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”

Articles

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 

-mutant disease (n = 7); and 42% in patients with 

 wild-type disease (n = 62). 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.

“The numbers are incredibly small, and I hesitate to make decisions based on these mutations, but we will be looking at these further,” said Reckamp.

To that end, the phase 2 Lung-MAP S1900E study (NCT04625647) is evaluating sotorasib specifically in patients with co-mutations, including 

Another research avenue is exploring the utility of SHP2 inhibitors in overcoming resistance to KRAS G12C inhibitors, said Reckamp. In an ongoing phase 1 trial (NCT03114319), the orally bioavailable, selective, first-in-class allosteric inhibitor of wild-type 

, TNO155, is being studied in patients with advanced solid tumors.

Initial findings from the study, which were presented during the 2021 ASCO Annual Meeting, demonstrated a best response of stable disease, lasting a median duration of 5.6 months (95% CI, 1.6-32.9).5

In another phase 1 trial (NCT03634982), results of which were presented during the 2021 AACR Annual Meeting, demonstrated a DCR of 75% (n = 12 of 16) with the SHP2 inhibitor RMC-4630 in patients with 

However, the modest single-agent activity of these agents and emerging data regarding the complexity of resistance to KRAS G12C inhibitors, including the activation of other RAS isoforms, other 

 activating mutations, the loss of G12C through a mutational switch to a different 

 mutation, and alteration of drug binding through 

 Y96D,7,8 underscore the importance of identifying effective combination strategies, explained Reckamp.

“Now, we’re trying to find the most rationale combinations by looking at MEK inhibitors, CDK4/6 inhibitors, SOS inhibitors, and SHP2 inhibitors, [targets] in adjacent pathways, such as EGF, and immunotherapy,” concluded Reckamp.

Jänne PA, Rybkin II, Spira AI, et al. KRYSTAL-1: activity and safety of adagrasib (MRTX849) in advanced/metastatic non–small-cell lung cancer (NSCLC) harboring KRAS G12C mutation. 

. 2020;138(suppl 2):S1-S2. doi:10.1016/S0959-8049(20)31076-5

Mirati Therapeutics’ adagrasib receives breakthrough therapy designation from US Food and Drug Administration for patients with advanced non-small cell lung cancer harboring the KRAS G12C mutation. News release. Mirati Therapeutics, Inc. June 24, 2021. Accessed July 31, 2021. https://prn.to/2SXZWqe.

Skoulidis F, Li BT, Govindan R, et al. Overall survival and exploratory subgroup analyses from the phase 2 CodeBreaK 100 trial evaluating sotorasib in pretreated KRAS p.G12C mutated non-small cell lung cancer. 

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

FDA approves first targeted therapy for lung cancer mutation previously considered resistant to drug therapy. News release. FDA. May 28, 2021. Accessed July 31, 2021. https://bit.ly/3c172Ah.

Brana I, Shapiro G, Johnson ML, et al. Initial results from a dose finding study of TNO155, a SHP2 inhibitor, in adults with advanced solid tumors. 

. 2021;39(suppl 15):3005. doi:10.1200/JCO.2021.39.15_suppl.3005

Koczywas M, Haura E, Janne PA, et al. Anti-tumor activity and tolerability of the SHP2 inhibitor RMC-4630 as a single agent in patients with RAS-addicted solid cancers. 

. 2021;81(13):LB001. doi:10.1158/1538-7445.AM2021-LB001

Tanaka N, Lin JJ, Li C, et al. Clinical acquired resistance to KRASG12C inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation. 

 Published online June 16, 2021. doi:10.1158/2159-8290.CD-21-0365

Akhave NS, Biter AB, Hong DS. Mechanisms of resistance to KRAS G12C-targeted therapy. 

. 2021;11(6):1345-1352. doi:10.1158/2159-8290.CD-20-1616

This article was originally published on OncLive as “

KRAS Inhibitors Reach New Milestones in NSCLC”

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. 

