targeted Therapy for EGFR Exon 20 Insertion NSCLC

Eric S. Nadler, MD, MPP

Medical Director, US Oncology Health Informatics and Internet Technology

Medical Oncologist

Texas Oncology-Baylor Charles A. Sammons Cancer Center

Dallas, TX

Targeted Oncology^TM: What are the recommendations of the National Comprehensive Cancer Network (NCCN) guidelines for biomarker testing in non– small cell lung cancer (NSCLC)?

NADLER: The recommendations have changed many times. [Recent recommendations say high-level] MET amplification is an emerging biomarker, whereas HER2 [was added after targeted therapy was] FDA approved [in August 2022].^1,2 [Biomarker testing] used to be recommended just for [adenocarcinomas], then it was recommended for all nonsquamous carcinomas, and then for squamous carcinomas in nonsmokers or oligo smokers. Now it [is recommended for] all nonsquamous carcinomas, and it should be very strongly considered [in all other situations].¹ Every center in the NCCN is ordering next-generation sequencing [NGS] on [all patients], in addition to PD-L1 testing.

The NCCN has broken it down from the classic EGFR mutations—[exon 19 deletion and L858R]—and atypical [mutations], including S768I and exon 20 insertion mutations. [The NCCN guidelines also make specific recommendations for mutations in] KRAS [G12C], for which we have [targeted] drugs, as well as ALK, ROS1, BRAF, NTRK1/2/3, MET, RET, and HER2. The NCCN guidelines also offer recommendations based on PD-L1 testing results.¹ The [recommendations] are getting [extensive]; it used to be 2 or 3 [biomarkers].

The recommendations for nonsquamous carcinoma are to test everybody. The recommendations for EGFR, ALK, and PD-L1 targeted therapy are all supported by category 1 data. For [all other mutations, the outcomes with targeted therapy] are still far better than [the outcomes] with chemotherapy or chemoimmunotherapy.¹ NGS is the standard of care. Whether you reflexively offer plasma testing at onset or just in certain instances [depends on] how you feel the practice patterns drive you, but [both options] are very standard and state of the art. If you order [immediate testing for every patient], that’s perfect. If you order it for just certain populations of your patients, that’s also perfect.

Most importantly, the NCCN guidelines say to consider— and I’d say strongly consider—having a testing panel that has RNA NGS in addition to DNA NGS.¹ The reason is that [this will show] you all the fusion effects. The fusion [mutations of interest are those in] NTRK1/2/3, ALK, ROS1, and RET. Testing options that are strong in RNA testing include Tempus and NeoGenomics. FoundationOne is moving toward RNA testing; my understanding is that they may have incorporated it recently, but they’ve historically not had that component, and some others also do not have it.

The NCCN guidelines also recommend you get [molecular testing results] before you start [immune checkpoint inhibitor] therapy. Another recommendation is that [even] if PD-L1 expression is high, you should still treat the [oncogenic] driver [over treatment with an immune checkpoint inhibitor].¹ If turnaround time is [problematic], you may want to order Guardant360 testing for a few patients to see whether the turnaround time with Guardant Health makes a difference for you. If it does, it’s certainly cost-effective to have that information and make a better treatment decision up front.

CASE UPDATE

• Tissue NGS showed an EGFR exon 20 insertion mutation (V769_D770insASV)
• PD-L1 expression was negative

What are the effects of EGFR mutations on EGFR function and on patient response to therapy?

The classic exon 19 deletion [changes] the binding cleft of EGFR, [rendering it active, and] the exon 20 insertions [cause a similar, activating conformational change].³ Fifty percent of [patients treated with] first-generation tyrosine kinase inhibitors [TKIs] had T790M mutations as an “escape mutation,” but primary T790M mutation can occur, as well.¹ Primary T790M mutations are very rare—[approximately] 2%.

Of all the EGFR mutations, approximately 10% are exon 20 insertion mutations. There are a variety of them, and they’ve been incredibly difficult to target. Progression-free survival [PFS] [is usually just] 1 or 2 months, and response rates are in the single digits. First-, second-, and third-generation EGFR-TKIs have just not worked.⁴

[The important thing is] to [identify] these mutations. NGS is much better [than targeted polymerase chain reaction–based approaches] at parsing out each of these individual events—the deletions, the insertions—and catching all of them.¹

CASE UPDATE

• The patient received carboplatin/pemetrexed chemotherapy and achieved a partial response.
• Four months later, the patient is reporting worsening back pain and shortness of breath.
• CT scan shows progression in primary tumor and a new adrenal metastasis
• Repeat brain MRI shows no metastases
• The patient preferred an oral therapy; mobocertinib (Exkivity) 160 mg oral once daily is initiated.

