The FDA has approved mobocertinib (Exkivity) for the 

indication of adult patients with locally advanced or metastatic non-small cell lung cancer

 (NSCLC) whose disease harbors an epidermal growth factor receptor (EGFR) exon 20 insertion mutation as detected by an FDA-approved test, either following or beyond platinum-based chemotherapy.

This first-in-class, oral tyrosine kinase inhibitor (TKI) is the first approved oral therapy engineered to target EGFR exon 20 insertion mutations, according to Takeda Pharmaceutical Company Limited, the manufacturer of the small-molecule TKI.

“EGFR Exon20 insertion+ NSCLC is an underserved cancer that we have been unable to target effectively with traditional EGFR TKIs,” said Pasi A. Jänne, MD, PhD, Dana Farber Cancer Institute, in a press release. “The approval of EXKIVITY (mobocertinib) marks another important step forward that provides physicians and their patients with a new targeted oral therapy specifically designed for this patient population that has shown clinically meaningful and sustained responses.”

The regulatory decision is based on findings from the phase 1/2 trial of Exkivity. In the trial, 114 patients with EGFR Exon20 insertions who had been previously treated with platinum-based therapy received mobocertinib at a 160-mg dosage. Findings revealed an overall response rate (ORR) of 28% through an independent review committee (IRC) and 35% through investigator analysis. The median duration of response (DOR) was 17.5 months. The median overall survival (OS) was 24 months, and the median progression-free survival (PFS) was 7.3 months. DOR, OS, and PFS were all determined by IRC.

Notable adverse events from the study drug included diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. Patients and providers should be aware that there is a risk of interstitial lung disease/pneumonitis, cardiac toxicity, and diarrhea associated with the drug.

“Patients with EGFR Exon20 insertion+ NSCLC have historically faced a unique set of challenges living with a very rare lung cancer that is not only underdiagnosed, but also lacking targeted treatment options that can improve response rates,” added Marcia Horn, executive director, Exon 20 Group at ICAN, International Cancer Advocacy Network. “As a patient advocate working with EGFR Exon20 insertion+ NSCLC patients and their families every day for nearly five years, I am thrilled to witness continued progress in the fight against this devastating disease and am grateful for the patients, families, healthcare professionals and scientists across the globe who contributed to the approval of this promising targeted therapy.”

A confirmatory trial will determine continued approval for the indication.

Takeda’s Exkivity (mobocertinib) approved by US FDA as the first oral therapy specifically designed for patients with EGFR Exon20 insertion _NSCLC. Takeda. News release. Accessed September 15, 2021. https://www.businesswire.com/news/home/20210915006101/en/Takeda%E2%80%99s-EXKIVITY%E2%84%A2-mobocertinib-Approved-by-U.S.-FDA-as-the-First-Oral-Therapy-Specifically-Designed-for-Patients-with-EGFR-Exon20-Insertion-NSCLC

Articles

The FDA has green lit mobocertinib for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer with an EGFR exon 20 insertion mutation. 



FDA Approves Mobocertinib for NSCLC with EGFR Exon 20 Insertion Mutations

Treating patients with resectable pleural mesothelioma with neoadjuvant cisplatin-pemetrexed plus atezolizumab (Tecentriq), followed by maintenance atezolizumab may be safe and effective, according to an updated analysis of the ongoing S1619 trial presented at the 2021 IASLC World Conference on Lung Cancer.

“When we speak about mesothelioma that is potentially surgically resectable, that is the patient population that we sort of consider potentially curable, although we know that recurrences occur,” explained Boris Sepesi, MD, The University of Texas MD Anderson Cancer Center. “The median survival in patients who undergo multimodality therapy that includes surgery range in different studies between 17 and 25 months… The aim of this study was really to test chemotherapy plus immunotherapy in surgically resectable mesothelioma based on the fact that these are occasionally immunogenic tumors that express PDL1 expression, which is associated with worse outcomes.”

The study sought to assess whether adding anti-PD-L1 inhibitors to neoadjuvant cisplatin-pemetrexed, followed by maintenance immunotherapy after surgical resection and adjuvant radiation would enhance T-cell activation against microscopic disease and potentially increase overall survival (OS) in patients with malignant pleural mesothelioma.

Overall, 21 patients successfully completed neoadjuvant therapy, although 7 were unable to proceed to surgical resection. Of those 7, 2 patients reported severe toxicity, 4 experienced disease progression, and 1 death occurred due to non-immune related renal and respiratory failure.

There were 18 patients with stable disease or partial response who were able to receive surgical resection, and 16 patients registered to receive maintenance atezolizumab for 1 year. Thus far, median progression-free survival is 18 months and OS has not been reached.

Participants were evaluable if they had received at least 2 cycles of the triplet neoadjuvant therapy, were chemo-naïve, had mesothelioma, and extended surgical staging. A total of 28 patients were screened between November 2017 and May 2020 with the intention of obtaining 24 eligible patients.

Patients were then administered the triple-combination regimen with the following dosage: 75 mg/m2 cisplatin, 500 mg/m2 pemetrexed, and 1200 mg IV atezolizumab every 3 weeks. As long as patients did not experience disease progression, they continued to resectable surgery. Following surgery, they were to be treated with 1 year of maintenance atezolizumab.

Within this pool of potential participants, 25 received at least 2 cycles of neoadjuvant cisplatin-pemetrexed-atezolizumab.

The median age of participants was 68 years. The majority of participants were Caucasian, and the patient pool was predominantly male. Four patients planned on receiving

extrapleural pneumonectomy (EPP) surgery, while 24 planned on receiving pleurectomy and decortication surgery (P/D).

The primary end point of the trial was to assess the safety and tolerability profiles, as well as better understand the feasibility, of 

neoadjuvant cisplatin-pemetrexed-atezolizumab treatment followed by surgery and maintenance atezolizumab. For the treatment to be considered safe or tolerable, there would be no reported grade 4 or 5 immune-related adverse events (irAEs). To be considered feasible, 75% of patients (18/24) needed to complete at least 1 dose of maintenance therapy.

