By Eugene Manley, Jr., PhD
Director, Scientific Programs
Posted August 26, 2021
This is the first technical leaning update from the Director of Scientific Programs at the Lung Cancer Research Foundation. These updates will review lung cancer conferences, scientific information, programs, and other news relevant to lung cancer researchers. This update covers the LCRF Mid-Year Review/TogetherSeparately™ hosted by Dr. Katherine Gold at the University of California – San Diego, the ASCO 2021 Annual Meeting, and the 2021 NSCLC Drug Development Summit.
We have seen a lot of progress in lung cancer diagnosis and treatment this year, including a number of FDA approvals and Breakthrough Designations, new therapies for driver mutations in NSCLC, small cell lung cancer (SCLC) heterogeneity, combination therapies, I/O, biomarkers, and diagnostics. Another major theme is increasing equity and access for all in care and clinical trials. Below I have incorporated Dr. Gold’s presentation with takeaways from meetings this summer. This will start with NSCLC targeted therapies and progress through other key areas.
NSCLC – about 80-85% of all lung cancer is NSCLC and has some key driver mutations
Key driver mutations
KRAS – KRAS is the most frequently mutated driver in lung cancer (~25-30%) (Ricciuti et al., 2016) and the most frequent mutation is G12C (Adderley, et al., 2019). For the last 20 years, no drugs had shown any efficacy in targeting KRAS, and it was thought to be “undruggable.” However, there is now some hope for patients with recent updates.
- Sotorasib (LUMAKRAS) (previously AMG 510) is orally administered irreversible selective KRAS G12C inhibitor and is the first FDA approved drug for mutant KRAS in NSCLC patients. In the Phase 2 CodeBreak 100 trial, advanced NSCLC patients previously treated with chemotherapy, I/O, or the combination were given sotorasib. The objective response rate was (ORR = 37.1%), and median duration of response was 11.1 months. Patients had increased progression-free survival (PFS = 6.8 mos), increased overall survival (OS =12. 5 mos), and it was well tolerated. Subgroup data also showed that sotorasib improved survival in STK11 co-mutated tumors, but not in KEAP1 co-mutated tumors.
- Adagrasib (MRTX849), similar chemically to sotorasib, is also orally administered and was given FDA Breakthrough Designation in June 2021 for patients with advanced KRAS G12C mutated NSCLC. Approval was granted based on the KRYSTAL-01 trial where 45% of patients responded, and it was presented at the 2021 European Lung Cancer Conference.
EGFR – 2nd most common mutations in NSCLC patients
- Osimertinib (Tagrisso), a third-generation TKI, was granted FDA approval in December of 2020 for EGFR mutant NSCLC in the ADAURA trial. Patients’ resected tumors were tested for EGFR mutations, and those with EGFR mutations were then randomized to receive either osimertinib or the standard of care (observation and regular CT scans). Osimertinib was shown to reduce the risk of the tumors returning, and this showed that a therapy for late-stage cancer can be applied to earlier stages.
- Poziotinib is another oral medication was granted Fast Track FDA designation in March 2021 for NSCLC patients with EGFR and HER2 exon 20 mutations. It had high response rates, but toxicity is a concern.
EGFRm therapies for patients progressing on standard therapies, as inevitably, resistance will occur.
- Amivantamab-vmjw (Ryrbrevant) is a bispecific antibody targeting EGFR and MET that is administrated intravenously to NSCLC patients with EGFR Exon 20 insertion mutations that had advanced on chemotherapy. It was given accelerated Breakthrough FDA approval in May of 2021. Lazertinib is a 3rd generation EGFR TKI that was combined with amivantamab in the CHRYSALIS Phase I trial that included patients whose tumors had progressed on or after treatment with osimertinib. The overall response rate (ORR) was around 40%, with a median response duration of 11.1 months. This is a promising therapy for osimertinib resistant NSCLC.
- Patritumab deruxtecan (HER3-DxD) is a bispecific antibody drug conjugate (ADC) that targets HER3 and is linked to a DNA Topoisomerase I inhibitor. This Phase 1 trial was conducted in patients with locally advanced/metastatic NSCLC that had been treated with multiple lines of therapy including platinum-based therapy and EGFR TKIs (including >86% with osimertinib) that had advanced. HER3-DXd showed efficacy regardless of mechanism of EGFR TKI resistance, it was well tolerated, responses were similar in those with and without brain
- metastases, and it was effective regardless of HER3 expression levels. These are two promising approaches for patients with acquired resistance to EGFR therapies.