What data support the use of mobocertinib in patients with platinum-pretreated metastatic NSCLC characterized by EGFR exon 20 insertions?

[These data come from a] phase 1/2 study of mobocertinib [NCT02716116] that included [multiple] cohorts, including the EXCLAIM [extension] cohort [NCT04129502].⁵

[Most patients represented in these data] had adenocarcinomas [98%] and were heavily pretreated [27% had 3 or more prior regimens]. The vast majority, 71%, were never smokers. These patients were young, with an average age of 60 years. There were more women than men [66% vs 34%, respectively], and they had a relatively good performance status of 0 [25%] to 1 [75%]. [Mobocertinib] is an oral drug and was given [at a dosage of] 160 mg daily.⁵ The [other drug for this target, amivantamab (Rybrevant)], is a monoclonal antibody. It’s intravenous and has a different toxicity profile.

[The results were] interesting. The objective response rate [ORR] was 35% [95% CI, 26%-45%] as assessed by the investigators and [28%; 95% CI, 20%-37%] as determined by independent review [Table⁵]. The median PFS was [7.3 months (95% CI, 5.5-9.2), and] the median duration of response was very robust, 17.5 months [95% CI, 7.4-20.3], [both as assessed by independent review]. A very large number of patients had stable disease or minor responses below partial response; the rate of stable disease was [43%] as assessed by the investigator and 50% as determined by independent review. The number of patients who didn’t have disease control with this drug was only [approximately] 10%.

What did this study show about the toxicity of mobocertinib?

This drug is an EGFR blockade, so diarrhea [is a substantial adverse event]. In this study, diarrhea of grade 3 or higher affected 21% of patients. There was no rash of grade 3 or 4, but 45% of patients had rash of grade 1 or 2. [Paronychia] of any grade affected [38%] of patients, and fatigue of any grade affected [14%]. There was a lot of grade 1 and 2 toxicity, but not a [great deal] of grade 3 or 4 toxicity. There was some stomatitis [of all grades, affecting 24% of patients]. Finally, 3% of patients had electrocardiogram QT prolongation [of grade 3 or 4] and [8%] had alanine aminotransferase [elevation of any grade]. But overall, [this was] a relatively well-[tolerated] drug. Lastly, I want to [mention that] these newer drugs, like we see with osimertinib [Tagrisso], are associated with cardiomyopathy [that we didn’t] see historically, and with a bit more pneumonitis. [In this study, cardiomyopathy affected 2.7% of patients, and interstitial lung disease/pneumonitis affected 4.3%.]^5,6

How does the efficacy of mobocertinib compare when assessed in the context of the current therapeutic landscape?

The current targets are classified into 2 groups. There are the [extremely] sensitive targets, such as the EGFR exon 19 deletion and L858R mutations, MET skipping mutations, and mutations in ALK, ROS1, RET, and NTRK. All of those have ORRs of approximately 75% to 80%. Then there is another group [of targets], which includes mutations in KRAS and HER2, EGFR exon 20 insertion mutations, and atypical EGFR mutations; these have ORRs that are only 30% to 40% and stable disease rates that are also 30% to 40%. Considering that nothing has worked [well] in this population before, [this drug] is a pretty good step up.

_REFERENCES

_{1. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 5.2022. Accessed October 3, 2022. https://bit. ly/3RPMugk}

_{2. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. FDA. Updated August 16, 2022. Accessed October 12, 2022. https://bit.ly/3VllY1c}

_{3. Vyse S, Huang PH. Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. Signal Transduct Target Ther. 2019;4:5. doi:10.1038/s41392-019-0038-9}

_{4. Meador CB, Sequist LV, Piotrowska Z. Targeting EGFR exon 20 insertions in non-small cell lung cancer: recent advances and clinical updates. Cancer Discov. 2021;11(9):2145-2157. doi:10.1158/2159-8290.CD-21-0226}

_{5. 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}

_{6. Exkivity. Prescribing information. Takeda Pharmaceuticals America Inc; 2021. Accessed October 3, 2022. https://bit.ly/3emUdoD}