The final analyses will separately assess patients who received EPP surgery and those who received P/D surgery for their resectable operation. Of the 18 that successfully received resection surgery, 17 received P/D and 1 received EPP. So far, 16 patients have registered to receive maintenance atezolizumab for 1 year. There are still 3 patients undergoing treatment with maintenance atelozimab therapy.

Investigators concluded that the triplet combination appeared to be reasonably tolerated in the patient population. There was only 1 patient who reported grade 4 or 5 AEs. Notably, that patient did experience multiple grade 4 AEs and 1 grade 5 AE. That patient experienced severe acute renal injury, sepsis, pneumonitis, and respiratory failure.

The most common neoadjuvant therapy-related AEs were nausea (n = 20), fatigue (n = 15), neutropenia (n = 11), anemia (n = 12), anorexia (n = 11), and vomiting (n = 7). Researchers also observed cases of hyponatremia (n = 5), creatinine increase (n = 6), constipation (n = 7), dysgeusia (n = 5), and infusion-related reactions (n = 3).

“These are some preliminary survival results which at this point seem rather encouraging although the median follow up is not the same as in some of the previous trials,” said Sepesi. “Some of these results are comparable to, [or] perhaps, slightly better to historical cohorts, but we will have to complete the trial, and complete the adequate follow-up to be able to make any conclusions from this regimen.”

“As always with mesothelioma, this trial highlights the challenging nature of the new adjuvant therapy, because of the heterogeneity of the disease, as well as how patients react as well as the difficult and complex surgical therapy,” he concluded. “However, I think this is a step forward in terms of complex treatment of mesothelioma.”

While Sepesi chose to refrain from speculating on the benefit of adding atezolizumab to the regimen, in a post-presentation discussion, he noted that future research will also need to look at patients based on nodal status (N0 vs N+) since those outcomes are different in surgically managed mesothelioma.

There are still 3 patients undergoing the therapy in this trial.

Tsao A, Qian L, Cetnar J, et al. A trial of neoadjuvant cisplatin-pemetrexed with atezolizumab combination and maintenance for resectable pleural mesothelioma. Presented at: 2021 World Conference on Lung Cancer; September 8-14, 2021; Virtual. Absract OA13.01

Updates from the ongoing S1619 trial suggest that a triplet combination regimen of neoadjuvant cisplatin, pemetrexed, and atezolizumab is effective and tolerable in the treatment of patients with resectable pleural mesothelioma. 

Neoadjuvant Triplet Regimen Safe, Effective in Patients With Resectable Mesothelioma

Flexible patient-focused approaches may increase clinical trial accessibility and enrollment in international lung cancer clinical trials beyond the COVID-19 pandemic, shared Matthew P. Smeltzer, PhD, at a virtual press briefing during the International Association for the Study of Lung Cancer (IASLC) 2021 World Conference on Lung Cancer.

Findings, which evaluated international lung cancer clinical trial enrollment before and throughout the pandemic, showed a derived benefit from flexibility in “place” and “time” to increase trial participation.

More specifically, trial sites reported that the most effective strategies to mitigate COVID–19-related challenges included telehealth visits, remote diagnostics, remote patient-reported symptoms, and remote consenting alternatives to address issues associated with trial “place.” To achieve flexibility in “time,” the findings suggested allowing delayed assessments and visits, as well as IRB changes.

“Overall, a more flexible approach, [and] removing unnecessary barriers may improve enrollment and access to clinical trials, even beyond the pandemic,” shared Smeltzer, an associate professor of epidemiology and biostatistics at the University of Memphis.

The study looked at the enrollment data from 173 clinical trial sites and 171 trials, across 45 countries. Data assessment included enrollment numbers from before the pandemic, in 2019, and continued across 2020 and 2021.

Significant disparities in enrollment were observed between 2019 and 2020. The average number of monthly trial enrollment shifted from 3.2 to 2.5 between April 2019 to April 2020. Similar changes were observed in May (3.4 to 1.8), June (3.1 to 1.5), July (3.2 to 1.7), and August (3.0 to 2.0).

The investigation considered results from a data collection survey which evaluated aggregate monthly enrollment for international lung cancer trials between 2019 to 2021, as well as from an action survey, which assessed the impact of COVID-19 on the conduct of clinical trials and identified mitigation strategies used.

“So, where the [changes] are the most discrepant was at the beginning of the pandemic and April to August. But we see, by September to December, the gap starts to close quite a bit,” explained Smeltzer. “And it looks like, relative to 2019, monthly 2020 enrollment started to rebound despite the drastic increase and total COVID-19 cases diagnosed each month across the world.”

Researchers then put together a survey to better understand how the pandemic specifically impacted the trial sites.

The surveys found that the most frequent site challenges included fewer eligible patients (67%), protocol compliance (61%), suspension of trials (60%), research staff availability (48%), and institutional closures (39%).

“Many trials were suspended,” Smeltzer summarized. “And so that was a challenge. Availability of research staff was [also] a major challenge, and institutional closure. These are all challenges that were sort of at the institutional level.”

The surveys also gained insight into the concerns and challenges faced by patients themselves. Sixty-three percent of patients reported that a willingness to visit trial sites was a challenge to participation. An ability to travel accounted for 60%, whereas access to trial site was reported to be a challenge by 52%. Forty percent of patients shared that an exposure-related quarantine impeded on their ability to participate in a trial, while 26% shared that a COVID-19 infection prevented their participation.

In addition, fear of COVID-19 infection (83%), travel restrictions (47%), securing transportation (38%), and lab-radiology access (14%) made up the bulk of concerns patients had in relation to lung cancer clinical trials between 2020 and 2021.

To respond to these challenges and concerns, trial sites implemented a variety of mitigation strategies. Besides the most effective strategies mentioned above, common mitigation strategies included modified monitoring requirements (44%), telehealth visits (43%), labs at non-study facilities (27%), modified required visits (25%), and mail-order medications (24%).