Additional EGFR Exon 20 – A rare and smaller population of EGFR mutations, and are enriched in women, non-smokers, Asian populations, and NSCLC with adenocarcinoma histology (Vyse and Huang, 2019; Oxnard et al., 2013)
- Mobocertinib (TAK-788) is an orally administered TKI in NSCLC patients treated with at least one line of therapy and roughly 1/3 of the patients had brain metastases. The objective response rate was 28%, median progression free survival was 7.3 months, and brain metastasis was reduced.
- DZD9008 is an irreversible EGFR inhibitor for NSCLC. In PDX models, DZD9008 was able to significantly inhibit tumor growth. In the subsequent Phase 1 WU-KONG1 and WU-KONG2 trials, patients had received prior therapies and 42% had brain
- metastases before DZD9008 administration. The half-life was 50 hours, was relatively well-tolerated, and showed some efficacy.
- CLN-081 (TAS6417) is a small molecule pyrrolopyrimidine that more specifically targets mutant EGFR Exon 20 (compared to others in this class) with minor HER2 activity. When compared to poziotinib, it spared WT EGFR, has more anti-tumor activity and less toxicity in xenograft models. Ph1/2b trials are underway to determine a MTD and anti-tumor activity.
- In a Phase 3 trial comparing aumolertinib/almonertinib, a third-generation EGFR TKI, versus gefitinib (Iressa) against EGFR (Exon 19 del or L858R mutations), aumolertinib was shown to still be more effective and is a better first-line therapy.
- Poziotinib – Orally administered medication for EGFR or HER2 Exon 20 mutations. It does have some efficacy, but there are toxicity concerns that still need to be monitored. FDA Fast track approval was given in March 2021.
- Benzimidazoles are being developed as orally deliverable potent 4th generation EGFR TKIs that are showing some promise in cell lines and xenograft models by working against some of the other acquired EGFR mutations, can pass the blood brain barrier, and spare EGFR WT
- BDTX-189, in the MasterKey-01 trial, is an orally delivered allosteric inhibitor of EGFR and HER2 Exon 20 mutations and allosteric HER2 mutations in advanced NSCLC patients. It was developed through a proprietary system that uses proteomic and genomic profiling to identify oncogenic mutations in a gene. In proof-of-concept studies, it showed anti-tumor activity in NSCLC tumors, regressed lesions in one patient, and is currently in Ph1 and Ph2 studies.
- Metastatic NSCLC patients with HER2 exon 20 mutation or insertions were treated with the combination of pertuzumab+trastuzumab+docetaxel and this combination had an overall response rate of 28%.
- T-DM1 (Ado-Trastuzumab Emtansine or Kadcyla) is an ADC that had an overall response rate of 50%
- T-DxD (Fam-Trastuzumab deruxtecan or Enhertu) is another ADC targeting HER2 mutant NSCLC that had and overall response rate of 62%.
- Updated NCCN guidelines recommended that HER2 mutation NSCLC patients would benefit from either of these two therapy combinations.
- There are now 5 approved therapies for ALK positive lung cancer: crizotinib (Xalkori), ceritinib (Zykadia), alectinib (Alecensa), brigatinib (Alunbrig), and lorlatinib (Lorbrena). While crizotinib was first in this class, and these additional therapies gives clinicians more options, they have not been compared against each other.
- Crizotinib is not preferred due to toxicity.
- The Phase 3 CROWN Study at AACR compared lorlatinib vs crizotinib in ALK+ advanced NSCLC patients. Lorlatinib was much better at increasing PFS and decreasing brain metastases than crizotinib.
- The Phase 3 J-ALEX study comparing alectinib versus crizotinib in ALK+ treatment naive NSCLC patients, showed that after 5 years alectinib treatment caused better PFS, but no difference in OS. This is different than the earlier data that showed alectinib increased both PFS and OS.
- Liquid biopsy was used to identify a RET fusion positive NSCLC patient that was identified during a presumed COVID screening. The patient was treated with selpercatinib (Retemvo) and this was able to reduce tumor mass.
- An additional case study using liquid biopsy showed that a metastatic NSCLC patient that developed resistance to osimertinib also acquired a RET-fusion. Treatment with selpercatinib and osimertinib was able to reduce the tumor.
- BOS172738 is an oral RET inhibitor and Phase 1 data in advanced NSCLC patients showed it is relatively safe, had efficacy, and reduced brain met lesions.
