An updated consensus on liquid biopsy to detect non-small cell lung cancer (NSCLC) use has been published by the International Association for the Study of Lung Cancer (IASLC).

The statement argues that liquid biopsy is now a favored method of molecular testing in various clinical settings and that it has demonstrated that it is effective in conjunction with tumor tissue testing.

 In addition, liquid biopsy offers unique opportunities such as serial monitoring and detection of minimal residual disease, according to the statement. Going forward, the IASLC expects a significant increase in the use of liquid biopsy.

The report discusses the inherent limitations of tumor tissue testing, which has traditionally been considered the gold standard for molecular analyses and argues that liquid biopsy approaches allow more varied methods of circulating analytes. According to the report, plasma circulating tumor DNA (ctDNA) represents the most widely studied and generally accepted alternative to tumor genotyping in solid tumors, including NSCLC.

“It is notable that the IASLC has taken the lead in detailing the current state of the art in this rapidly expanding field,” stated Gandara, MD, director of thoracic oncology, professor of medicine emeritus, in a news release. “Non-small cell lung cancer, in particular, is an ideal disease area for application of liquid biopsy due to the increasing availability of targeted therapies for this genomically complex malignancy. Liquid biopsy, and especially plasma ctDNA, can be used in many clinical settings where tissue is not applicable, such as the detection of minimal residual disease (MRD).”

The report builds upon a statement released by the IASLC in 2018 and was coauthored by a group of distinguished international lung cancer clinicians and experts.

In the report, the recommendations are as follows:

In clinical practice, ctDNA collection, sample handling and automated processing should be performed using standardized and clinically validated procedures to reduce operator variability and false-negative results.

Due to the growing number of guideline-recommended oncogene targets to be assessed in advanced NSCLC, testing of plasma ctDNA should be performed by a clinically-validated next-generation sequencing (NGS) platform rather than single gene PCR-based approaches, both in treatment-naïve patients and those associated with multiple mechanisms of acquired resistance to targeted agents. Where plasma NGS is not available due to technical and/or economic constraints, single gene or low multiplex-based approaches may represent appropriate alternatives. Use of limited PCR analysis for 

mutations as the initial step in molecular assessment, for example, remains highly relevant in areas of the world where the 

mutation rate is high. However, single gene testing should not be considered complete, and if negative, serial testing for additional actionable biomarkers must be pursued.

The benefit of tissue and plasma NGS is now established in several clinical practice settings. It is anticipated, due to broad-based coverage of requisite oncogenes, decreased turn-around times and emerging data on cost effectiveness, that in the near future NGS will become increasingly available worldwide. Implementation of a multidisciplinary MTB to assist clinicians in treatment decision-making is advisable, as described above.

Plasma ctDNA can now be considered a valid tool for genotyping of newly diagnosed patients with advanced NSCLC, and results are often complementary to tissue analysis. At the time of acquired resistance after tyrosine kinase inhibitor (TKI) therapy in an oncogene-driven NSCLC, initial use of ctDNA is preferred for determination of mechanisms of resistance ("plasma-first”), with repeat tissue biopsy if plasma ctDNA is uninformative. Due to ease of serial sampling and high patient acceptance, ctDNA is also emerging as the preferred method for real time monitoring.

In patients with oncogene-addicted NSCLC, liquid biopsy is emerging as not only complementary to tissue-based analysis but also acceptable as the initial approach (“plasma first”) for biomarker evaluation at the time of diagnosis, as well as for monitoring the efficacy of targeted therapies. Finally, a plasma-first approach is appropriate for identification of mechanisms of acquired resistance to targeted therapies in many clinical settings.

Indications for liquid biopsy in patients with non-oncogene addicted NSCLC are less well-defined at this time, although there are several promising areas of investigation. As noted above, tumor mutation burden is an emerging biomarker, pending completion of ongoing prospective randomized trials and refinement of methodology.

The 2021 World Conference on Lung Cancer, which will be held this upcoming September, will present a series of abstracts related to liquid biopsy methodologies and offer information regarding lung cancer screening, diagnoses, and therapeutic efficacy.

IASLC issues consensus updated report on liquid biopsies. IASLC. Press release. July 8, 2021.

Rolfo C, Mack P, Scagliotti GV, Aggarwal C, Arcila ME, Barlesi F, Bivona T, Diehn M, Dive C, Dziadziuszko R, Leighl N, Malapelle U, Mok T, Peled N, Raez LE, Sequist L, Sholl
L, Swanton C, Abbosh C, Tan D, Wakelee H, Wistuba I, Bunn R, Freeman-Daily J, Wynes M, Belani
C, Mitsudomi T, Gandara D, Liquid Biopsy for Advanced Non-Small Cell Lung Cancer: A Consensus Statement from The International Association for the Study of Lung Cancer (IASLC), Journal of Thoracic Oncology (2021), doi: https://doi.org/10.1016/j.jtho.2021.06.017.

Articles

The International Association for the Study of Lung Cancer (IASLC) has published an updated consensus on the use of liquid biopsy in screening non-small cell lung cancer (NSCLC).