“We asked them ‘What were the most frequent mitigation strategies that they used? What did they do to try to improve the conduct of the trials both in terms of enrollment and compliance?’’’ said Smeltzer. “Modifying monitoring requirements was the No.1 response followed closely by telehealth visits.”

Other popular strategies involved radiology at non-study facilities (20%), altered trial schedules (19%), electronic consent processes (10%), and an altered consent process (7%).

“We think there's some good lessons learned here,” said Smeltzer. He concluded by sharing that the results of this trial provide a good base assessment into the rigor needed to maintain the value and quality of clinical trials while also allowing flexibility to ensure that trials are feasible, accessible, and patient friendly. Furthermore, researchers are optimistic that the results of this assessment will continue to be beneficial beyond the COVID-19 pandemic.

Smeltzer MP, Bunn PA, Clark R, et al. Study of the impacts of COVID-19 on international lung cancer clinical trials. Presented at: 2021 World Conference on Lung Cancer; September 8-14, 2021. Virtual. PL02.09

International lung cancer clinical trial sites reported that flexibilities in time and place were effective strategies to mitigate COVID–19-related patient concerns and to increase participation. 

Modified Monitoring Requirements, Telehealth Increase Lung Cancer Clinical Trial Enrollment in COVID-19 Era

Mobocertinib (formerly TAK-788) induced improved patient-reported outcomes (PROs) in patients with previously treated non-small-cell lung cancer (NSCLC) harboring 

 exon 20 insertion mutations, according to a poster presentation of the EXCLAIM extension cohort made available as part of the 2021 World Conference on Lung Cancer.

In patients considered to have difficult-to-treat disease who were treated as part of a phase 1/2 trial (NCT02716116), superior PROs were evidenced by better core NSCLC symptoms within 2 months of treatment initiation which was maintained for the duration of therapy and was consistent with clinical activity.

“Overall health-related quality of life was maintained during therapy, despite the occurrence of adverse events such as rash and gastrointestinal-related symptoms,” Maria Rosario Garcia Campelo, MD, of the University Hospital A Coruña in Spain, said during a presentation of the data.

The objective of the current analysis was to evaluate PROs associated with daily oral mobocertinib at 160 mg daily in the discussed patient population. PRO tools used included the European Organisation for Research and Treatment of Cancer Core Quality-of-Life Questionnaire (EORTC QLQ-C30) for cancer-related functions and symptoms, the European Organisation for Research and Treatment of Cancer Core Quality-of-Life Questionnaire lung cancer module (EORTC QLQ-LC13) for lung cancer–specific symptoms, the EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) and visual analogue scale (VAS) for general health-related quality of life, and selected items from Patient-Reported Outcomes–Common Terminology Criteria for Adverse Events Questionnaire (PRO-CTCAE) to assess symptomatic toxicity in these patients. Questionnaires were given prior to clinical evaluation or procedures at baseline, at select visits, and at 30 days following the last dose of treatment.

Compliance rates were above 80% for all instruments and were often above 90% for most cycles. At the data cutoff of November 1, 2020, 25 out of 96 patients (26%) remained on treatment with mobocertinib for a median time of treatment of 6.8 months (range, 0.0-18.8). Median patient age was 59 years (range, 27-80), with most patients being women (65%) and never smokers (73%) and the majority having adenocarcinoma histology (99%) and an ECOG performance status of 1 (71%). The median number of prior therapies was 1, with prior platinum-based chemotherapy accounting for 90% of patients, prior immunotherapy in 34%, and prior 

 inhibitors in 31%. Baseline brain metastases were present in 34% of patients.

Clinically meaningful lung cancer symptom improvement by EORTC QLQ-LC13 was defined as a 10-point or greater decrease in symptom score. At a median follow-up of 13.0 months (range, 0.7-18.8), clinically meaningful changes in dyspnea occurred in 54.4% of patients, with a mean change to baseline symptoms of –3.2 (

 = .019). Cough improved in 46.7% of patients with a mean baseline improvement of –9.3 (

 < .001). For chest pain, improvement occurred in 38.9% of patients with a mean baseline improvement of –8.2 (

 < .001). In over 50% of the patients examined, dyspnea, cough, and chest pain were improved or stable throughout the study.

By EORTC QLQ-C30, baseline scores were maintained or improved in most patients treated with mobocertinib, for a least square mean change of –1.8 (95% CI, –4.8 to 1.2; 

 = .235). By PRO-CTCAE, the majority of adverse effects of were not categorized in the 2 highest categories of “severe” or “very severe”, with only diarrhea and dry skin escalating to above 10% of events being in the highest categories (22.2% and 11.1%, respectively). By EQ-5D VAS, patient-reported general health-related quality of life remained largely stable during treatment. 

Previously reported data from the trial demonstrated efficacy of mobocertinib in this patient population, with a confirmed overall response rate of 28% (95% CI, 20%-37%), a median overall survival of 24.0 months (95% CI, 14.6-28.8), and a median progression-free survival was 7.3 months (95% CI, 5.5-9.2). The mechanism of action of mobocertinib is unique in that it selectively targets exon 20 insertion mutations in EGFR

“Exon 20 insertion mutations account for up to 12% of NSCLC tumors with 

 mutations. Most of these patients are treated in the first line with platinum-based chemotherapy, but their disease, unfortunately, progresses very rapidly,” Campelo said. Use of mobocertinib in these patients may fulfill an unmet clinical need.

Garcia Campelo MR, Zhou C, Ramalingam SS, et al. Mobocertinib (TAK-788) in EGFR exon 20 insertion+ metastatic NSCLC: patient-reported outcomes from EXCLAIM extension cohort. Presented at: 2021 World Conference on Lung Cancer; September 8-14, 2021. Virtual. Abstract FP09.02.

Selectively targeting the EGFR exon insertion mutations was associated with improved outcomes in patients with previously treated non-small cell lung cancer. 



