Clinical Trials and Emerging Therapies for Lung Cancer
Emily Duffield, MPH, MSN, ANP-BC
Clinical research continues to identify and develop novel treatment options for lung cancer patients. Multiple new treatments have been made commercially available over the past few years, while others still in the developmental pipeline remain available only to patients who participate in clinical trials. There are several different classes of systemic therapy used to treat lung cancer, including chemotherapy, targeted therapy, and immunotherapy. Although traditional chemotherapy remains an important tool for lung cancer treatment, both targeted therapies and immunotherapies are playing an increasingly important role in treatment, particularly for patients diagnosed with advanced stages of the disease.
Instead of attacking all rapidly dividing cells the way chemotherapy does, targeted therapies concentrate on specific genetic abnormalities unique to some tumors, often resulting in fewer side effects and the potential for improved cancer control. Targeted therapies can pinpoint specific DNA mutations in the tumor and utilize them to prevent cancer cells from growing and dividing out of control. Targeted therapies may be used alone or in combination with other treatments to improve overall survival. The drawback to targeted therapies is that they can only be utilized by a select group of patients who have tumors with unique DNA mutations. As a result, these therapies are not indicated for all patients.
Immunotherapy is a newer type of targeted therapy that is appropriate for many lung cancer patients. Immunotherapy medications interact with certain receptors on tumor cells and immune cells to change the way the body reacts to a tumor, often allowing the immune system to recognize and attack tumors. In some cases, turning on the immune system with the help of immunotherapy can even cause the body to completely eliminate the tumor. Immunotherapies are showing great promise in lung cancer as well as in many other types of advanced malignancies.
While many of the recently approved therapies appear to be very promising, chemotherapy remains an important part of the treatment plan for many lung cancer patients, and researchers continue to evaluate the effect of combining chemotherapy with immunotherapies and targeted therapies in an effort to further improve outcomes for patients diagnosed with lung cancer. Other areas of research include the utilization of targeted agents and chemotherapy for lung cancer maintenance therapy (prevention of relapse) and medications to prevent lung cancer (chemoprevention) in patients at high risk for developing this disease. The recently approved targeted and immunotherapies are already improving progression-free and overall survival rates for lung cancer patients, but there is more work to be done. Research and clinical trials continue to evaluate the best use of novel therapeutic agents in an effort to improve the quality of life and longevity of patients with lung cancer.
Drug development begins with the identification of new substances that show anti-cancer activity in research laboratories. Following extensive laboratory testing, clinical trials are done to establish whether these substances are safe and effective at fighting cancer in people. The purpose of clinical trials is to identify new agents that can improve survival or quality of life compared to currently available treatments.
Clinical trials of new drugs are done in a series of phases, each with a specific purpose. If the drug is safe and provides benefit in an early phase trial, it is further tested in subsequent phases:
- Phase 1: the drug is tested for the first time in people to establish safety, tolerability, dosage, and treatment schedule for subsequent studies.
- Phase 2: the drug is tested in a larger group of people to continue to evaluate efficacy and safety, and to identify the range and severity of side effects.
- Phase 3: the drug is tested in an even larger group of people to determine whether or not the new drug is more effective than existing treatments. Side effects and safety also are monitored. FDA approval for drugs is typically based on the results of Phase 3 trial data.
- Phase 4: after approval by the United States Food and Drug Administration (FDA), the drug is available for use in the general population and further monitored for safety, efficacy, and long-term side effects.
During Phases 1 to 3, the drugs are available only to patients who participate in the clinical trial. In phase 4, the drugs are commercially available through drug stores and specialty pharmacies. Clinical trials have historically been available only at major medical centers but are increasingly becoming available at smaller community medical centers due to the expansion of hospital networks. A list of all clinical trials available for lung cancer patients is provided on the Internet site of the National Cancer Institute (http://www.cancer.gov/clinicaltrials/search). The treating oncologist may recommend trials that are available locally as well as at regional medical centers.
