Targeted therapy paradigm grows in NSCLC, as overcoming resistance is the next hurdle
“We need to be able to better use molecular tests, to identify our patients, [and] don’t leave any gene blocked… Biomarker tests are here [to stay] in so many different contexts. We need to stay sophisticated and get this problem under control, ”said Balazs Halmos, MD, MS, director of thoracic oncology and clinical cancer genomics at Montefiore Medical Center.
In a presentation to 5th annual International Congress on Oncology & Pathology ™, a program led by Physician’s Education Resource®, Halmos and Co-Chair Lynette M. Sholl, MD, 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 the 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 therapies.
RET Alterations in advanced NSCLC
On May 8, 2020, the FDA granted fast-track 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 the results of the phase 1/2 trial LIBRETTO-001 (NCT03157128), in which selpercatinib induced an overall response rate (ORR) of 64% in 105 patients with RET Fusion-positive NSCLC who had received previous platinum-based chemotherapy and 84% in 39 patients with treatment-naïve disease.3
Shortly after approval and at the height of the COVID-19 pandemic, a 54-year-old woman was diagnosed with bronchoscopically confirmed extensive lung adenocarcinoma and leptomeningeal disease, explained Halmos, who presented the first case of the discussion. She was a non-smoker and there was no more tissue available for the test. Circulating tumor DNA (ctDNA) was therefore sent for testing. The test gave the patient ‘life-changing results’ and revealed a RET merger, said Halmos.
The patient received selpercatinib and achieved 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 Updated data from the phase 1/2 ARROW trial (NCT03037385), which was presented at the ASCO annual meeting in 2021, demonstrated an ORR of 69% with pralsetinib in 216 patients with RET Fusion-positive NSCLC.5
Clinical scenarios like this underscore the importance of molecular testing for patients with NSCLC, Halmos said. In particular, as tissue-based testing remains the gold standard, it is essential to capitalize on the available tissue samples.
Conventional smear preparations, although not actively used in molecular testing, could offer an alternative resource to liquid cytology preparation “even though we are constantly being told that we can only take a tissue sample. or maybe a cell block, ”Sholl said.
Coming back to the case, the 54-year-old patient had to be hospitalized because the burden of her illness was great. However, molecular testing is typically done on an outpatient basis, posing a challenge for inpatients who might be eligible for targeted therapy, Sholl explained.
A study published in JCO Precision Oncology demonstrated that next-generation sequencing (NGS) of cell-free DNA (cfDNA) prior to pathologic diagnosis in hospitalized patients with suspected metastatic NSCLC resulted in reduced genotyping time compared to standard ambulatory workflows .6
“[We can] really reduce the window from, say, 3 weeks between the time of diagnosis and the molecular results to 3 days… when [we] are able to use cell-free assays in these hospital settings, ”Sholl said.
Notably, in patients with central nervous system involvement, such as the 54-year-old woman, cerebrospinal fluid (CSF) offers a potential molecular testing strategy, Sholl said. By extracting CSF, which harbors a high level of concentrated cfDNA, and running a standard molecular gene panel, cfDNA results can be obtained in cases where tissue is not available.
MEETex14 Skip mutations in locally advanced NSCLC
Sholl presented another case of a 47-year-old woman who never smoked who presented with pleuritic chest pain with extension of the chest wall and a history of PIK3CA Mutant E545K adenocarcinoma. Molecular profiling of the chest wall biopsy, which was conducted to understand the relationship to the primary tumor and inform potential targeted therapies, revealed a MEETex14 skipping the mutation and a PIK3CA Mutation E542K.
Historically, crizotinib (Xalkori) would have been the standard treatment approach, Halmos said. However, the recently approved agents by the FDA, capmatinib (Tabrecta) and tepotinib (Tepmetko) are now available for use in patients with MEETex14 – Corrupted NSCLC.7.8
Both agents have demonstrated good durability, tolerability and [central nervous system] penetrance, therefore “[hitting] all the strengths for a good targeted agent, ”said Halmos.
Notably, in this case, curative treatment could have been considered over targeted single-agent therapy, added Halmos. Systemic treatment could shrink the tumor to allow for improved surgical resection or provide a smaller area to irradiate.
“[This case shows us] that access to this molecular data goes beyond just reading the report we receive from any company. If we have a difficult case, communication is the key, ”said Halmos.