Patients Report Improved Outcomes Following Mobocertinib Treatment for NSCLC Subtype

The phase 3 CheckMate-73L trial (NCT04026412) is assessing the safety and efficacy of combining immunotherapy and chemotherapy with radiation in patients with stage III non–small cell lung cancer (NSCLC) that is unable or not planned to be removed by surgery.

Nagla Abdel Karim, MD, professor of medicine, medical director, Georgia Cancer, discussed how investigators plan to monitor patient responses and prepare for potential adverse events associated with treating patients with ipilimumab (Yervoy) plus nivolumab, along with chemotherapy.

“We are aware that patients can have inflammation of the esophagus, some difficulty swallowing, some inflammations. We have the nausea, the vomiting, the best supportive care works well to control those side effects,” she explained. “In addition, and if we are adding immunotherapy during that period of time, or later on in the consolidation.. we pay attention to the autoimmune side effects. That’s why we monitor the thyroid function, we monitor if patients get diarrhea, if there are sides of colitis or pneumonitis, if they have inflation of the lungs, if they get a shortness of breath, or just [are] out of breath while doing daily activities, we monitor oxygen level.”

Videos

Nagla Abdel Karim, MD, explains how researchers will address safety and manage potential adverse events in the ongoing phase 3 CheckMate-73L trial.

Symptom Management in CheckMate-73L Trial

Expanding the use of osmertinib (Tagrisso) so that it is efficacious as a frontline treatment will help pave the way for a new era of success in treating lung cancer, said Jonathan W. Riess, MD, MS.

The expert spoke about the EGFR tyrosine kinase inhibitor, and the key to unlocking its potency, at the 22nd Annual International Lung Cancer Congress.

The largest hurdle facing investigators is identifying and overcoming resistance mechanisms. First-and-fourth-generation (TKIs) in combination with osimertinib may prevent the emergence of known resistance mechanisms, particularly C797S; however, the future of care will lean heavily on the identification of more actionable targets.

Riess, associate professor of medicine at the University of California School of Medicine, UC Davis Comprehensive Cancer Center, provided an overview of the available data for osimertinib, establishing its role in the present and future of care for patients with EGFR-mutant non–small cell lung cancer (NSCLC).

“I can’t emphasize enough the need to find these [targets] as early as possible to forestall resistance developing in [patients with] EGFR-mutant lung cancer,” Riess said during a live presentation of the data. “In later lines of therapy, there’s so much clonal heterogeneity, and it becomes really challenging to target [these mechanisms] with only a few [available] targeted therapies.”

Osimertinib made its way into the frontline setting for patients 

with EGFR-mutant NSCLC in 2018 based on data from the phase 3 FLAURA trial (NCT02296125),

 which showed the clinical benefit of the agent compared with standard first-generation EGFR TKIs (erlotinib [Tarceva] or gefitinib [Iressa].

Specifically, a 54% reduction in the risk of progression was observed with a median progression-free survival (PFS) of 18.9 months (95% CI, 15.2-21.4) reported with osimertinib compared with 10.2 months (95% CI, 9.6-11.1) with erlotinib or gefitinib (HR, 0.46; 95% CI, 0.37-0.57; P < .0001). Overall survival (OS) data trended similarly with a reported median OS of 38.6 months (95% CI, 34.5-41.8) and 31.8 months (95% CI, 26.6-36.0), respectively (HR, 0.799; 95% CI, 0.641-0.997; P = .0462).

“You can see here a tremendous improvement in PFS,” Riess said. “And over 3 years, [there is] a 6-month improvement in OS compared with first-generation in EGFR TKIs. But for a 30-year-old patient with children who has EGFR-mutant metastatic lung cancer, it’s a cold comfort to know that there’s a 6-month improvement at 3 years. I’m always reminded that we could always do better, and we need to do better.”

Riess noted that deeper in the FLAURA data, the forest plots demonstrate that there are certain subsets that do not perform quite as well as others indicating that they may provide opportunities for improvement. “[These include] patients with the L85AR mutations, as opposed to those with exon 19 deletions,” he said. “Although [the trial was] underpowered in subset analysis, [osimertinib] did not show any clear benefit vs first-generation [TKIs].”

The identification of patients who perform well with frontline osimertinib begins to stratify the population a bit further, opening avenues to determine new treatment strategies for those who perform worse on first-line EGFR TKIs. Investigators have identified that those patients with EGFR-mutant disease who also harbor TP53 and TP53/RB1 mutations have a shorter time to discontinuation of treatment.1,3 In an analysis of 863 patients, those whose disease only harbored an EGFR mutation discontinued treatment after a median of 36.6 months, those with EGFR/TP53 at 12.3 months, and those with EGFR/TP53/RB1 mutant disease discontinued at a median of 9.5 months.

This extended to a survival analysis which demonstrated a media OS of 56.4 months, 40.5 months, and 20.1 months across the mutations, respectively.1,3 Additionally, investigators noted that patients with the triple mutation are approximately 25% more likely to experience disease transformation to small cell lung cancer.

Although identified in only a small subset of patients in a retrospective analysis, MET amplification was also a marker of poor prognosis with frontline EGFR TKIs, Riess said.

Investigators have also determined that the presence of circulating tumor DNA (ctDNA) as a marker of poor prognosis. In a mutational analysis of the FLAURA trial, patients with ctDNA present at baseline had a median PFS was 15.2 months with osimbertinib vs 9.7 months with standard EGFR TKI. Those with no ctDNA present at baseline experienced a greater benefit regardless of treatment with reported median PFS of 23.5 and 15 months, respectively.

“I would highlight those patients with baseline, detectable ctDNA and those with ctDNA that persists at week 3 and week 6 appear to do worse,” Riess said, who cited data from the analysis of the FLAURA trial in which investigators examined early clearance of plasma EGFR mutations after 3 and 6 weeks of EGFR TKI therapy.5 The median PFS for all patients with detectable EGFR at 3 weeks was 9.5 months (95% CI, 7.0-10.9) compared with 13.5 months (95% CI, 11.1-15.2) regardless of therapy received (HR, 0.50; 95% CI, 0.3-0.8; P = .001). At 6-week analysis, the median PFS was the same for those with no detectable EGFR in plasma analysis, but worsened to 8.3 months (95% CI, 6.8-10.9) for those who maintained measurable EGFR, for an HR of .70 (95% CI, 0.4-1.2; P = .191).

