Targeted Therapy Paradigm Grows in NSCLC, While Overcoming Resistance Represents Next Hurdle


The field of targeted therapy for patients with non–small cell lung cancer has grown exponentially in recent years, with inhibitors for RET, MET exon 14 skipping, and KRAS G12C mutations transforming the paradigm.

Balazs Halmos, MD, MS

Balazs Halmos, MD, MS

The field of targeted therapy for patients with non–small cell lung cancer (NSCLC) has grown exponentially in recent years, with inhibitors for RET, MET exon 14 skipping (METex14), and KRAS G12C mutations transforming the paradigm. However, acquired resistance to targeted therapy remains a common and challenging clinical scenario, so developing ways to overcome resistance is an area of considerable research.1

“We need to be able to use molecular testing better, identify our patients, [and] leave no gene stranded…Biomarker testing is here [to stay] in so many different settings. We need to stay sophisticated and on top of this issue,” said Balazs Halmos, MD, MS, director of Thoracic Oncology and Clinical Cancer Genomics at Montefiore Medical Center.

In a presentation at the 5th Annual International Congress on Oncology & Pathology™, a program run by Physician’s Education Resource®, Halmos and co-chair Lynette M. Sholl, MD, an associate pathologist at Brigham And Women’s Hospital and associate professor of pathology at Harvard Medical School, participated in a case-based discussion that highlighted important advances made with targeted therapy for patients with NSCLC, how treatment strategies have evolved, and what is being done to overcome acquired resistance to targeted treatments.

RET Alterations in Advanced NSCLC

On May 8, 2020, the FDA granted an accelerated approval to selpercatinib (Retevmo) for the treatment of patients with RET fusion–positive NSCLC, medullary thyroid cancer, and other thyroid cancers.2

The regulatory decision was based on findings from the phase 1/2 LIBRETTO-001 trial (NCT03157128), in which selpercatinib induced an overall response rate (ORR) of 64% in 105 patients with RET fusion–positive NSCLC who had received prior platinum-based chemotherapy and 84% in 39 patients with treatment-naïve disease.3

Shortly following the approval and during the height of the COVID-19 pandemic, a 54-year-old female was diagnosed with bronchoscopy-confirmed, extensive lung adenocarcinoma and leptomeningeal disease, explained Halmos, who introduced the first case of the discussion. She was a nonsmoker with no available tissue left for testing, so circulating tumor DNA (ctDNA) was sent for testing. The test yielded “life-transforming results” for the patient and revealed a RET fusion, Halmos said.

The patient received selpercatinib and derived a substantial response, Halmos explained.

Notably, on September 4, 2020, the FDA approved a second RET inhibitor, pralsetinib (Gavreto), for use in patients with RET fusion–positive NSCLC.4 The approval was based on ORRs of 70% in treatment-naive patients and 57% in previously treated patients that were noted with pralsetinib. Updated data from the phase 1/2 ARROW trial (NCT03037385), which were presented during the 2021 ASCO Annual Meeting, demonstrated an ORR of 79% with pralsetinib in 216 patients with RET fusion–positive NSCLC.5

Clinical scenarios such as this underscore the importance of molecular testing for patients with NSCLC, Halmos said. Notably, as tissue-based testing remains the gold standard, capitalizing on available tissue specimens is critical.

Conventional smear preparations, although not actively used in molecular testing, could offer an alternative resource to liquid-based cytology preparation “even though we are constantly told that we can only take a tissue specimen or maybe a cell block,” said Sholl.

Returning back to the case, the 54-year-old patient required hospitalization because her disease burden was significant. However, molecular testing is typically conducted as an outpatient procedure, which presents a challenge for hospitalized patients who could be eligible for targeted therapy, Sholl explained.

A study published in JCO Precision Oncology demonstrated cell-free DNA (cfDNA) next-generation sequencing (NGS) before pathologic diagnosis in hospitalized patients with suspected metastatic NSCLC resulted in shorter time to genotyping compared with standard outpatient workflows.6

“[We can] really narrow the window from, say, 3 weeks from the time of diagnosis to the molecular results to 3 days…when [we] are able to employ cell-free testing in these inpatient settings,” said Sholl.

Notably, in patients who have central nervous system involvement, such as the 54-year-old female, cerebrospinal fluid (CSF) offers a potential molecular testing strategy, Sholl said. By extracting the CSF, which houses a high level of concentrated cfDNA shed, and running a standard molecular gene panel, cfDNA results may be obtained in cases where tissue is unavailable.

METex14 Skipping Mutations in Locally Advanced NSCLC

Sholl presented another case of a 47-year-old female never-smoker who presented with pleuritic chest pain with chest wall extension and a history of PIK3CA E545K mutant–adenocarcinoma. Molecular profiling of the chest wall biopsy, which was conducted to understand the relationship with the primary tumor and inform potential targeted therapies, revealed a METex14 skipping mutation and a PIK3CA E542K mutation.

Historically, crizotinib (Xalkori) would have been the standard treatment approach, said Halmos. However, the recently FDA-approved agents capmatinib (Tabrecta) and tepotinib (Tepmetko) are now available for use in patients with METex14–altered NSCLC.7,8

Both agents demonstrated good durability, tolerability, and [central nervous system] penetrance, thus “[hitting] all the sweet spots for a good, targeted agent,” said Halmos.

Notably, in this case, curative therapy could have been considered vs single-agent targeted therapy, added Halmos. Systemic treatment could debulk the tumor to allow for improved surgical resection or provide a smaller area to radiate.

“[This case shows us] that having access to that molecular data goes beyond just reading the report that we get from whatever company. If we have a challenging case, communication is key,” said Halmos.