KRAS G12C mutations and resistance mechanisms in NSCLC
KRAS alterations have historically been difficult to target in the field of oncology, said Halmos. 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 trial results demonstrated that sotorasib induced an ORR of 37.1% in patients with KRAS G12C mutant NSCLC that had progressed after treatment with immunotherapy and / or chemotherapy.ten
“[The approval of sotorasib] certainly warrants [molecular] tests, ”Halmos said. “Whether [KRAS inhibitors] will be [used as part of] a first line suit [strategy] or will stay in the second line setting [remains unknown]. “
With this in mind, Sholl presented the latest case of a 44-year-old woman with an 18 pack-year smoking history, multifocal lung involvement with TTF-1-positive adenocarcinoma, and KRAS G12C, KEAP1, and STK11 mutations. The patient had progressed on carboplatin / pemetrexed / pembrolizumab (Keytruda), docetaxel and an experimental combination of MEK inhibitor and CDK4 / 6 inhibitor.
The patient participated in a clinical trial evaluating adagrasib (MRTX849), another KRAS G12C inhibitor. She had a good response to the agent for 15 months until she developed resistance, Sholl explained.
“The capacity for action of KRAS [mutations] does not appear to depend on co-mutations or immune biomarker status. [We] can use with confidence [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 that we can match the right drug for the right patient, ”added Halmos.
Despite the advances made with KRAS G12C inhibitors, resistance remains a challenge. In the 44-year-old patient, multiple acquired mutations, including one KRAS Y96C alteration was seen with repeated testing, Sholl said.
“It turns out that in studies that model alterations in different parts of the [KRAS] protein, alterations at this site can actually interfere with the activity of G12C inhibitors, ”Sholl said.
In addition, 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 appendicular (n = 1) cancer treated with adagrasib. Of these patients, 18% had multiple coincident mechanisms.11
“Maybe it’s talking about the evolution of several clones within the tumor as she goes through this kind of stress,” Sholl speculated.
Understanding and overcoming acquired resistance is also an area of ongoing research regarding osimertinib (Tagrisso) in patients with EGFR– NSCLC transferred, Halmos said. Emerging agents, such as the antibody-drug conjugate (ADC) patritumab deruxtecan targeting HER3 and the combination of amivantamab and lazertinib, have been shown to be effective in the treatment of patients with osimertinib-resistant NSCLC.
As new actionable targets, such as NRG1 mergers and ERBB2 as mutations emerge, simultaneous tissue and fluid-based molecular tests are needed to understand the heterogeneity of resistance mechanisms in lung cancer, Sholl concluded.
- Halmos B, Sholl LM. New targets and evolving treatment strategies in the NSCLC (including ERBB2, Exon20, MET, EGFR). Presented at: 5th Annual International Congress on Oncology and Pathology ™: Towards Harmonization of Pathology and Oncology Standards; June 26, 2021. Virtual.
- The FDA approves selpercatinib for lung and thyroid cancers with mutations or fusions in the RET gene. Press release. FDA. May 8, 2020. Accessed June 29, 2021. https://bit.ly/3Ae5224.
- 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
- The FDA approves pralsetinib for lung cancer with RET gene fusions. Press release. FDA. September 4, 2020. Accessed June 29, 2021. https://bit.ly/361H24s.
- Curigliano, G, Gainor JF, Griesinger F, et al. Safety and efficacy of pralsetinib in patients with 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]
- Cheng ML, Milan MSD, Tamen RM et al. Plasma genotyping of cfDNA in hospitalized patients with suspected metastatic NSCLC. JCO Precision Oncology. 2021; 5: 726-732. doi: 10.1200 / PO.21.00029
- The FDA grants fast-track approval to capmatinib for metastatic non-small cell lung cancer. Press release. FDA. May 6, 2020. Accessed June 29, 2021. https://bit.ly/3h4sxmX.
- FDA grants fast-track approval to tepotinib for metastatic non-small cell lung cancer. Press release. FDA. February 3, 2021. Accessed June 29, 2021. https://bit.ly/3hoWLjA.
- FDA grants fast-track approval to sotorasib for KRAS G12C-mutated NSCLC. Press release. FDA. May 28, 2021. Accessed June 29, 2021. https://bit.ly/3jqh0Qk.
- Skoulidis F, Li BT, Govindan R, et al. Overall survival and exploratory subgroup analyzes of the Phase 2 CodeBreaK 100 trial evaluating sotorasib in pretreated patients 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
- Awad MM, Liu S, Rybkin II et al. Acquired resistance to inhibition of KRASG12C in cancer. N English J Med. 2021; 384 (25): 2382-2393. doi: 10.1056 / NEJMoa2105281