“How can we better use ctDNA to select those patients who are going to do worse with first-line osimertinib and intervene in the first line setting? I think this is an area we really need to improve on.”

Resistance to osimertinib also depends on the line of therapy, Riess explained. In an analysis of 62 patients with EGFR-mutant NSCLC, the most common off-target genetic resistance obeserved in patients treated with first-line osimertinib were MET amplification (7%), RET fusion (4%), BRAF fusion (4%), and KRAS fusion (4%); on-target acquired mutations were EGFR amplification (4%) and EGFR G724S (4%). In later lines of therapy off-target and on-target genomic alterations increased, the most notable of which is the reported incidence of EGFR C797 which was reported for 27% of patients.

“After the first line, you see a high rate of on-target mutations, including C797 and others, whereas with first-line osimertinib, you still see those, but the on-target mutations appear at a diminished frequency,” Riess said.

“EGFR C797 is the primary target resistance mechanism; it impedes covalent bond formation with irreversible EGFR inhibitors, such as osimertinib,” Riess explained, adding that recent data of osimertinib in combination with gefitinib has demonstrated that this strategy may have the potential to stall the development of C797.

In a phase 1 study (NCT03122717) of 27 treated patients, the combination resulted in rapid plasma clearance of EGFR with an objective response rate of 87.9% (95% CI, 71.9%-96.1%) and a disease control rate of 100% (95% CI, 87.5%-100%). The median depth of response was 58.5% (range, 6.5%-94.2%), and no grade 4 or 5 adverse effects were reported with the therapy.

Combination strategies leveraging fourth-generation EGFR inhibitors also have potential to overcome acquired resistance mechanisms. In particular BLU-945 has demonstrated efficacy in patients whose disease harbors activated L858R or exon 19 deletion mutations, plus acquired T790M and C797S mutations. “In xenograph models, the combination of osimertinib with BLU-945 looked to be the most efficacious in terms of tumor growth inhibition,” Riess said. “I think is definitely a promising avenue to reduce these, these on target resistance mechanisms and improve clinical outcomes.”

Other areas for exploration include the ability to inhibit other mechanisms of resistance, in particular RAS/RAF/MAPK alterations. Riess highlighted the phase 2 study (NCT03392246) in which investigators are evaluating osimertinib in combination with the MEK inhibitor selumetinib (Koselugo) for patients with EGFR inhibitor–naïve advanced EGFR-mutant lung cancer.

The future, Riess explained, will depend on treatment selection based on ctDNA analysis to determine indicators of poor prognosis and then finding a window of opportunity to optimal induction of osimertinib in combination with proven effective therapies.

Strategies outlined by alteration may include osimertinib plus carboplatin/etoposide for those with a TP53 mutation; osimertinib in combination with a MET inhibitor for those with a MET amplification; osimertinib plus a MEK inhibitor for those with RAS/RAF/MAPK alterations; and osimertinib plus a fourth-generation EGFR TKI for those with C797 alterations.

First line osimertinib: what can we add to enhance activity? Presented at: 22nd Annual International Lung Cancer Congress; July 29-31, 2021; virtual.

Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. Ann Oncol. 2017;28(suppl 5):V635. doi:10.1093/annonc/mdx440.050

Offin M, Chan JM, Tenet M, et al. Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes. J Thorac Oncol. 2019;14(10):P1784-P1793. doi:10.1016/j.jtho.2019.06.002

Gray JE, Okamoto I, Sriuranpong V, et al. Tissue and plasma EGFR mutation analysis in the FLAURA trial: osimertinib versus comparator EGFR tyrosine kinase inhibitor as first-line treatment in patients with EGFR-mutated advanced non–small cell lung cancer. Clin Cancer Res. 2019;25(22):6644-6652. doi:10.1158/1078-0432.CCR-19-1126

Zhou C, Imamura F, Cheng Y, et al. Early clearance of plasma EGFR mutations as a predictor of response to osimertinib and comparator EGFR-TKIs in the FLAURA trial. J Clin Oncol. 2019;37(suppl 15):9020. doi:10.1200/JCO.2019.37.15_suppl.9020

Schoenfeld AJ, Chan JM, Kubota D, et al. Tumor analyses reveal squamous transformation and off-target alterations as early resistance mechanisms to first-line osimertinib in EGFR-mutant lung cancer. Clin Cancer Res. 2020;26(11):2654-2663. doi:10.1158/1078-0432.CCR-19-3563

Rotow JK, Botelho Costa D, Paweletz CP, et al. Concurrent osimertinib plus gefitinib for first-line treatment of EGFR-mutated non-small cell lung cancer (NSCLC). J Clin Oncol. 2020;38(suppl 15):9507. doi:10.1200/JCO.2020.38.15_suppl.9507

This article was originally published on OncLive as “Optimizing Osimertinib Treatment Strategies Relies on Identification of Resistance”

Identifying targets early can help forestall resistance and improve the efficacy of osimertinib, a EGFR tyrosine kinase inhibitor, in the first-line setting.



Early Target Identification Will Help Maximize Osimertinib Treatment

The phase 3 CheckMate-73L trial (NCT04026412) will evaluate the potential benefit of adding more immunotherapy in the treatment of patients with stage III non–small cell lung cancer (NSCLC) by examining nivolumab  plus chemoradiation followed by nivolumab and ipilimumab (Yervoy).The study will build upon the understanding gleaned from the pivotal phase 3 PACIFIC trial (NCT02125461) of durvalumab (Imfinzi) following chemoradiation in an effort to provide more mature data, explained Nagla F. Abdel Karim, MD.

“It is good that we have [seen] success with including immunotherapy in the consolidation phase, but we need more mature data,” Karim said. “Is the addition of more drugs better? Or does it just come [at the cost of] more financial and autoimmune toxicity?”