- The GEOMETRY mono-1 Phase 2 trial showed that capmatinib is effective for Met Exon 14 (METex14) skipping metastatic NSCLC patients as a first-line therapy (ORR = 65.6%) and PFS of 10.8 months.
- The Phase 2 VISION treated patients with METex14 mutations with tepotinib that were enrolled based on MET that was detected with a Guardant360 liquid biopsy. Tepotinib had some efficacy in patients with MET amplified NSCLC, which was a continuation of their results from an earlier study.
- Zenocutuzumab (MCLA-128) is a new drug for NRG1 gene fusions in advanced solid tumors including NSCLSC. A Phase 1/2 trial showed that zenocutuzumab was relatively safe and reduced tumors.
- Seribantumab is an anti-HER3 monoclonal antibody that blocks HER3 activation and dimerization of HER2-HER3 to target NRG1 fusions. In vitro and in vivo, seribantumab impaired downstream signaling cascades and significantly decreased tumor growth in a dose-dependent manner. In the Phase 2 CRESTONE trial, patients with NRG1 fusion positive cancers that have advanced on prior therapy with or without actionable molecular alterations.
- AUM302, a first-in-class small molecule oral kinase inhibitor combining pan-PIM kinase (PIM-1, -2, and -3), pan-PI3K, and mTOR. It is designed to partly block PIM activation as a resistance mechanism to PI3K and mTOR inhibitors. PIM1 is also a poor prognosis marker in NSCLC. The combination of the three-in-one agent in vitro more potently kill cancer cells and inhibit signaling cascades than either inhibitor alone. It is in late preclinical stages, has been tested in male and female mice with no alterations in drug metabolizing cytochrome P450 enzymes, and is going through IND-enabling studies.
- Bemcentinib (BCBC008), a first-in-class oral inhibitor of AXL, has been combined with chemotherapy and other immunotherapies. In a Ph2 trial, patients were treated with BCBC008 in combination with pembrolizumab and compared to pembrolizumab alone, and it was found that the combination was able to slow progression in AXL+ tumors and was relatively well-tolerated.
Immunotherapy for NSCLC
Early-stage lung cancer
- Phase 3 Checkmate 9LA trial presented the two-year update in which patients with advanced NSCLC treated with 4 cycles of chemotherapy or the combination of nivolumab (Opdivo), ipilimumab (Yervoy), and 2 cycles of chemotherapy. The combination increased OS and PFS compared to chemotherapy alone. Subgroup analysis also showed that the combination had better OS compared to chemotherapy when looking at squamous and nonsquamous histology, patients with brain metastases, and across PD-L1 expression levels.
- Checkmate 227 trial presented four-year follow-up of advanced NSCLC patients with expression of PDL1 ≥ 1% or < 1% treated with nivolumab, ipilimumab, or nivolumab + ipilimumab showed that the combination was more effective patients with both PD-L1 ≥ 1% and PD-L1 < 1% than the solo therapies.
- FDA presented an analysis of clinical trials that compared advanced NSCLC patients with PD-L1 (1-49%) treated with I/O alone or the combination of chemotherapy and I/O. The chemo and I/O combination is still the best first-line treatment option as it improves OS and PFS compared to I/O alone. Also noted that only 2% of patients across these trials were Black or African-American, which does not represent the proportion of actual patients battling lung cancer.
- PACIFIC Trial presented its five-year update data on patients with unresectable stage III NSCLC that had progressed following chemoradiation therapy. They found that with chemoradiation and durvalumab (IMFINZI) increased OS by 18.4 months and PFS by 11.3 months compared to placebo. This may be an option for these patients.
- The use of antibiotics before or at the start of immune checkpoint inhibitors is associated with worse overall survival, but this does not occur with chemotherapy.
- The Phase 2 TACTI-002/KEYNOTE-798 trial combined two immunotherapies IMP321 (Eftilagimod Alpha), a soluble LAG-3 protein, with pembrolizumab (Keytruda), in NSCLC patients. LAG-3 is an immune checkpoint that is expressed on TILs and cytotoxic T cells, and also binds to MHC II on APCs. The LAG-3/APC interaction is considered a new immune checkpoint (Shan, Li, and Zhang; 2020). LAG-3 The combination was relatively safe and had an overall response rate of 41.7%.