Updated IASLC Report Calls Liquid Biopsy Preferred Method of Molecular Testing

Preliminary evidence from an ongoing phase 1/2a trial (NCT04263090)1 has shown that treatment with the novel combination of rigosertib and nivolumab (Opdivo) may be associated with potential anticancer activity in patients with advanced metastatic KRAS-mutated non-small cell lung cancer (NSCLC).

The maximum-tolerated dose (MTD) for the doublet has not yet been reached in the 3 cohorts that are being assessed in the dose-escalation phase of the trial. Notably, participants enrolled to the trial have previously received multiple lines of therapy and have progressed on various combinations of immune checkpoint inhibitors.

Investigators continue to enroll patients to the expansion phase of the trial, to examine the highest dose of oral rigosertib defined in the current protocol. Based on positive preliminary data, a protocol amendment is being prepared that will permit the assessment of increased rigosertib doses in combination with the full dose of nivolumab, as recommended in the product label.

“The preliminary results from the phase 1/2a trial are very encouraging and demonstrate the potential of rigosertib to address a critical unmet medical need by overcoming checkpoint inhibitor resistance in 

-mutated lung adenocarcinoma,” Mark S. Gelder, MD, chief medical officer of Onconova, stated in a press release. “The observation of preliminary evidence of efficacy in combination with acceptable safety of the doublet in this extremely challenging patient population provides a promising signal.”

The open-label phase 1/2a study enrolled patients aged 18 years or older who had a histologically or cytologically confirmed diagnosis of stage IV metastatic lung adenocarcinoma and progressed on or were intolerant of standard-of-care frontline treatment with PD-1 monotherapy or in combination with platinum-doublet chemotherapy.2

Patients also needed to have measurable disease per RECIST v1.1 criteria and investigator assessment, a life expectancy of at least 3 months, an ECOG performance status of 0 to 2, and acceptable organ function. They could not be receiving any other investigational drugs or have tumors that harbored an 

 translocation. Patients also could not have untreated central nervous system metastases or carcinomatosis meningitis.

The trial is comprised of 2 phases: the dose-escalation phase 1 portion and the dose-expansion phase 2a portion. Study participants are given oral rigosertib twice daily on days 1 through 21 and intravenous nivolumab at a fixed dose of 240 mg on days 1 and 15 of 28-day treatment cycles. Rigosertib is currently under examination at the following 3 dose levels: 280 mg twice daily, 560 mg in the morning and 280 mg in the evening, and 560 mg twice daily.

The primary end points of the trial are to establish the MTD, and the overall response rate achieved with the regimen. Key secondary end points include progression-free survival and overall survival.

Previously, rigosertib was examined as a single agent and in combination with immune checkpoint blockade in immunocompetent mouse models with 

Results showed that rigosertib was well tolerated when given at a dose of 300 mg/kg in mice. The agent resulted in approximately 50% inhibition of tumor growth as a single agent and approximately 70% when given in combination with a PD-1 agent and a CTLA-4 agent.

Tumor growth inhibition induced by rigosertib was found to be dependent on CD40 upregulation in melanoma cells followed by immunogenic cell death; this led to enriched dendritic cells and activated T cells in the tumor microenvironment. Moreover, tumor suppression initiated by the drug was partially reversed by either knockdown of CD40 expression in melanoma cells or depletion of CD8+ cytotoxic T cells.

Moreover, treatment with dabrafenib (Tafinlar) and trametinib (Mekinist) or with rigosertib increased the number of CD40+ SOX10+ melanoma cells in the tumors of patients with melanoma, as well as in patient-derived xenografts. A high expression level of CD40 was found to correlate with beneficial T-cell responses and improved survival in a TCGA dataset of patients with melanoma.

“The phase 1 study supports the preclinical observation in melanoma of the up-regulation of crucial cell surface molecules by rigosertib which may synergize with immune checkpoint blockade, as was recently published in 

, and strongly supports the continued clinical development of rigosertib/checkpoint inhibitor combination therapy,” Gelder added.

Preliminary data with the combination will be shared at the 3rd Annual RAS Targeted Drug Development Summit that is being held in September 2021. As the data mature, they will be presented at a future medical meeting.

“We are very pleased both with the safety and preliminary efficacy signal we have seen from the 

-mutated NSCLC trial to date, considering the multiple lines of therapy many of these patients have previously failed, including checkpoint inhibitors in various combinations,” Steven M. Fruchtman, MD, president, and chief executive officer of Onconova, added in the release. “We are supportive of the plan to expand dose-escalation of rigosertib to determine the optimal recommended phase 2 dose of the combination; and are eagerly anticipating results of important correlative science that is part of the trial.”

Onconova Therapeutics provides an update on the phase 1/2a trial of rigosertib-nivolumab combination in KRAS+ non-small cell lung cancer. News release. Onconova Therapeutics, Inc. June 28, 2021. Accessed July 6, 2021. https://bit.ly/2SSjJav

Rigosertib plus nivolumab for KRAS+ NSCLC patients who progressed on first-line treatment. ClinicalTrials.gov. Updated July 1, 2021. Accessed July 6, 2021. https://clinicaltrials.gov/ct2/show/NCT04263090

Yan C, Saleh N, Yang J, et al. Novel induction of CD40 expression by tumor cells with RAS/RAF/PI3K pathway inhibition augments response to checkpoint blockade. 