®, a sister publication of Oncology Nursing News®, Karim, a medical oncologist at Augusta University Medical Center, further discussed the ongoing CheckMate-73L trial in patients with stage III NSCLC, the potential impact of the research on the paradigm, and future areas of exploration.

®: What was the rationale for the CheckMate-73L trial?

: Stage III NSCLC has been a very difficult disease [to treat], and until recently, we just did concomitant chemoradiation [for these patients]. Additionally, we had used consolidation chemotherapy following the chemoradiation, but this has been proven to be not beneficial, and in fact, even harmful. As such, [we stopped doing that].

Then, the PACIFIC trial examined the initiation of immunotherapy after the chemoradiation for all comers, and [that approach resulted in an increase in] median progression-free survival from 5.6 months to 17.2 months; this was significant. Additionally, the median overall survival for patients who received 1 year of immunotherapy with durvalumab had not been reached vs 28.7 months for those who received standard-of-care chemoradiation alone.

This is [a great option], and we do offer that to our patients. However, we know that [patients with a lower PD-L1 expression did not [experience] the benefit that those with a higher PD-L1 expression did [from that approach]. We also know that administering durvalumab less than 14 days [after] the chemoradiation yielded the highest benefits. However, we still have patients who do not do as well [with this approach], with an 18-month PFS rate of just 44%. That means that more than half of patients are going to ultimately progress. We have to improve on that.

In the CheckMate-73L trial, we are examining the combination of 2 types of immunotherapy that have different mechanisms of action. [By using them in] the consolidation phase, [we] should ultimately [see a] synergistic antitumor response. The 2 agents that are being used are ipilimumab and nivolumab. Ipilimumab blocks the interaction between the CTLA-4 on T cells, and the CD80 and CD86 on those presenting cells; this is in addition to the anti–PD-1 inhibitor which is nivolumab. Having this combination should lead to a stronger or synergistic mechanism in the consolidation [phase], and [we hypothesize that] this will subsequently [result in] a better clinical outcome in terms of progression-free survival [PFS] and overall survival [OS].

What was the design of the trial, and what were some of the eligibility criteria?

The eligibility criteria are straightforward: patients with stage III NSCLC who are not candidates for surgery. Eligible patients should not have received any prior chemotherapy or other anticancer treatments and should be newly diagnosed with stage III disease. They should not have [any underlying conditions, such as] acute infections, a history of transplant, or other conditions that might make them sick from the chemotherapy or from this approach.

In terms of stratification, we have learned so much from melanomas and other tumor types [in terms of how to] use immunotherapies. Patients in arm A will receive chemotherapy, which is [comprised of] carboplatin and paclitaxel and is standard of care. However, the only difference in this trial is that [the chemotherapy] will be given for 1 day every 3 weeks; it is not [given] weekly as we used to do. The chemotherapy will be given in addition to nivolumab. Again, this is given 1 time every 3 weeks, plus the radiation therapy. Then this arm will continue with the consolidation after finishing chemoradiation, using ipilimumab plus nivolumab for 1 year. The reason I mention that we learned from other diseases is because we are using a 1-mg/kg dose of ipilimumab [that is given] every 6 weeks. [We know this dose] is not as toxic and is supposed to be better tolerated with this combination.

The only difference in arm B is that consolidation will not include ipilimumab; it is just going to be nivolumab, given every 4 weeks for 1 year. Arm C is just the standard of care, with just chemotherapy plus radiotherapy, and that will be followed by 1 year of durvalumab.

What do you anticipate seeing in terms of safety with this approach?

We do not yet have a standard of care of immunotherapy plus chemotherapy given at the same time as radiation. This is something also that we are looking into with this trial. However, prior trials have shown that these treatments are safe to combine with radiation therapy. Of course, this is a larger-scale clinical trial, so we are going to ensure that our patients are safe and closely monitored.

With chemotherapy plus radiation, we are aware that patients can have inflammation of the esophagus or some difficulty swallowing. [With AEs like] nausea and vomiting, the best supportive care works well to control those toxicities. In addition, if we are adding immunotherapy during that period, or later in the consolidation [phase], we pay attention to autoimmune AEs. That is why we monitor thyroid functions, we monitor if patients get diarrhea, if there are signs of colitis or pneumonitis, if they have inflammation of the lungs, if they experience shortness of breath. [We have ways to stay] on top of those AEs.

Is there anything that you would like to add about this research?

The trial started in August 2019 and is anticipated to conclude between 2022 and 2024. Notably, trial is being conducted at 175 study sites in 26 countries; this is important because we will have information on diverse populations [who reside in] different areas of the world. This will [allow us to determine whether there are] any vulnerable populations in terms of autoimmune adverse effects [AEs] experienced with the approach, or [whether any] efficacy differences [exist between] the sites.

If this trial proves to be positive, how might this research impact the paradigm for this population?

We want to look into PFS and OS. If these patients are going to live longer, with less AEs [or a similar] toxicity [profile] compared with [what has been seen with] durvalumab, then this [new approach] could be the standard of care. If patients can tolerate the dual-immunotherapy combination, and they have a better outcome with less toxicity, then we would recommend that our patients [receive this treatment].

Having mentioned that, we like to personalize treatment for our patients with lung cancer. Our patients are not all the same; some might have more problems with specific treatments. As such, we will benefit so much from knowing more about markers or translational components. In this trial, we are looking into molecular markers, and other markers that can help us identify which patients are going to benefit the most [from this kind of approach], as well as which patients might experience more AEs. We still [have a lot to] learn, but certainly this is a very important trial.

This article was originally published on OncLive as 

“CheckMate-73L to Examine Nivolumab/Ipilimumab Following Nivolumab/Chemoradiation in NSCLC”

The ongoing CheckMate-73L trial seeks to determine if nivolumab plus ipilimumab following nivolumab plus chemoradiation could become the new standard of care in treating non-small cell lung cancer, says Nagla F. Abdel Karim, MD.