Sometimes new drugs that demonstrate a major increase in efficacy compared with older therapies are granted FDA Breakthrough Therapy or Fast Track status. The status expedites the development and FDA review process with the goal of making these exciting new treatments available to patients in the shortest possible time while still preserving the research process and maintaining patient safety. Drugs with Fast Track Status or Breakthrough Therapy designation are initially available only in clinical trials, but typically move through the clinical trial process and become widely available through commercial dispensing pharmacies much more quickly than if they had followed traditional approval pathways. Certain targeted therapies have shown such improvement in efficacy and tolerability compared to standard therapies that they have moved from Phase 1 “first in human trials” to FDA approval in under four years. Shortening the timeline for moving novel drugs from the laboratory into the clinic for patient use has clear benefit for improving patient outcomes, particularly in lung cancer where for many years, there has been a clearly documented need for new and improved treatments.
Chemotherapy drugs work by killing cancer cells that multiply rapidly. However, many normal cells also multiply rapidly, such as cells of the digestive tract, hair follicles, and blood. When these normal cells are affected by chemotherapy drugs, undesirable side effects occur. Targeted therapy includes newer drugs that interfere with specific aspects of cancer cells, minimizing damage to normal cells. Targeted therapy consists of either monoclonal antibodies (drug names ending in “-ab”) that target the outside surface of the cancer cell or small molecules (drug names ending in “-ib”) that target the inside of the cancer cell.
As genetic research advances, great strides are being taken to better understand the molecular make-up of tumors, and to determine the mechanisms which drive tumor development, growth, and spread to other organs (metastasis). The wider availability of full genome sequencing of tumor DNA is opening up the opportunity for truly personalized medicine, in which therapies are targeted to the specific genetic make-up of an individuals’ tumor. Genome sequencing offers the opportunity to identify rare mutations and then design a treatment plan to block the exact mechanism that is making the cancer grow. Examples of well-studied mutations that are common in lung cancer are EGFR mutations, EML4-ALK gene rearrangements, and KRAS mutations. Newer targets being researched in lung cancer include ROS1, BRAF, HER2, MET, PIK3CA, RET, MEK, and NTRK. Several drugs used to target these mutations have been approved by the FDA for either lung cancer or other types of cancer, while many of the novel agents listed below are available only through clinical trials.
Monoclonal antibodies are one type of signaling molecule that binds to receptors on the cell surface. When these signaling molecules stimulate cell surface receptors, they initiate a cascade of messages inside the cell that promotes cellular growth and development. The normal cellular controls for this process are absent in malignant cells, and cellular replication proceeds uncontrolled. Antibodies are produced by the immune system to fight infections caused by bacteria or viruses, and the body produces specific antibodies for each type of infectious agent (antigen) to which the body is exposed. Identification of tumor-specific antigens allows novel drugs to use the immune response to recognize and fight cancer cells. This class of drugs, known as monoclonal antibodies, are produced in a laboratory and are designed to bind with a very specific target, such as a cell surface receptor or other defects unique to cancer cells.
Monoclonal antibodies fight cancer cells through several mechanisms, including:
- Blocking cell surface receptors to turn off the downstream cell signaling cascade.
- Targeting specific defects in the cancer cells or labeling the cancer cells, making them more vulnerable to destruction by the body’s immune system.
- Delivering other drugs or substances directly to the cancer cells.
It should be noted that many of the recently approved immunotherapies used in treating lung cancer patients are monoclonal antibodies. See Chapter 4: Systemic Therapy for Non-Small Cell Lung Cancer
Trastuzumab is a monoclonal antibody that targets HER2 overexpression. It has been used in HER2 positive breast cancer (received FDA approval for this application in 1998) and is now being evaluated in lung cancers with the same mutation. Common side effects include nausea, vomiting, loss of appetite, fatigue and muscle or joint aches.1 Cardiac toxicity can be a serious complication, and warrants close monitoring.2 Allergic reactions may occur during the infusion of this drug. If used in combination with chemotherapy, it may contribute to decreased white blood cell count and increased risk of infection.
Tiragolumab is an anti-TIGIT antibody that is being evaluated in combination with atezollizumab. Overall response rate was 37% in an unselected cohort, but when PD-L1 expression was over 50%, the response rate was 66%.3 Side effect profile was similar to what has been demonstrated with atezolizumab alone, suggesting very little added toxicity associated with Tiragolumab dosing. This combination has been granted breakthrough status by the FDA,4 and the Phase III SKYSCRAPER-01trial (NCT04294810) is ongoing.