KRAS Inhibitors Meet New Turning Point in Non-Small Cell Lung Cancer 

Ongoing research seeks to determine which biomarker-selected cohorts of patients with lung cancer might respond to PARP inhibitors, shared Sandip Patel, MD, said in a presentation during the 

 International Lung Cancer Congress®, a program hosted by Physicians’ Education Resource®, LLC.1

While PARP inhibitors have been successfully utilized across various subspecies of oncology, including breast cancer, ovarian cancer, and prostate cancer, they have not yet proved to be effective in treating thoracic malignancies such as non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

The way in which PARP inhibitors work can be defined by 2 distinct mechanisms: synthetic lethality and PARP trapping. The former leads to chromosomal catastrophe in the cancer cells, which makes them unable to survive or replicate.2 With PARP trapping, although this is more nuanced and varied amongst the different inhibitors, DNA strands are trapped and the replication of cancer cells is blocked, according to Patel.

“Predictive biomarkers for PARP inhibition sensitivity often involves having a baseline mutation that already effects ability to conduct DNA repair” Patel, an associate professor in the Department of Medicine at UC San Diego Health, explained. “These drugs were FDA approved initially for [those with] germline mutations in 

, followed by some somatic mutations initially in breast and ovarian cancers. There have been data in pancreatic and prostate cancer, as well. As such, the idea that this can be a pan-histology biomarker was initially met with enthusiasm. However, over time, it looks like some of these efficacy changes are context specific.”

In terms of genomic correlates of response to these agents, certain pathways have been found to be more strongly associated with synthetic lethality than others.3 Those pathways include:

 pathway, which repairs single- and double-strand breaks in DNA

The SLFN11 pathway, which results in the killing of cells undergoing replication stress

The loss of heterozygosity (LOH), which is an assay that can be used to look for homologous recombination deficiency (HRD)

“There are multiple mechanisms by which you can have an underlying issue in terms of DNA repair in cancer cells, for which a PARP inhibitor can be that second ‘key’ on the nuclear summary to lead to chromosomal catastrophe,” Patel noted.

Rationale for PARP in Thoracic Malignancies

 mutations have been found to be present in approximately 14% of patients with NSCLC, and 12% of those with SCLC.4 As such, if these mutations prove to be viable therapeutic targets as they have in other cancer types, PARP inhibition could have potential as the third leading targeted treatment in thoracic malignancies, after 

In the phase 1/2 ATF-07 trial (NCT02412371) the PARP inhibitor veliparib (ABT-888) was examined in combination with concurrent chemoradiotherapy to induce DNA damage in patients with stage III NSCLC.5 The regimen yielded some activity, with an objective response rate (ORR) of 64.3%. “These are reasonable rates of activity but nothing that substantially moved the needle to want to incorporate [this into practice], and there was toxicity that was predominantly related to cytopenias,” Patel said.

Similarly, the Lung-MAP SWOG S1400G trial (NCT02154490) examined talazoparib (Talzenna) in patients with advanced, refractory squamous cell lung cancer whose tumors harbor 

 mutations. The agent yielded an ORR of just 4%.6

“The most elite responder was HRD negative, and so the biomarker was not exactly predicting the limited biologic effect we saw here,” Patel noted.

Modest efficacy was observed, however, in the Lung-MAP SWOG S1900A trial (NCT03845296) that examined rucaparib in the second-line treatment of patients with 

-mutant, LOH advanced NSCLC.7 Results from the study demonstrated a potential benefit in patients with homozygous 

 mutations, although the overall efficacy was muted, according to Patel.

Efforts to Incorporate PARP Inhibition in SCLC

SCLC remains a disease where targeted therapeutic approaches have yet to be established, despite the disease being characterized by mutations in DNA repair.8 Due to this, ongoing studies are examining the potential for PARP inhibition in this patient population.