. 2021;20(1):85. doi:10.1186/s12943-021-01366-y

This article was originally published on OncLive as 

“Rigosertib/Nivolumab Combo Shows Early Potential in KRAS-Mutated NSCLC”

The preliminary results of an early-phase study of rigosertib combined with nivolumab for the treatment of advanced metastatic KRAS-mutated non-small cell lung cancer are scheduled to be presented at an upcoming medical conference. 

Early Study Results Show Novel Combo Therapy May Be Effective in Lung Cancer Subtype

The addition of neoadjuvant durvalumab (Imfinzi) to stereotactic body radiotherapy evoked major pathological responses compared with durvalumab alone in patients with early-stage non-small-cell lung cancer (NSCLC), according to results from a phase 2 trial.

In the single-center, open-label, randomized, controlled, phase 2 trial (NCT02904954), 16 out of 30 patients treated with neoadjuvant durvalumab following stereotactic body radiotherapy demonstrated significant pathological responses, including 8 patients who achieved a complete pathological response. In contrast, only 2 out of 30 patients in the durvalumab monotherapy group reported major pathological responses.

There were no dose reductions or interruptions reported within a cycle. Three patients (10%) in the neoadjuvant therapy group reported immune-related adverse events (AE). The second cycle of durvalumab for these patients was withheld as a response. These patients reported grade 3 hepatitis, grade 2 pancreatitis, and grade 3 fatigue and thrombocytopaenia.

Furthermore, 5 (17%) patients in the monotherapy group and 6 (20%) in the neoadjuvant therapy group reported grade 3 to 4 AEss, the most common being hyponatraemia and hyperlipasaeima.

No deaths, treatment-related or otherwise, were reported within the 30 days following surgery.

“In contrast to prevailing strategies, combining immunotherapy with stereotactic body radiotherapy might be associated with a more favorable safety profile and higher patient compliance than is currently reported using combinations with full-dose chemotherapy or chemoradiation,” explained lead study author Nasser K Altorki, MD, Department of Cardiothoracic Surgery, and colleagues. “Additionally, in our current trial, the median time to surgical resection was only 5.3 weeks, calculated from the day therapy was initiated, which is considerably shorter than the 12 to 16 weeks commonly required for preoperative therapy using chemotherapy or chemoradiotherapy, without higher toxicity or any apparent reduction in activity, as measured by major pathological response.”

The trial screened 96 patients from NewYork Presbyterian and Weill Cornell Medical Center, both in New York City, and enrolled 60 participants between January 5,2017, and September 15, 2020. Selected patients qualified through a biopsy-proven diagnosis within clinical stage I to IIIA disease deemed surgically resectable with curative intent. To be eligible for the trial, patients were required to have an ECOG performance score of either 0 or 1, be 18 years or older, and to have sufficient cardiopulmonary, hematological, or other end organ function.

The participants were randomized 1:1 to receive either neoadjuvant durvalumab plus stereotactic body radiotherapy (8 Gy × 3 fractions) or durvalumab monotherapy. All patients were slated to receive 2 cycles of durvalumab 3 weeks apart at a dose of 1.12 g by intravenous infusion over 60 minutes.

In both groups, 26 (87%) patients had already had their tumors surgically resected.

The presence of 10% of fewer viable tumor cells in the primary tumor was considered a major pathological response. A tumor without any viable tumor cells in the resected lung cancer specimen and all sampled regional lymph nodes was considered a complete pathological response.

Secondary end points, which include 2-year disease-free survival for the whole cohort, defined as the time from randomization to tumor recurrence or death, will be reported on at a later date. Data has not yet sufficiently matured.

Altorki noted the study was limited by its small sample size. However, the results have established the value for a larger trial sample, and an ongoing, slightly larger trial (n = 90) by the Swiss Group for Clinical Cancer Research (NCT 04245514) will study the effect of neoadjuvant durvalumab that various doses and fractionations of radiotherapy have on major pathological responses.

Furthermore, he added, it is important to note that neither major pathological response nor complete response directly equate to survival. As a result, Altor recommends that ongoing large, randomized trials should seek to validate the relationship between pathological response and survival by assessing neoadjuvant chemotherapy plus immune checkpoint blockade with major pathological response as the primary end point.

Finally, since there was no monotherapy group treated solely through the stereotactic body radiotherapy, researchers were left to wonder what the effect would have been from 8 Gy radiotherapy alone. Current published literature on radiotherapy is limited and there is very little about the effect in major pathological response, they wrote.

“In summary, our results show that a neoadjuvant regimen of durvalumab combined with stereotactic body radiotherapy given as 3 fractions of 8 Gy to the primary tumor is well tolerated, safe, and associated with a significant improvement in major pathological response,” wrote Altorki and colleagues. “Enhancement of the anti-tumor immune response mediated by this regimen could potentially be driven by enhanced recruitment and activation of antigen-presenting cells and increased expression of MHC molecules. Efforts are ongoing to initiate a similar trial with a larger sample size.”

