4 Novel Drug Classes Demonstrate Early Promise for EGFR-Mutated NSCLC

Osimertinib has emerged as the standard of care for patients with EGFR-mutated non–small cell lung cancer, but the need for novel agents is underscored as disease progression on the agent is inevitable.

Osimertinib (Tagrisso) has emerged as the standard of care for patients with EGFR-mutated non–small cell lung cancer (NSCLC), but the need for novel agents is underscored as disease progression on the agent is inevitable, according to Karen Kelly, MD. To this end, bispecific antibodies, antibody-drug conjugates (ADCs), EGF vaccines, and fourth-generation EGFR TKIs are all under development and showing early potential to enrich the treatment paradigm.

“It is really important that we develop novel classes of EGFR inhibitors beyond the TKIs for the treatment of [patients with] EGFR-mutated lung cancer,” Kelly, the associate director for Clinical Research at University of California Davis Comprehensive Cancer Center, said in a presentation during the 22nd Annual International Lung Cancer Congress.1 “As we consider the future, and we think about having more agents, [we have several] questions. How do we combine them? Are we headed to triple-drug combinations in the first-line setting? Quadruple-drug combinations? How do we then sequence these? What’s going to be the optimal strategy to help our patients in their cancer journey to make them live longer?”

Breaking Down Breakthroughs With Bispecific Antibodies

Amivantamab-vmjw (Rybrevant) is the first bispecific antibody to target both EGFR and MET, according to Kelly. In May 2021, the FDA approved the agent for use in adult patients with NSCLC who harbor EGFR exon 20 insertion mutations.2 However, the drug has also been investigated in patients with EGFR-sensitizing mutations, Kelly noted.

Moreover, the third-generation TKI lazertinib (YH25448) has also been found to have potent activity in patients with NSCLC who have activating EGFR mutations, T790M, and central nervous system (CNS) disease. Because of the agent’s low rates of adverse effects (AEs), such as rash and diarrhea, lazertinib has been hypothesized to be amenable for use in combination with other anti-EGFR molecules.

The phase 1 CHRYSALIS trial (NCT02609776) enrolled patients with metastatic/unresectable NSCLC who had measurable disease and EGFR exon 19 deletion or exon 21 (L858R) mutation. In an expansion cohort of 45 patients who had relapsed on osimertinib and were chemotherapy naïve, investigators examined the safety and efficacy of amivantamab plus lazertinib.

An update presented during the 2021 ASCO Annual Meeting demonstrated that the overall response rate (ORR) achieved with the doublet in this population was 36% (95% CI, 22%-51%), with a median duration of response (DOR) of 9.6 months (95% CI, 5.3–not reached).3 The clinical benefit rate (CBR) observed with the combination was 64% (95% CI, 49%-78%), and the median progression-free survival (PFS) was 4.9 months (95% CI, 3.7-9.5).

Notably, no new safety signals were observed with amivantamab plus lazertinib, and the AEs that were most frequently experienced with the doublet included infusion-related reactions (IRRs, 78%), rash (acneiform dermatitis, 51%, plus rash 27%), and paronychia (49%). However, the majority of the effects were grade 1 or 2.

In a subset of 17 patients with EGFR/MET-based resistance per next-generation sequencing, the ORR with the doublet was 47%, with a median DOR of 10.4 months, a CBR of 82%, and a median PFS of 6.7 months. In the 28 patients without identified EGFR/MET-based resistance, the ORR was 29%, the median DOR was 8.3 months, the CBR was 54%, and the median PFS was 4.1 months.

In the phase 1 CHRYSALIS-2 trial (NCT04077463), the combination will be evaluated in 4 cohorts. Notably, cohort A will include patients with NSCLC and EGFR exon 19 deletion or L858R in whom both osimertinib and chemotherapy has failed. Cohort D is evaluating the combination following first- or second-line osimertinib in patients with NSCLC and EGFR exon 19 deletion or L858R who are amenable to tumor biopsy for biomarker validation.

“This is the cohort of patients to which we’re going to try to understand that biology, and that is such an important cohort,” Kelly noted. “I applaud them for doing this cohort.”