Antibody-Drug Conjugates (ADCs)
Antibody-drug conjugates are formed when an antibody is fused with a drug via a linking structure. The antibody portion serves to identify and target cancer cells, allowing for delivery of the cytotoxic “payload” directly to the tumor. This technique has the potential to improve therapeutic response while minimizing the risk for side effects. Resistance to these types of therapies can develop when either the cell decreases expression of the antibody target, when there is decreased internalization of the drug payload, or when there is increased export of the therapeutic compound out of the cell before it can have an anti-tumor effect.
Ado-trastuzumab emtansine (T-DM1) is an ADC directed against HER 2. Although it appeared to be quite effective in breast cancer, the impact in lung cancer has been less significant. In a trial with 49 patients, there were only 4 partial responses, and these were seen only in those patients 7 with the highest level of HER2 overexpression. Median progression free survival was 2.7 months. The TDM1 was well tolerated with fatigue being the only grade 3 adverse event reported in more than one patient. Also noted were risks of infusion related reactions and thrombocytopenia.5
U3-1402 is an ADC directed against HER3. Its toxic therapy is DC 8951, which is a topoisomerase 1 inhibitor. It is currently being evaluated in a phase 1 clinical trial for patients whose metastatic NSCLC has an EGFR mutation and whose disease has progressed on an oral EGFR directed targeted therapy. Initial trial results are not yet available, but are expected to be published in 2022.6
Sacituzumab govitecan (IMMU-132) is an ADC targeting Trop-2 that is combined with a toxic payload of SN-38, the active metabolite of irinotecan and a topoisomerase 1 inhibitor. Fifty four heavily pretreated NSCLC patients were evaluated in a phase 1 expansion cohort with a demonstrated response rate of 17%, with median PFS of 5.2 months and median OS of 9.5 months. However, 67% of patients were seen to have a reduction of tumor size from baseline. Side effects included neutropenia, GI upset (diarrhea, nausea) and fatigue.7
Telisotuzumab Vedotin (ABBV-399) is a c-Met–targeted antibody-drug conjugate. Results of the Phase 1b study of telisotuzumab vedotin in combination with erlotinib in patients with lung cancer harboring an EGFR mutation and c-Met amplification showed a response rate of up to 35%. Side effects included rash, diarrhea, nausea, vomiting, fatigue, neuropathy, and loss of appetite. An increased risk of blood clots was seen as well.8
Targeted Therapy - Small Molecules
Small molecule drugs are a large class of medications that work by entering the cell and blocking the sequence of reactions that cause cellular proliferation. By blocking this sequence of reactions in cancer cells, the small molecule drugs kill the cancer cells and slow or stop tumor growth. In normal cells, tyrosine kinase enzymes activate a phosphorylation cascade that regulates signals sent to the cell nucleus and governs the timing of cellular proliferation, differentiation, and programmed cell death (apoptosis). In malignant cells, this communication cascade may be switched on permanently, resulting in unregulated cellular proliferation and tumor growth. Tyrosine kinase inhibitors are small molecule drugs that interfere with this sequence of reactions, stopping cell proliferation and causing cell death. New tyrosine kinase inhibitors continue to be studied for use in lung cancer, and several are now commercially available for patients with specific, targetable mutations in tumor DNA. During treatment with small molecules the cancer cells may develop additional mutations that confer resistance to first line therapy. Identification of second and third-line therapies that continue to exploit the underlying driver mutation but also block resistance mutations has become increasingly important. EGFR and ALK are two well established therapeutic targets for small molecule inhibitors. However, multiple newer targets continue to be identified, offering patients a chance at treating their disease while maintaining better quality of life with fewer side effects than they might have with chemotherapy.
Multiple EGFR targeting drug therapies have been developed for lung cancer over the past 10 years. The challenge now is to identify which therapies will allow patients to remain on targeted therapy for longer, and maximize clinical benefit either by blocking resistance mechanisms from the outset, or by adding in additional therapies to address resistance mechanisms as they develop over time.