Altorki NK, McGraw TE, Borczuk AC, et al. Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial. 

Out of 30 patients, 16 demonstrated significant pathological responses and 8 achieved a complete pathological response. 

Neoadjuvant Durvalumab Plus Radiotherapy Elicits Major Pathological Response in Early-Stage NSCLC

on the phase 2 CodeBreaK100 trial (NCT03600883) reported continued durable clinical benefit with Sotorasib (Lumakras) in the treatment of KRAS p.G12C-mutated non-small cell lung cancer (NSCLC).

At a median follow-up of 15.3 months, sotorasib was associated with a median overall survival (OS) of 12.5 months (95% CI, 10.0–not evaluable [NE]), a median progression-free survival (PFS) of 6.8 months (95% CI, 5.1-8.2), and an objective response rate (ORR) of 37.1% (95% CI, 28.6%-46.2%), which included 4 complete responses (CRs). The median duration of response (DOR) was 11.1 months (95% CI, 6.9–NE).

“This makes sotorasib the first KRAS G12C inhibitor to demonstrate an OS benefit in a registrational phase 2 clinical trial,” Ferdinandos Skoulidis, MD, PhD, lead study author and assistant professor in the Department of Thoracic and Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, said in a presentation during the meeting. “The efficacy of sotorasib was observed across various patient subgroups prespecified by baseline patient characteristics.”

Additionally, sotorasib had activity in molecularly-defined subgroups from exploratory analyses within the study, including in those with 

-mutant tumors remain poor, and novel therapies are needed for those who progress on frontline therapy with checkpoint inhibition alone or with platinum-doublet chemotherapy, Skoulidis said.

Sotorasib is a first-in-class, irreversible, and selective KRAS G12C inhibitor that has demonstrated durable clinical benefit in previously treated patients with 

 p.G12C-mutant NSCLC. Based on earlier findings of CodeBreaK, the FDA approved sotorasib in May 2021 as the first treatment for adult patients with non–small cell lung cancer whose tumors harbor 

 G12C mutations and who have received at least 1 prior systemic therapy.3

With the longer follow-up of the phase 2 CodeBreaK100 trial, investigators presented updated efficacy and safety data, including mature OS, with a data cutoff date of March 15, 2021. The findings also incorporated data from biomarker subgroups and baseline characteristics.

In the phase 2 CodeBreaK100 trial, investigators enrolled 126 patients with locally advanced or metastatic NSCLC with a 

 p.G12C mutation as assessed by central testing of tumor biopsies to receive sotorasib orally at 960 mg once daily until disease progression. Patients with stable brain metastases were permitted.

Patients underwent radiographic scans every 6 weeks up to week 48 and once every 12 weeks thereafter. The primary end point of the trial was ORR via RECIST v1.1 criteria by independent central review; key secondary end points include DOR, disease control rate (DCR), time to response, PFS, OS, and safety.

The median age was 63.5 years (range, 37-80), and 30.2% of patients had an ECOG performance status of 0. Most patients (92.9%) were current or former smokers, and patients either had 1 (42.9%), 2 (34.9%), or 3 (22.2%) prior lines of systemic therapy. The types of prior treatment were platinum-based chemotherapy (89.7%), PD-1/PD-L1 inhibition (91.3%), or platinum-based chemotherapy plus PD-1/PD-L1 inhibition (81.0%).

The 37.1% ORR was comprised of a 3.2% (n = 4) CR rate and a 33.9% (n = 42) partial response rate; the stable disease rate was 43.5% (n = 54), and 16.1% (n = 20) of patients had progressive disease. Four patients could not be evaluated or were missing scans. The DCR was 80.6% (95% CI, 72.6%-87.2%), and the median time to response was 1.35 months.

The clinical activity observed with sotorasib was consistent across prespecified subgroups, including age, ECOG performance status, number of prior lines of treatment, and prior PD-1/PD-L1–directed therapy alone or in combination with platinum-based chemotherapy. Notably, for patients who received a prior PD-1/PD-L1 inhibitor but not chemotherapy, the ORR was 69.2% (95% CI, 38.6%-90.9%) and the median OS was 17.7 months (95% CI, 11.7–NE).

Efficacy was also evaluated in exploratory analyses of molecularly defined subgroups. Skoulidis noted that the likelihood of response to sotorasib was independent of whether patients had a 

 p.G12C mutant allele frequency. Tumor mutational burden (TMB) was also not a predictive factor of response; the ORR was 40% in those with TMB-high disease (≥10 mutations/megabase [mb]) and 42% in patients with TMB-low disease (<10 mutations/mb). Moreover, responses occurred in patients with co-occurring mutations in 

“This is important because inactivating somatic mutations in 

 have been previously associated with worse clinical outcomes with standard-of-care systemic therapies, including chemoimmunotherapy, platinum-doublet chemotherapy, checkpoint inhibitor monotherapy, as well as chemotherapy with docetaxel,” Skoulidis said.