CheckMate-73L To Explore Ipilimumab and Nivolumab Combo in Non-Small Cell Lung Cancer Treatment

Patients with non-small cell lung cancer (NSCLC) and specific driver mutations respond better to targeted therapy compared with chemotherapy, explained Beth Sandy, MSN, CRNP, Abramson Cancer Center, University of Pennsylvania, during a presentation at the 5th Annual School of Nursing Oncology Meeting.

According to a pooled analysis of patients who received National Comprehensive Cancer Network (NCCN)-guided therapies in accordance with their biomarkers, overall survival (OS) was significantly improved in patients who receive targeted therapy (18.6 months) compared with patients who do not received targeted therapy (11.4 months).

“You can never treat a mutation that you never found,” emphasized Sandy. “We must test and find out what this biomarker is because [their treatment] is going to be better if they get their targeted therapy for that driver mutation.”

Current NCCN recommendations for biomarker testing say that, whenever feasible, providers should recommend a broad panel-based, molecular test. Next generation sequencing (NGS) is the most common way to complete this. These can be performed either in-house or through a commercial company. If no biomarkers are uncovered, providers should consider an RNA sequencing panel to detect RNA fusions.

In addition, all patients with metastatic NSCLC with non-squamous histologic subtypes should be tested for biomarkers. Testing should be considered in any patients with squamous histology or with early stage resected NSCLC. The minimum testing recommendations include 

; however, testing should be considered for 

Yet, despite the NCCN guidelines, less than 50% of patients with NSCLC are actually tested for the minimum 5 recommended biomarkers, according to the MYLUNG Consortium Data, presented at the 2021 ASCO annual meeting.

NGS is a broad molecular panel that tests for over 100 gene alterations. While there only 9 necessary tests, each additional test can help guide treatment. Additionally, even the variant of uncertain significance can be useful for future clinical trials, Sandy said.

NGS tests are often more efficient than individual tests for different biomarkers because it requires less tissue. While they may have a reputation for being expensive for the patient, Sandy says that most companies will absorb or reduce the payment.

She also outlined reflex testing, or the testing of all samples of NSCLC that has been identified by pathologists as non-squamous histology. The diagnostician who performs the biopsy suspected to be NSCLC will automatically check a box ordering the molecular test.

It is important to note that the pathologist cannot order the test because it is considered a conflict of interest. This new way of ordering tests is much quicker because now the medical oncologist has the results, or they are being processed by the time they see the patient.

Current challenges for molecular testing include the fact that lung cancer biopsies are less cellular than other solid tumors. Bone biopsies yield poor samples; they need to be decalcified. Furthermore, the tests can take weeks so they can present a logistical challenge. Occasionally, the test can return saying QNS, or quality not sufficient, which means that all the efforts need to be attempted again from square 1. There needs to be 10% to 20% of viable cancer cells in the sample to get a reliable result.

DNA sequencing scans tissue for an activating somatic mutation, like insertions, point substitutions, and in-frame deletions. This test will detect mutations in 

. DNA sequencing can be performed via PCR, a direct sequencing or NGS. Direct sequencing tends to be the most tedious and time consuming.

RNA fusion panels differ from DNA sequencing because they detect gene rearrangements, not mutations. 

 are all fusion abnormalities that are through these tests. While these aren’t necessarily clinically useful in NSCLC, they can be helpful for future clinical trials. 

 can both be detected through fluorescence in situ hybridization (FISH) or HCL, although the latter is not considered an acceptable result per NCCN guidelines.

Sandy acknowledged that the results of these tests can be difficult to decipher, “One time my RNA fusion reported an 

 mutation. And I was like, ‘Oh, they have 

,’ I called molecular pathology, and they said, ‘No, no, no, that's a gene rearrangement, not a DNA mutation… So, don't be afraid to call molecular pathology, I have them on speed dial.”

Liquid biopsies can work great in conjunction with a tissue biopsy, said Sandy. The advantages of the blood test are its minimally invasive nature, and its strong ability to detect any resistance mutations. Unfortunately, the liquid biopsy functions by detecting DNA shedding from the tumor in the bloodstream, and shedding can vary. So, depending on the day, the test’s sensitivity might be different. In addition, these tests cannot detect histology, and cannot therefore determine a “small cell transformation” from 

The Nile study (NCT03615443) found that performing both tissue and liquid biopsy identifies the highest amount of circulating tumor DNA (ctDNA) and the highest number of mutations. Some institutions, including the Abramson Cancer Center hospital at the University of Pennsylvania in Philadelphia, where Sandy works, perform both the blood and tissue scans on their patients. “Test. Test. Test.” she emphasized.

Approved Targeted Therapies for Different Driver Mutations

Sandy also outlined different approved agents that are preferred to treat common mutations in NSCLC.

Osimertinib (Tagrisso) is the preferred treatment for 

 exon 19 or 21. These mutations are fairly common: They consist of about 30% of 

 mutations. Osimertinib demonstrated superiority over erlotinib (Tarceva) and dacomitinib (Visimpro) in the FLAURA trial (NCT02296125) through a clinically significant improvement in progression-free survival (PFS). Patients in the osimertinib arm reported a PFS of 18.9 months, compared with 10.2 months with either erlotinib or dacomitinib. With a hazard ratio (HR) of (95% CI, 0.37-0.57; 

 < .0001), it was pretty clear evidence, Sandy said.

While some patients reported grade 1 or 2 rash in clinical trial, these symptoms can usually be managed with topicals or doxycycline. About half of trial patients also reported diarrhea, and that is manageable with over-the-counter anti-diarrheal agents. Overall, the drug is fairly tolerable.

Osimertinib is also now approved in the early stage, post-operative setting.

 mutations, however, it is actionable, and it has approved targeted therapy, amavantamab (Rybrevant). Sandy noted that “this is the only target therapy that's IV. It's a monoclonal antibody, and it's got a pretty odd administration, scheduled weekly for 4 weeks and every other week as a high infusion reaction with the first dose… but it's not analyphylactic, it's usually mild, and we can get them through it.”