KRAS G12C Mutations and Mechanisms of Resistance in NSCLC

KRAS alterations have been historically challenging to target across the field of oncology, Halmos said. However, on May 28, 2021, the FDA approved sotorasib (Lumakras) for the treatment of patients with previously treated NSCLC whose tumors harbor KRAS G12C mutations.9

The approval was based on data from the phase 2 CodeBreaK 100 trial (NCT03600883). Updated findings from the trial demonstrated that sotorasib induced a 37.1% ORR in patients with KRAS G12C–mutant NSCLC who had progressed following treatment with immunotherapy and/or chemotherapy.10

“[The approval of sotorasib] certainly mandates [molecular] testing,” Halmos said. “Whether [KRAS inhibitors] are going to be [used as part of] a first-line combination [strategy] or will stay in the second-line setting [remains unknown].”

With this in mind, Sholl presented the final case of a 44-year-old woman with an 18 pack-year smoking history, multifocal lung involvement by TTF-1–positive adenocarcinoma, and KRAS G12C, KEAP1, and STK11 mutations. The patient had progressed on carboplatin/pemetrexed/pembrolizumab (Keytruda), docetaxel, and an experimental MEK inhibitor plus CDK4/6 inhibitor combination.

The patient enrolled on a clinical trial evaluating adagrasib (MRTX849), another KRAS G12C inhibitor. She derived a good response to the agent for 15 months until developing resistance, explained Sholl.

“The actionability of KRAS [mutations] doesn’t seem to depend on co-mutations or immune biomarker statuses. [We] can confidently use [sotorasib or, potentially, adagrasib] for [our] KRAS G12C–positive patients. [The agents] have slightly different toxicity profiles, so it will be nice to have 2 agents so we can tailor the right drug to the right patient,” Halmos added.

Despite the advances made with KRAS G12C inhibitors, resistance remains a challenge. In the 44-year-old patient, multiple acquired mutations, including a KRAS Y96C alteration, were observed upon repeat testing, Sholl said.

“It turns out that in studies that model alterations in different parts of the [KRAS] protein, alterations at this site can in fact interfere with the activity of G12C inhibitors,” said Sholl.

Moreover, a study published in the New England Journal of Medicine reported that putative mechanisms of resistance to KRAS G12C inhibitors were identified in 45% of patients with lung (n = 27), colorectal (n = 10), and appendiceal (n = 1) cancers who were treated with adagrasib. Of these patients, 18% had multiple coincident mechanisms.11

“Maybe this speaks to the evolution of multiple clones within the tumor as it is undergoing this type of stress,” hypothesized Sholl.

Understanding and overcoming acquired resistance is also an area of ongoing research with regard to osimertinib (Tagrisso) in patients with EGFR-mutated NSCLC, Halmos said. Emerging agents, such as the HER3-targeted antibody-drug conjugate (ADC) patritumab deruxtecan and the combination of amivantamab and lazertinib, have demonstrated efficacy in treating patients with osimertinib-resistant NSCLC.

As novel actionable targets, such as NRG1 fusions and ERBB2 mutations are emerging, concurrent tissue-based and liquid-based molecular testing is required to understand the heterogeneity of resistance mechanisms across the lung cancer field, Sholl concluded.


  1. Halmos B, Sholl LM. Novel targets and evolving treatment strategies in NSCLC (including ERBB2, Exon20, MET, EGFR). Presented at: 5th AnnualInternational Congress on Oncology & Pathology™: Towards Harmonization of Pathology and Oncology Standards; June 26, 2021. Virtual.
  2. FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. News release. FDA. May 8, 2020. Accessed June 29, 2021.
  3. Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of selpercatinib in RET fusion–positive non–small-cell lung cancer. N Engl J Med. 2020;383(9):813-824. doi:10.1056/NEJMoa2005653
  4. FDA approves pralsetinib for lung cancer with RET gene fusions. News release. FDA. September 4, 2020. Accessed June 29, 2021.
  5. Curigliano, G, Gainor JF, Griesinger F, et al. Safety and efficacy of pralsetinib in patients with advanced RET fusion-positive non-small cell lung cancer: update from the ARROW trial. J Clin Oncol. 2021;39(suppl 15):9089. doi:10.1200/JCCO.2021.39.15_suppl.9089[CS5] [JH6]
  6. Cheng ML, Milan MSD, Tamen RM, et al. Plasma cfDNA genotyping in hospitalized patients with suspected metastatic NSCLC. JCO Precision Oncology. 2021;5:726-732. doi:10.1200/PO.21.00029
  7. FDA grants accelerated approval to capmatinib for metastatic non-small cell lung cancer. News release. FDA. May 6, 2020. Accessed June 29, 2021.
  8. FDA grants accelerated approval to tepotinib for metastatic non-small cell lung cancer. News release. FDA. February 3, 2021. Accessed June 29, 2021.
  9. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. News release. FDA. May 28, 2021. Accessed June 29, 2021.
  10. Skoulidis F, Li BT, Govindan R, et al. Overall survival and exploratory subgroup analyses from the phase 2 CodeBreaK 100 trial evaluating sotorasib in pretreated KRAS p.G12C mutated non-small cell lung cancer. J Clin Oncol. 2021;39(suppl 15):9003. doi:10.1200/JCO.2021.39.15_suppl.9003
  11. Awad MM, Liu S, Rybkin II, et al. Acquired resistance to KRASG12C inhibition in cancer. N Engl J Med. 2021;384(25):2382-2393. doi:10.1056/NEJMoa2105281
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