Additionally, investigators noted that in patients with 

 wild-type disease (n = 22), the ORR with sotorasib was 50%, the median PFS was 11.0 months, and the median OS was 15.3 months. The ORR was 23% in patients with 

-mutant disease; and 42% in patients with 

 wild-type disease. Also in these subgroups, the median PFS was 2.6 months, 5.5 months, and 6.8 months, respectively; the median OS was 4.8 months, 7.5 months, and not evaluable, respectively.

“Although, it should be noted that objective responses to sotorasib were observed in 20% of 

Regarding safety, mostly grade 1/2 treatment-related adverse events (TRAEs) were observed. All-grade TRAEs occurred in 69.8% of patients and grade 3 events in 19.8% of patients. The most common grade 3 TRAEs included diarrhea (4.0%), increased alanine aminotransferase (ALT; 6.3%), increased aspartate aminotransferase (AST; 5.6%), increased blood alkaline phosphatase (0.8%).

TRAEs that led to dose modifications occurred in 22.2% (n = 28) of patients, and treatment discontinuations due to TRAEs occurred in 7.1% (n = 9) of patients. The latter included drug-induced liver injury (n = 3), liver function test increase (n = 1), increased ALT (n = 2), increased AST (n = 2), increased alkaline phosphatase (n = 1), increased transaminases (n = 1), pneumonitis (n = 2), and dyspnea (n = 1).

The confirmatory phase 3 CodeBreak200 trial (NCT04303780), which is evaluating sotorasib vs docetaxel in patients with pretreated 

 p.G12C-mutated NSCLC, is currently ongoing.

1. 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 

p.G12C mutated non-small cell lung cancer. 

. 2021;39(suppl 15):9003. doi:10.1200/JCO.2021.39.15_suppl.9003

2. Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with 

. Published online June 4, 2021. doi:10.1056/NEJMoa2103695

3. FDA approves first targeted therapy for lung cancer mutation previously considered resistant to drug therapy. News release. FDA. May 28, 2021. Accessed June 4, 2021. 

This article was originally published on Cancer Network as 

“Sotorasib to Treat KRAS p.G12C+ NSCLC Produced Durable Clinical Benefit”

Sotorasib produced continued durable clinical benefit in patients with pretreated KRAS p.G12C+ NSCLC.  

Sotorasib Produces Durable Clinical Benefit in Treatment of KRAS p.G12C + NSCLC 

Retevmo (selpercatinib) demonstrated response improvements in previously treated patients with 

 fusion-positive non-small cell lung cancer (NSCLC), according to findings presented at the virtual 2021 ASCO Annual Meeting.

“However, results should be interpreted with caution, as a limitation of this analysis was that immediate prior response assessment was based on physician-reported best response in patients’ medical history and may not follow RECIST criteria,” the researchers said.

This study consisted of 218 evaluable patients (median age 61 years) who previously received platinum-based chemotherapy. The majority had an ECOG (or the measurement to describe a patient’s level of functioning in terms of ability to care for themselves, daily activity and physical ability; with zero being fully active and four being disabled) of 0/1, with an average of two (range: 1-15) prior systematic therapies, across 89 sites in 16 countries.

The primary endpoint of the study was objective response rate (or the rate of a measurable response to the treatment), with secondary endpoints of progression-free survival (time during and after treatment when the patient lives without disease progression), duration of response (or the length of time that a tumor continues to respond to treatment without the cancer growing or spreading) and safety.

The study compared each patient’s best overall response to their prior therapy to the response elicited from Retevmo.

The objective response rate with Retevmo was 57% which was “markedly higher,” the researchers wrote, than responses for prior treatment at 16%.

A total of 108 patients (50%) did not respond to prior therapy but did respond to Retevmo. There were 16 patients (7%) who responded to both Retevmo and prior therapy, 18 patients (8%) who responded to prior therapy but not Retevmo and 76 patients (35%) who did not respond to either.

Objective response rate was improved regardless of prior therapy, chemotherapy plus immune checkpoint inhibitor (57% versus 14%), single-agent immune checkpoint inhibitor (48% versus 3%) or chemotherapy (58% versus 15%).

Fewer patients had progressive disease with Retevmo best overall response (2%), compared with immediate prior therapy (28%). Median duration of response was also longer compared with prior therapy, with an average of 11.8 months versus 3.4 months.

“A global, randomized, phase 3 trial (LIBRETTO-431; NCT04194944) evaluating (Retevmo) compared with standard frontline therapy (Altima/ carboplatin with or without Keytruda) is ongoing,” the researchers concluded.

For more news on cancer updates, research and education, don’t forget to 

Previously treated patients with non-small cell lung cancer tended to have better responses with Retevmo than they did with prior treatments. 

Retevmo Shows Improvement for Previously Treated Patients With Non-Small Cell Lung Cancer 

Pralsetinib (Gavreto) elicited promising responses and tolerability in patients with 

 fusion-positive non-small cell lung cancer (NSCLC), including those who were not eligible for platinum-based therapy.

“These data are real important because it supports the importance of early biomarker testing for all patients with metastatic NSCLC prior to treatment initiation to inform optimal healthcare decisions,” said Giuseppe Curigliano, MD, PhD, associate professor of medical oncology at the University of Milano in Italy and head of the division of early drug development at the European Institute of Oncology in Italy, at the 2021 virtual ASCO Annual Meeting about updated data from the ARROW trial.