In the phase 3 MARIPOSA trial (NCT04487080), amivantamab plus lazertinib is being compared with osimertinib in the frontline treatment of patients with locally advanced or metastatic NSCLC.4

Marking Advances Made With ADCs

Patritumab deruxtecan (U3-1402) is an ADC that is comprised of 3 components: a fully human anti-HER3 IgG1 monoclonal antibody, patritumab, that is covalently linked to a topoisomerase I inhibitor payload, an exatecan derivative, through a tetrapeptide-based cleavable linker.5

“It is noteworthy that HER3 is not a resistance mechanism for EGFR TKIs and that the reason why HER3 is being used here is because it is highly expressed in NSCLC, at 83%,” Kelly explained.

Previously, the agent was found to inhibit tumor growth in HER3-expressing, EGFR-mutated, EGFR TKI–resistant PDX models.6 “Activity with this agent [was observed] across a variety of H-scores and several EGFR resistance models,” Kelly noted.

In the phase 1 U31402-A-U102 trial (NCT03260491), the agent was evaluated in patients with locally advanced or metastatic NSCLC with EGFR mutations who had progressed on previous EGFR TKI treatment.

In the dose-escalation portion of the research, the ADC was evaluated at the following doses: 3.2 mg/kg (n = 4), 4.8 mg/kg (n = 15), 5.6 mg/kg (n = 12), and 6.4 mg/kg (n = 5). A total of 57 patients with EGFR TKI–resistant, EGFR-mutated NSCLC received the agent at the recommended phase 2 dose of 5.6 mg/kg every 3 weeks.

Results indicated that the agent demonstrated durable activity following failure of EGFR TKI and platinum-based chemotherapy. At a median follow-up of 10.2 months (range, 5.2-19.9), the confirmed ORR with the agent per blinded independent central review and RECIST v1.1 criteria was 39%. The median DOR was approximately 7.0 months and the median PFS was 8.2 months.

“Importantly, this agent does have activity across a wide range of the known EGFR TKI resistance mechanisms,” Kelly said. “HER3 expression level also didn’t seem to play a role in terms of that, even at very low levels of HER3 expression, you still saw some activity. [This means that] as long as [a patient has] HER3 expression, [they] have an opportunity to respond to the agent.”

The ADC was found to have a manageable toxicity profile, with a low rate of discontinuations due to AEs. Among 81 patients, the rate of treatment-emergent AEs (TEAEs) across the doses was 64%, and treatment-related TEAEs were observed in 96% of patients.

“I do want to point out that the interstitial pneumonitis was low, at 5%, and no grade 4 or 5 interstitial pneumonitis was reported,” Kelly added.

Patritumab deruxtecan is also under evaluation in patients with metastatic or locally advanced NSCLC with an activating EGFR mutation (exon 19 deletion or exon 21 [L858R] mutation) who have received and progressed on or after at least 1 EGFR TKI and 1 platinum-based chemotherapy-containing regimen, as part of the phase 2 HERTHENA-Lung 01 trial (NCT04619004).7

Additionally, another phase 1 trial (NCT04676477) is examining the safety of the agent in combination with osimertinib in patients with locally advanced or metastatic EGFR-mutated NSCLC.8

Other EGFR ADCs under investigation include AVID 100, RN765C, and SHR-A1307, all of which have been examined preclinically in EGFR-mutated, TKI-resistant NSCLC and have demonstrated activity. “Only the first agent has entered into phase 1 testing,” Kelly said. “I expect that the others are going to be just behind.”

Examining Lessons Learned With EGF Vaccines

“This is a really exciting area. CiMAvax-EGF isn’t quite the most exciting one, but it is the first one, and we can learn lessons here,” Kelly said. “Remember that the mechanism of action of EGF vaccines is that they elicit the production of anti-EGF antibodies, which then bind circulating EGF proteins that avert receptor binding and signal activation.”

To examine the overall survival, safety, immunogenicity, and EGF concentration in serum following treatment with CiMAvax-EGF, a phase 3 trial was conducted in patient with advanced NSCLC.9 After receiving 4 to 6 weeks of frontline chemotherapy, 405 patients with stage IIIB/IV NSCLC were randomized to the vaccine or best supportive care.