“The thought has been to combine temozolomide [Temodar], a drug commonly used in glioblastoma but that can also be used in SCLC, in combination with PARP inhibitors as a rational, biologically-designed approach in patients with refractory SCLC,” Patel said.9 “However, although some patients had benefit, overall, the response rates were limited.”

In a multicenter phase 2 clinical trial (NCT01638546), investigators compared the use of temozolomide plus veliparib or placebo in the second- or third-line treatment of patients with relapsed SCLC.9 Results indicated a significant difference in ORRs between those who received veliparib/temozolomide vs those who were given temozolomide alone, at 39% and 14%, respectively (

= .016). However, no significant difference was observed with regard to the 4-month progression-free survival rates in the investigative and control arms, at 36% and 27%, respectively (

Similarly, temozolomide was examined in combiantion with olaparib (Lynparza) in patients with refractory SCLC, and although some responses were observed, the durability of those responses was limited, Patel said. Additionally, the toxicity associated with this treatment was prohibitive to some patients, according to Patel.10

What’s Next with PARP Inhibition in Lung Cancer?

An area of research that has yielded promising outcomes in other disease types, such as ovarian cancer, is the combination of immunotherapeutic agents with PARP inhibitors, Patel said. In fact, recent data have shown that even those patients with 

 wild-type mutations are experiencing responses to PARP inhibition combined with PD-1 inhibition, that would be expected with either therapy alone.

“This is an area of potential interest across other tumor types,” Patel concluded. “The mechanism by which this biology leads to benefit, and potentially durable benefit, for patients is still unclear, but it is an exciting avenue of research.”

Patel S. Incorporation of PARP inhibitors. Presented at: 

 International Lung Cancer Congress; July 29-31, 2021; Huntington Beach, CA. Accessed July 29, 2021.

Lord CJ, Ashworth A. PARP inhibitors: synthetic lethality in the clinic. 

. 2017;355(6330):1152-1158. doi:10.1126/science.aam7344

Murai J, Tang S-W, Leo E, et al. SLFN11 blocks stressed replication forks independently of ATR. 

. 2018;69(3):371-384. doi:10.1016/j.molcel.2018.01.012

Ji W, Weng X, Xu D, et al. Non-small cell lung cancer cells with deficiencies in homologous recombination genes are sensitive to PARP inhibitors. 

. 2020;522(1):121-126. doi:10.1016/j.bbrc.2019.11.050

Kozono DE, Stinchcombe T, Salama JK, et al. Veliparib (Vel) in combination with chemoradiotherapy (CRT) of carboplatin/paclitaxel (C/P) plus radiation in patients (pts) with stage III non-small cell lung cancer (NSCLC) (M14-360/AFT-07). 

. 2019;37(suppl 15):8510. doi:0.1200/JCO.2019.37.15_suppl.8510

Owonikoko TK, Redman MW, Byers LA, et al. Phase 2 study of talazoparib in patients with homologous recombination repair-deficient squamous cell lung cancer: Lung-MAP substudy S1400G. 

. 2021;22(3):187-194. doi:10.1016/j.cllc.2021.01.001

Reiss JW, Redman MW, Wheatley-Price P, et al. A phase II study of rucaparib in patients with high genomic LOH and/or BRCA 1/2 mutated stage IV non-small cell lung cancer (Lung-MAP Sub-Study, S1900A). 

. 2021;39(suppl 15):9024. doi:10.1200/JCO.2021.39.15_suppl.9024

Knelson EH, Patel SA, Sands JM. PARP inhibitors in small-cell lung cancer: rational combinations to improve responses. 

. 2021;13(4):727. doi:10.3390/cancers13040727

Pietanza MC, Waqar SN, Krug LM, et al. Randomized, double-blind, phase II study of temozolomide in combination with either veliparib or placebo in patients with relapsed-sensitive or refractory small-cell lung cancer. 

. 2018;36(23):2386-2394. doi:10.1200/JCO.2018.77.7672


Researchers are using biomarker-testing to determine which patients with lung cancer might benefit from PARP inhibitors. 


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