The phase 1/2 study was conducted at 84 sites in 13 countries. In particular, the safety population for this study included 233 patients with 

 fusion-positive NSCLC and 238 patients with other RET-altered solid tumors. In particular, 216 patients (median age, 60 years; 48% men) with 

fusion-positive NSCLC had measurable disease.

Originally patients who were treatment-naïve were not eligible, which was a requirement that was later removed by a protocol amendment. There were 25 patients who were enrolled after this eligibility revision (median age, 54 years; 44% men).

The study had a primary endpoint of objective response rate (ORR). Follow-up was conducted for a median of 17.1 months.

For the 216 patients who received pralsetinib and were 

 fusion-positive, the ORR was 69% (95%, CI, 62-75), DCR was 92% (95%, CI; 87-95), CBR was 77% (95%, CI; 71-82) and median DoR was 22.3 months (95%, CI; 15.1-not reached).

In the post-eligibility population with 25 patients, the ORR was 88% (95% CI, 69-98), CBR was 88% (95% CI, 69-98), DCR was 96% (95% CI, 80-100). In addition, median DoR and median PFS was not reached.

“The most important observation is that in the expansion cohort of real-world and first-line treatment of (non-small cell lung cancer) patients with 

fusion-positive tumor, the overall response rate was 88%, providing support for RET inhibitor as a first-line standard of care because the response rate was better in this population (with) respect to the previous eligibility criteria population,” Curigliano said.

The median duration of response in patients with prior platinum-based chemotherapy was 22.3 months (95% CI, 15.1-not reached). Curigliano added that it was too early to analyze data regarding the duration of response in treatment-naïve patients.

Overall, 26 patients (6%) out of 471 patients in the entire study discontinued treatment due to treatment-related adverse events. In all tumor types, 15% of patients had treatment-related neutropenia leading to treatment interruption whereas 14% had neutropenia from the treatment which resulted in a dose reduction. Less than 1% of patients discontinued treatment from treatment-related neutropenia.

“It means that pralsetinib was very well tolerated,” Curigliano said.

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. Presented at: 2021 ASCO Annual Meeting; June 4-8, 2021; Virtual. Abstract 9089.

Pralsetinib elicited promising responses and tolerability in patients with RET fusion-positive non-small cell lung cancer (NSCLC), including those who were not eligible for platinum-based therapy.  

 Pralsetinib Is Tolerable, Durable in RET Fusion+ NSCLC

The FDA approved sotorasib (Lumakras) for the treatment of patients with non-small cell lung cancer (NSCLC) whose tumor have a KRAS G12C mutation and have received 1 or more prior systemic therapy. The approval marks the first targeted therapy for KRAS-mutant tumors, which account for about 25% of mutations in NSCLC.

“KRAS mutations have long been considered resistant to drug therapy, representing a true unmet need for patients with certain types of cancer,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, 

The approval is based on findings from a clinical trial including 124 patients with locally advanced or metastatic KRAS G12C-mutant NSCLC whose disease progressed after treatment with a checkpoint inhibitor and/or platinum-based chemotherapy. Patients on sotorasib had a 36% objective response rate, and 58% of them had a duration of response that lasted 6 months or longer.

The FDA approved a 960 mg dose of the drug, and since it was granted an accelerated approval, the agency will conduct a post-marketing trial to determine if a lower dose has a similar clinical effect.

Common adverse events seen in patients taking sotorasib include musculoskeletal pain, nausea, fatigue, liver damage, and cough.

If a patient develops symptoms of interstitial lung disease, sotorasib should be withheld. If interstitial lung disease is confirmed, the drug should be stopped permanently. Additionally, if a patient develops liver damage, sotorasib should be withheld, dose-reduced, or permanently discontinued.

Patients should not take acid-reducing agents, drugs that induce or are substrates for certain liver enzymes, and drugs that are substrates of the P-glycoprotein while they are taking sotorasib.

“Today’s approval represents a significant step towards a future where more patients will have a personalized treatment approach,” Pazdur said

FDA. FDA Approves First Targeted Therapy for Lung Cancer Mutation Previously Considered Resistant to Drug Therapy. May 28, 2021. 

https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-lung-cancer-mutation-previously-considered-resistant-drug#:~:text=Today%2C%20the%20U.S.%20Food%20and,least%20one%20prior%20systemic%20therapy

Sotorasib is the first targeted therapy approved for KRAS-mutant non-small cell lung cancer. 

FDA Approves Sotorasib for KRAS G12-Mutant NSCLC 

Patients with oncogene-driven non–small cell lung cancer (NSCLC) stand to benefit from the availability of targeted therapy in the clinic, but also in clinical trials, explained Andrea Saltos, MD, making broad molecular testing all the more essential to lung cancer care.