Kelly added that although the trial with this vaccine “had a lot of flaws and it didn’t meet its end point,” the approach was found to be safe. Moreover, vaccination was found to induce anti-EGF antibodies and decreased serum EGF concentration.

In the safety population, the median survival time was 10.83 months in the vaccine arm vs 8.86 months in the control arm, although the differences noted between the arms were not determined to be significant according to the standard log rank (HR, 0.82; P = .100).

“However, when you go from an unselected patient population to trying to look at a selected patient population, the preclinical models in the EGFR TKI–resistance arena did show activity,” Kelly said. “When you combined this with an EGFR TKI, you were able to see enhanced cell killing.”

As such, a phase 1 EPICAL trial (NCT03623750) was launched to evaluate EGF-PTI, an anti-EGF vaccine, in combination with afatinib (Gilotrif) as frontline treatment in patients with EGFR-mutated NSCLC.10 The trial has been completed, according to Kelly, and the results are highly anticipated.

Perusing Progress With Potent Fourth-Generation EGFR TKIs

BLU-945 is an investigational fourth-generation EGFR TKI that was designed to suppress activating and on-target resistance EGFR mutations, and spare wild-type EGFR.11 The agent is also hypothesized to be able to treat or prevent CNS metastases.

The drug has previously been shown to be a selective and potent inhibitor of double- or triple-mutant EGFR (T790M or exon 19 deletion/T790M/C797S), and to have strong antitumor activity in preclinical models.

Additional preclinical evidence indicated that BLU-945 had intracranial activity in a NSCLC PDC-luc (exon 19 deletion/T790M/C797S) model per total photon flux measurements over the course of treatment and at week 13. Moreover, when delivered orally, the agent resulted in significant tumor regression in an EGFR exon 19 deletion/T790M/C797S PDCX model that was resistant to osimertinib. Notably, in another osimertinib-resistant, EGFR exon 19 deletion/T790M/C797S PDCX model, YU-1097, the agent also demonstrated significant tumor regression when used as single agent or in combination with either osimertinib or gefitinib (Iressa).

In April 2021, an international phase 1 dose-escalation trial (NCT04862780) was launched to evaluate the agent in patients with EGFR-driven NSCLC.12

Looking to the Future

There is an expanding role for novel classes of EGFR inhibitors beyond TKIs for the treatment of patients with EGFR-mutated NSCLC, according to Kelly. Notably, fourth-generation TKIs are under investigation and with the emerging options, come several opportunities for novel combinations and sequential strategies that bring the field one step closer to the elusive goal of a cure, Kelly said.

“We must not forget that we need to continue to investigate immunotherapies, with the hope that they will, at one point in time, join this class of active agents for EGFR,” Kelly concluded. “I know that’s a stretch, but I do believe that we have that as a goal. We really would like to see immunotherapies be effective in this group of patients, as well.”


  1. Kelly K. Novel drug classes for EGFR mutation–positive NSCLC. Presented at: 22nd Annual International Lung Cancer Conference; July 29-31, 2021; Huntington Beach, CA. Accessed July 30, 2021.
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  9. Rodriguez PC, Popa X, Martínez O, et al. A phase III clinical trial of the Epidermal Growth Factor vaccine CIMAvax-EGF as switch maintenance therapy in advanced non-small cell lung cancer. Clin Cancer Res. 2016;22(15):3782-3790. doi:10.1158/1078-0432.CCR-15-0855
  10. E GFR TKI and EGF-P TI C Ombination in EGFR mut Ant NSCL C (EPICAL). ClinicalTrials.gov. Updated September 3, 2020. Accessed July 30, 2021. https://clinicaltrials.gov/ct2/show/NCT03623750
  11. Lim SM, Park C-W, Zhang Z, et al. BLU-945, a fourth-generation, potent and highly selective epidermal growth factor receptor tyrosine kinase inhibitor with intracranial activity, demonstrates robust in vivo anti-tumor activity in models of osimertinib-resistant non-small cell lung cancer. Blueprint Medicines Corporation. Accessed July 30, 2021. https://bit.ly/3j4QwCe
  12. Study targeting EGFR resistance mechanisms in NSCLC. ClinicalTrials.gov. Updated April 28, 2021. Accessed July 30, 2021. https://clinicaltrials.gov/ct2/show/NCT04862780