- IMpower010 trial showed that atezolizumab (a PD-L1 inhibitor) given adjuvant chemotherapy reduces the chances of the tumor returning compared to chemotherapy alone after resection of early-stage NSCLC. This was also more effective in patients with tumors that expressed PD-L1 >1%.
- The Phase 3 CheckMate 816 trial that compared nivolumab + platinum-doublet chemotherapy versus chemo alone in patients with resectable NSCLC showed that after 4 years, the combination was more effective at improving survival than chemotherapy alone in the neoadjuvant setting.
- The VIOLET randomized clinical trial for early-stage lung cancer patients showed that video-assisted thoracoscopic surgery (VATS) reduced pain, resulted in fewer in-hospital complications, and shorter hospital stays compared to open surgery for resection. The improved patient recovery with no compromise in outcomes suggests that VATS could be a standard of care option.
- Biomarker testing is necessary to provide high quality and standards of care to all patients.
- Lung Cancer Mutation Consortium (LCMC4) LEADER Trial
- We are happy to announce that recruitment will begin soon for the LCRF and LCMC: LCRF LEADER Trial Neoadjuvant Screening Trial: LCMC4 Evaluation of Actionable Drivers in Early Stage Lung Cancers (Clinical Trials Number : NCT07412877)
- The objective of this trial is to screen 1,000 lung cancer patients for 10 oncogenic driver mutations by taking tissue for histology and blood for liquid biopsy
- Those that have an identifiable driver mutation, will be offered the option to enroll in a clinical trial by a sponsor with a trial for that target
- For those without a targetable driver mutation, we will be able to capture the range of other mutations and alterations that occur in lung cancer patients, and this may help identify new potential biomarkers and therapies.
- The MYLUNG Consortium showed that
- In community-based settings, many in the South-Eastern US, the rates of testing for at least one of these 5 biomarkers (ALK, BRAF, EGFR, ROS1, and PD-L1) was 90%, while only 46% were tested for all 5 biomarkers prior to therapy. This may be not targeting people to appropriate clinical trials or therapies
- FLATIRON Health database retrospective study
- While there was no difference between white and black patients in gene alterations, black patients were 10% less likely to receive NGS testing, and 7% less likely to receive NGS testing before targeted therapy,
- These differences also manifested in access and enrollment in clinical trials, where white patients were 2x more likely to be enrolled than black patients.
- Some of the barriers to biomarker testing include tissue limitations, provider education and keeping up with all the newly developing therapies and diagnostics, and patient access.
- Dr. Aggarwal described a female never-smoking patient that had metastatic NSCLC that was found during a screening for presumed SARS-CoV2 infection by using liquid biopsy. After finding RET fusions and other mutations, they treated the patient with selpercatinib (Retemvo) and was able to reduce tumor mass and reduced lymphadenopathy.
- Dr. Aggarwal thinks biomarkers for NSCLC fall generally into 3 buckets. (Though now with the recent approval of sotorasib for KRAG G12C, this could likely move to the must have column.)
- The must haves: PD-L1 IHC, EGFR, ALK, ROS1, BRAF, RET, MET exon 14, NTRK (and these all have approved targeted therapies)
- Emerging: KRAS – G12C (is most commonly seen, and likely should move up with sotorasib approval), Erb2/HER2
- Not ready for clinical implementation: NRG1, STK11, KEAP, PTEN, TMB
- Natera has developed a ctDNA Signatera™ residual disease test (MRD) for identifying MRD and monitoring that can detect relapse in 93% of patients and develops a patient-specific panel of 16 somatic mutations.
- Biodesix is a lung diagnostics company and has services that cover the continuum of care from diagnosis, treatment, and response. They have the nodifylung® to identify if nodules are benign or malignant, a genomics test for 6 targetable mutations called genestrat, and a proteomics test to predict I/O outcomes called veristrat.
Disparities (also see biomarkers)
- LCRF and AME Church Health Commission has partnered to increase awareness, education, and screening of lung cancer in Black Americans. Black men are 11% more likely to be diagnosed with lung cancer and 9.8% more die. Part of this partnership is development of a guide book and documentary, PSAs airing nationally in November for National Lung Cancer Awareness Month, one feature with the grandson of Jessie Owens (who died of lung cancer), one feature with Dr. Marjory Charlot at UNC Chapel Hill who is a 2020 LCRF Research Grant on Disparities in Lung Cancer awardee, and web content. This program was funded in part with support from Bristol Myers Squibb, Novartis, Pfizer, Lilly, AstraZeneca, and Genentech, a member of the Roche Group.