ALK inhibitors make up about 4% to 6% of NSCLC and their preferred first-line treatment include alectinib (Alecensa), brigatinib (Alunbrig), lorlatinib (Lorbrena), and alectinib is also recommended for second- andthird-line treatment.

, though uncommon, makes up to 3% of NSCLC cases, and has 4 approved drugs that are recommended in accordance with NCCN guidelines: crizotinib (Xalkori), entrectinib (Rozlytrek), ceritinib (Zykadia), and lorlatinib. Crizotinib is the most trusted treatment of those 4.

Sotorasib (Lumakras) is the recommended drug for a 

mutation. Sandy advised that nurses should “remember that this is more common in smokers. So again, we’ve got to be testing everybody, not just the never-smokers. It's a pill and it's taken in 8 tabs daily, all at once. So, this is a little bit hard for adherence. We have to work with these patients for sure.”

Dabrafenib (Tafinlar) plus trametinib (Mekinist) is recommended for 

, which is more common in smokers than non-smokers. MET exon14 skipping has 3 approved agents: capmatinib (Tabrecta), crizotinib, and tepotinib (Tepmetko), while a RET rearrangement can be treated by the any of the following 4: selpercatinib (Retevmo), pralsetinib (Gavreto), cabozantinib (Cabometyx), and vandetanib (Caprelsa). 

, though extremely rare (less than 1 out of 1,000 cases), has 2 approved targeted drugs: entrectinib and larotrectinib (Vitrakvi).

“Our take home messages here are that the NCCN guidelines recommend testing in these populations of patients, especially the non-squamous [NSCLC], which is [the] majority, and adenocarcinoma. You can never treat a mutation that you never found,” said Sandy.

With so many approved targetable agents available in the metastatic setting, (as well as 1 approved drug in the early-stage setting), each with different dosages, and adverse event profiles, there is a lot more for nurses to keep up with, Sandy concluded. Her best advice? A team-based approach. Diagnosticians, medical oncologists, oncology nurses, and pathology all need to collaborate and communicate in order to ensure that patients are being tested and that the patient has access to the best resources available to treat their disease.

Sandy B. Molecular Testing and Targeted Therapies in NSCLC. Presented at: 5th Annual School of Nursing Oncology; August 6-7, 2021; Virtual.

Patients with non-small cell lung cancer driver mutations respond better to targeted treatments compared to chemotherapy, yet less than half of these patients receive next generation sequencing. 

More Broad Molecular Tests Are Needed to Accurately Treat Non-Small Cell Lung Cancer

KRAS G12C inhibitors have developed greatly over recent years, expanding the number of effective targeted therapies in non-small cell lung cancer (NSCLC). Researchers expect that efforts to assess predictive co-mutations, acquired resistance, and combination strategies will continue to advance the effectiveness of these agents even more, explained Karen L. Reckamp, MD.

“We’re still in the very early stages of understanding KRAS signaling, even though it has been studied for decades. We’re really at the tip of the iceberg in evaluating KRAS in NSCLC. The next steps are going to include defining the subsets that benefit and can be predictive for benefit to specific inhibitors or specific combinations,” said Reckamp, director of the Division of Medical Oncology, the associate director of Clinical Research, and the medical oncology director of the Lung Institute at the Samuel Oschin Cancer Center at Cedars-Sinai Medical Center.

In a presentation during the keynote lecture on KRAS pathway inhibitors in lung cancer at the 

 International Lung Cancer Congress®, a program hosted by the Physicians’ Education Resource®, LLC, Reckamp highlighted the data with adagrasib and sotorasib (Lumakras), 2 highly selective and potent oral small-molecule KRAS G12C inhibitors, and outlined ongoing research targeted toward improving patient selection and efficacy of these agents.

In the registrational phase 1/2 KRYSTAL-1 trial (NCT03785249), adagrasib was evaluated in previously treated patients with 

Among 51 patients evaluable for efficacy, 45% achieved a partial response to adagrasib (n = 23) at a twice-daily dose of 600 mg, with a disease control rate (DCR) of 96% (n = 49).1

“Most patients benefitted from this therapy, and the majority of patients had some tumor shrinkage,” said Reckamp.

“We’ve also seen some data with adagrasib on co-mutations, [suggesting that] KEAP1 mutations seem to be problematic and may be less responsive [to adagrasib] than patients with 

On June 25, 2021, the FDA granted a breakthrough therapy designation to adagrasib for use in patients with KRAS G12C–mutated NSCLC following previous systemic therapy based on findings from KRYSTAL-1.2

In the phase 2 CodeBreaK 100 trial (NCT03600883), sotorasib was evaluated in patients with pretreated 

 G12C–mutated NSCLC. Updated findings from the trial, which were presented during the 

, demonstrated that at a median follow-up of 15.3 months, sotorasib, given at 960 mg once daily, was associated with a median overall survival (OS) of 12.5 months (95% CI, 10.0–not evaluable [NE]) and a median progression-free survival (PFS) of 6.8 months (95% CI, 5.1-8.2).3

The objective response rate (ORR) was 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), and the DCR rate was 80.6% (95% CI, 72.6%-87.2%).3

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).

“As we get larger trials, we can start to tease out these subgroups a little bit more to see who is actually responding. For patients who had had only prior [treatment with a] PD-1 [inhibitor], we see the highest response rate and the longest OS,” said Reckamp.

Based on earlier findings of CodeBreaK 100, the FDA approved sotorasib in May 2021 as the first targeted treatment for adult patients with NSCLC whose tumors harbor 

 G12C mutations and who have received at least 1 prior systemic therapy.4

Additionally, sotorasib demonstrated activity in molecularly-defined subgroups from exploratory analyses within the study, including in those 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.3 The ORR was 23% in patients with 

The continued development of KRAS G12C inhibitors for the treatment of non-small cell lung cancer shows that researchers are making breakthroughs in the treatment landscape. 

Lung Cancer