“These are very effective new drugs that were not available a couple of years ago for mutations that may not have been considered standard to test for a couple of years ago. [The availability of these drugs] highlights the importance of broad genomic profiling for every patient with advanced NSCLC,” said Saltos. “It’s always important to know the full genetic makeup of your patient’s cancer, because there really are a lot of new targeted treatments that are being worked on beyond [those for mutations in], 

, and it’s really exciting to see that these drugs are effective in the populations that they’re targeted for.”

® during an Institutional Perspectives in Cancer webinar on lung cancer, Saltos, a medical oncologist and Clinical Research Medical Director in the Department of Thoracic Oncology at Moffitt Cancer Center, provided perspective on the use of targeted therapy across 

®: With regard to the ADAURA trial, is it necessary to wait to see an overall survival (OS) benefit with adjuvant osimertinib (Tagrisso) before you start recommending it to your patients with early-stage

: It’s a key first step to wait for the long-term data, but it’s always going to come down to a patient and physician discussion. As far as the risks and benefits go, it’s very true that OS is not necessarily always found to be significant in a study where [disease]-free survival [DFS] was significant. There are examples with other EGFR-targeted therapies, such as erlotinib [Tarceva], where that was true.

On the other hand, the hazard ratio [for DFS] is very striking. There’s also something to be said of having a markedly improved DFS. Some patients who progress may have brain metastases or very symptomatic events, so sometimes if the therapy can forestall progression, it may have some merits on its own in that context, especially if the therapy is tolerable.

That’s where the tolerability of osimertinib really comes into play. Certainly, there are patients who have a lot of adverse effects [AEs] with osimertinib, but there are some who don’t, and individualization of a plan and careful monitoring are going to be a key part of that anyway.

In a bigger context, when we’re designing these adjuvant therapy clinical trials, we know there’s a tradeoff between having a more readily available outcome for quick readout like DFS vs the gold standard of OS.

What research is being done to build off of the benefit achieved with osimertinib in the advanced

The big ones are the combination of osimertinib and chemotherapy and the combination of osimertinib with anti-VEGF therapy, both of which have some have some pretty good clinical backgrounds to support the hypothesis that those combinations might be of benefit to patients.

The FLAURA 2 study is looking at randomization of osimertinib with or without platinum-based chemotherapy in the first-line setting. Hopefully that trial will answer the question about the chemotherapy combination. As far as the combination in the RELAY trial, which was conducted with erlotinib plus the VEGF inhibitor ramucirumab [Cyramza], this was positive and led to the FDA approval of the combination. Where that exactly fits into first-line therapy compared with osimertinib is not completely clear.

We’re also running a clinical trial at Moffitt Cancer Center looking at combining ramucirumab with osimertinib, taking the next logical step. Hopefully, we’ll have information on whether those [combinations] work [soon].

Poziotinib showed encouraging data in patients with

-exon 20 mutant NSCLC in the ZENITH20 trial. What are your thoughts on the doses that are being tested?

The tolerability of EGFR TKIs has been kind of a concern, especially in the early days with some of the earlier agents that had more wild-type EGFR inhibition. Some of those same toxicities are emerging with drugs like poziotinib. A lot of clinical experience with these agents and knowing what supportive care to institute and when can maximize the ability to tolerate the drug for many patients. Early institution of things like topical steroids, topical antibiotics, or oral antibiotics for dermatologic toxicities [can help]. I even often institute things like oral non-absorbable steroids, such as budesonide, for patients who have severe diarrhea. There are a lot of different tricks that can help.

 exon 20 mutations, historically, have been very difficult to target, but there are a few drugs [in development]. There’s also amivantamab, which is a bispecific antibody targeting 

fusions, how do the data seen with pralsetinib (Gavreto) and selpercatinib (Retevmo) stack up against the data with next-generation EGFR and ALK inhibitors?

 fusions are proving to be like a true driver mutation that is highly targetable, much in the same way of 

. The clinical benefit rates and response rates to both of these drugs, from the LIBRETTO[-001] and ARROW studies, are phenomenal. Patients who had no prior therapy on the selpercatinib trial had an 85% response rate, and only 3% of patients had confirmed progression of disease on the drug. That’s pretty much in line with what we see with the ALK and EGFR next-generation TKIs. It’s a very similar story with pralsetinib. The treatment-naïve patients had about a 75% response rate, but these are small trials.

It’s difficult to do cross-trial comparison, but clearly, most of these drugs are highly effective and fairly well tolerated. The incidence of grade 3 toxicity with both of these drugs is very acceptable. With both drugs, a majority of patients with central nervous system (CNS) metastases had a significant response, which means that patients with asymptomatic brain metastases, who have historically been treated with whole brain radiation, can maybe be spared that [approach] up front, which can be very meaningful for quality of life.

amplification, how have capmatinib (Tabrecta) and tepotinib (Tepmetko) affected the paradigm? Where do you see research headed?

 amplification is its own entity in lung cancer, and sometimes it goes hand in hand with exon 14 skipping, but clearly the patients who are more sensitive to these drugs are the ones who have the exon 14 skipping mutations.

The response rates are not quite as high as what we see with the EGFR, ALK, and RET inhibitors, but still a majority of patients have a response to both of these drugs in the frontline setting, somewhere in the 50% to 60% range. Both agents are quite well tolerated and also have good CNS activity.