- Dr. Melinda Aldrich at Vanderbilt University Medical Center is a 2019 LCRF Research Grant on Disparities in Lung Cancer Awardee. Part of her work is to understand differences in lung cancer risk and treatment in different ethnic groups and admixed populations. She recently shared with us an infographic about the importance of screening for early detection of lung cancer in TN.
- COVID-19 has made disparities much worse in minority communities as they are not seeing their primary care doctors regularly, they are putting off necessary screenings, and they may be more hesitant to go out with all the deaths in their vicinities. It has exacerbated disparities in care for and hurt access to care for people that were already struggling.
- These delayed screenings could lead to diagnosing cancer even later than normal.
- Many clinical trials are conducted at Major Medical Centers and while this is great for streamlining the trials, the demographics of the clinicians and patient population are less likely to reflect the populations seen in community settings.
- Telehealth has increased during the COVID-19 pandemic. One the one hand, doctors can see their patients without them traveling or coming to the clinic. However, this may not allow doctors to observe patients in person to see how they are walking and breathing. As with access to care, many minority communities and socioeconomically distressed do not have routine access to internet. This makes telehealth another divide.
- The US Preventative Task Force has updated its recommendations for lung cancer screening, but there are still problems in getting screening when people do not have access to large medical centers or health care providers. While the recommendations account for smoking history, it is not recommended for non-smokers at this time.
- One the one hand it is great to see the smoking rates have come down in the US, but now we are seeing more never-smokers with lung cancer. This population was always present, but the data and cases were likely caught in the background with the heavy emphasis on smokers. While we are still trying to understand why never-smokers get cancer, and it appears that their cancers develop differently than smokers.
- Unlike mammograms, which do not necessarily prevent deaths, lung cancer screening clearly saves lives as tumors can be detected and removed sooner or treated. However, partly due to stigma, they are not advertised enough or promoted.
- It is tricky though to screen a person with a nodule that may or may not become lung cancer, it requires some expertise to determine the best way to monitor these patients.
SMALL CELL LUNG CANCER (SCLC) – very aggressive form of lung cancer that does not have great survival and no therapeutic options.
- Recent work has showed that SCLC is not one distinct tumor, but is heterogeneous and has multiple subtypes that are driven by different transcription factors that can be categorized into 4 groups. They currently are SCLC-A (ASCL1), SCLC-N (NEUROD1), SCLC-P (POU2F3), SCLC-I (Inflammed), and SCLC-I may have/predict sensitivity to immunotherapies.
- Another group characterized the subtypes as SCLC-A, SCLC-N, SCLC-Y, SCLC-P, and SCLC-mixed.
- A third group identified 3 subtypes, and found that increased PLCG2 may be associated with more metastatic tumors and worse outcomes.
- Schlaffen-11 (SLFN11) may be a predictive biomarker of sensitivity to PARP-inhibitors, and the SWOG 1929 Phase 2 trial is assessing impact of treating SLFN11+ extensive stage SCLC patients with atezolizumab or the combination of talazoparib (a PARP inhibitor) and atezolizumab.
Lung cancer risk reduction
Vaping and reducing teen smoking
- There have been no published studies on vaping and smoking risk. It is too early to see any links between vaping and lung cancer, as it takes a considerable amount of time (sometimes 10-20 years) for smokers to develop lung cancer.
- Inherently, anything that is an irritant or that you inhale can put you are greater risk for lung cancer. In addition to smoking, marijuana is another irritant, and these irritants can cause DNA damage in the lung.
- Quitting smoking is difficult due to how it is marketed and how nicotine drives addiction.
Other risk reduction strategies
- Raising cigarette taxes, as many states have done
- Quitting smoking
- Maintaining a healthy weight
- Light alcohol use, as opposed to moderate or severe.
- There are some very promising therapies and new approaches for diagnosing and treating NSCLC.
- We are learning more about SCLC biology and this may lead to targeted therapies.
- Immunotherapies are improving patient outcomes as solo and sometimes combination therapies. More characterization of the tumor immune microenvironment may lead to discovery of additional checkpoint inhibitors.
- There are disparities in lung cancer from the patient/enrollment side and the trainee/academic/clinical/leadership side, and more diverse trainees and working environments will be necessary to create and ensure more equitable care for all patients.
- Lung cancer screening saves lives.
- Reducing and minimizing smoking, and likely vaping, will reduce lung cancer risk.
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