We know how to target patients who have these high-level 

 amplifications. Both of these drugs do show activity in that amplification setting. There certainly are some patients who have 

 amplification, independent of any driver mutations, but there are also some patients with EGFR-mutant lung cancer who progress on osimertinib. It’s a very common scenario where they become resistant to osimertinib through 

 amplification. Many clinical trials are looking at these drugs in combination with EGFR inhibitors for those patients, as well as those who have 

The second area of important research will be novel drugs to target 

 and what the resistance mechanisms might end up being for patients who progress on these drugs. Some patients may progress through resistance mutations within the 

 gene, but a lot of patients may progress through alternate pathways, which is what we see with the other driver mutations in NSCLC. Being able to characterize and develop more targeted strategies beyond the first line will be important, but for now, these 2 new drug approvals represent a nice milestone for those patients.

This article was originally published on OncLive as, "

Targeted Therapies Continue to Make Strides in Oncogene-Driven NSCLC

Molecular testing is more essential than ever, thanks to the targeted therapy options for non-small cell lung cancer.

Targeted Therapies Move Forward in Oncogene-Driven Lung Cancer

The FDA approved amivantamab-vmjw (Rybrevant) for the treatment of adults with non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 20 insertion mutations. This is the first targeted therapy approved for this subset of lung cancers.

The agency also approved a companion diagnostic — Guardant360 CDx.

“Advances in precision oncology continue to facilitate drug development, allowing diseases like lung cancer to be subset into biomarker-defined populations appropriate for targeted therapies,” said Julia Beaver, MD, chief of medical oncology in the FDA’s Oncology Center of Excellence and acting deputy director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, in a statement.

The approval was based on findings from a clinical trial that included 81 patients with NSCLC with EGFR exon 20 insertion mutations whose disease progressed on or after receiving platinum-based chemotherapy. The overall response rate in patients who received amivantamab-vmjw was 40%, and average duration of response was 11.1 months. Sixty-three percent of patients had a response that lasted 6 months or longer.

Common adverse events of the targeted agent include: rash, skin infections around the finger and toenails, infusion-related reactions, muscle and joint pain, nausea, fatigue, shortness of breath, swelling in the lower legs or hand or face, mouth sores, constipation, cough, vomiting, and changes in some blood tests.

If patients start to show symptoms of interstitial lung disease, treatment with amivantamab-vmjw should be stopped; if interstitial lung disease is confirmed, treatment with the drug should be discontinued permanently.

Nurses should also talk to patients about sun exposure, which should be limited for 2 months after treatment with amivantamab-vmjw, as well as the possibility of vision problems occurring. Before prescribing the drug, clinicians should be sure that women are not pregnant.

“With today’s approval, for the first time, patients with non-small cell lung cancer with EGFR exon 20 insertion mutations will have a targeted treatment option,” Beaver said.

FDA. FDA Approves First Targeted Therapy for Subset of Non-Small Cell Lung Cancer. May 21, 2021. https://content.govdelivery.com/accounts/USFDA/bulletins/2da97ee

This is the first targeted therapy regimen approved for this patient population. 

FDA Approves Amivantamab-vmjw for EGFR Exon 20-Mutant NSCLC

A biologics license application (BLA) for sintilimab injection plus pemetrexed and platinum-based chemotherapy for the frontline treatment of patients with nonsquamous non–small cell lung cancer (NSCLC) has been accepted for FDA review, according to an announcement from Innovent Biologics, Inc.1

The application, which was submitted to the regulatory agency in March 2021, was based on data from the phase 3 ORIENT-11 trial (NCT03607539), which demonstrated that the regimen significantly improved progression-free survival vs chemotherapy alone in the frontline treatment of patients with locally advanced or metastatic nonsquamous NSCLC.2

At a median follow-up of 8.9 months, the median PFS with sintilimab was 8.9 months (95% CI, 7.1-11.3) per an independent radiologic review committee (IRRC) vs 5.0 months (95% CI, 4.8-6.2) with chemotherapy alone; this translated to an estimated 52% reduction in the risk of disease progression or death (HR, 0.482; 95% CI, 0.362-0.643; 

Under the Prescription Drug User Fee Act, the FDA is slated to make a decision on the BLA in March 2022. The regulatory agency did not identify any potential review issues in its acceptance letter, and it will be holding an Advisory Committee meeting to further discuss the application.

“The acceptance of this application – the first for sintilimab in the United States and outside of China – is an important milestone in Innovent’s global commercialization strategy and in our collaboration with Lilly,” Yongjun Liu, MD, PhD, president of Innovent, stated in a press release. “We look forward to working closely with the FDA to potentially bring this sintilimab/pemetrexed/platinum chemotherapy combination as a treatment option in the United States, following the regimen’s regulatory approval in China earlier this year.”

phase 3 ORIENT-11 study examined the safety and efficacy of sintilimab in combination with pemetrexed and platinum-based chemotherapy

A biologics license application for sintilimab injection plus pemetrexed and platinum-based chemotherapy for the frontline treatment of patients with nonsquamous non–small cell lung cancer has been accepted for FDA review.

Lung Cancer