BLU-945 is a fourth generation EGFR inhibitor that has activity against both “double mutants” with EGFRm and T790m, as well as “triple mutants” with EGFRm, T790m and C797s.9 Both T790m and C797s mutations have been well documented as resistance mechanisms to EGFR TKI drugs. Fourth generation compounds such as BLU-945 seek to block not only the original EGFR mutation, but also the more common resistance mechanisms which may develop, thereby prolonging a patients response and extending the time to progression on first line therapy. Although there are only pre-clinical data available at this time, a phase 1 clinical trial is planned to start enrollment in the summer of 2021.10
Nazartinib (EGF816) is a third generation EGFR inhibitor with activity against exon 19 deletion, L858R and T790m mutations. It is currently being evaluated in Phase III trials in the first-line setting. Common side effects included rash, diarrhea, itching, mouth sores, and fatigue. Response rate in the Phase 2 trial was 64%, The 6-month duration of response rate was 91%, and the median duration of response was not estimable. Nazartinib also demonstrated good intracranial efficacy, with 53% of patients with baseline brain metastasis experiencing resolution of their intracranial disease. Currently this drug is available only through clinical trials.11
Because of the higher prevalence of EGFR mutations in Asian patients, there are several trials being conducted exclusively in Asia to evaluate the safety and tolerability of novel EGFR directed compounds. Unfortunately, all patients on EGFR targeted therapies will eventually progress, and much effort is being focused on how to extend time to progression on first line therapy, as well as how best to identify and treat resistance mechanisms that can arise. In the front line setting osimertinib is being combined with earlier generation EGFR TKIs (NCT03122717 ), with chemotherapy such as carboplatin and pemetrexed, as well as with VEG-F inhibitors including bevacizumab and ramucirumab. It is critical to obtain additional molecular profiling after progression of first line therapy to try to identify the nature of the acquired resistance mechanism as that can guide the selection of subsequent therapy. For example, if a MET alteration is identified then trial combining osimertinib with a MET inhibitor such as tepotinib12 or savolitinib13-15 could be considered. Alternatively, if a C797S mutation is identified, then changing to a first generation ERGFR TKI such as erlotinib or gefitinib may be appropriate. Additional cell signaling pathways and drug combinations being evaluated include blocking MEK (osimertinib + selumetinib) and Aurora Kinase A (osimeritnib + alisertib).
Since its identification as a therapeutic target in NCSLC, multiple drugs have been FDA approved for use in patients with an ALK rearrangement (aka mutation). Similarly to what is observed in the EGFR mutant patient population, despite initial excellent response rates to TKI therapies, essentially all patients will eventually develop resistance and progress. Much effort is being dedicated into understanding the ideal sequencing of ALK inhibitors to obtain the best clinical response for patients, as certain resistance mechanisms are more likely to develop after some of the drugs than others. The G1202R mutation is identified as a resistance mechanism in up to 43% of patients who progress on ALK targeted therapies.16 It can only sometimes be overcome by treatment with the third generation drug lorlatinib. In addition to the single agent therapies being evaluated for use in ALK mutation positive patients described below, multiple trials are looking at combinations of ALK TKIs with other drugs, including MEK, VEGF and mTOR inhibitors.17
TXP-0131 is a novel ALK inhibitor that demonstrated potent activity against many known ALK resistance mutations in pre-clinical studies, most excitingly it was active against G1202R as well as all the known compound or “double” resistance mutations which have been challenging to target previously. A phase 1/2 trial (FORGE-1) evaluating TXP-0131 is expected to open and begin enrollment in 2021.18
Ensartinib (X-396) is a potent ALK inhibitor with anti-cancer activity against both treatment naïve tumors and those that developed resistance to first-line therapy with Crizotinib. In the Phase 1 trial over 80% of patients responded to therapy, with observed activity in the brain.19 Response lasted for a median duration of more than 20 weeks with some responses lasting for over 50 weeks. Common side effects included rash, fatigue, nausea, vomiting and swelling. Responses were also observed in the central nervous system, with an intracranial response rate of 64%. Phase 3 data from the eXalt3 trial comparing TKI treatment naïve patients randomized to crizotinib vs ensartinib showed improved PFS in the ensartinib arm and time to treatment failure at 12 months was 4.2% for ensartinib vs 23.9% for crizotinib.20 Ensartinib also conferred improved disease control in the brain, with an intracranial ORR of 64% on the ensartinib arm compared to 21% with crizotinib. Safety data was consistent with earlier trials, with ensartinib being well tolerated. One unique AE was a sunburn like rash that was typically mild. However, it is unclear how this agent would fit into the treatment paradigm, as it does not appear to have unique properties when compared to current ALK-inhibitors that are already FDA approved.
Because the ROS1 signaling receptor target is conformationally quite similar to that of ALK and TRK, Lorlatinib (FDA approved for use with ALK rearrangements) is also being evaluated for efficacy against ROS1 in Phase 2 trials, with promising results.21 Although not FDA approved, Lorlatinib is recommended by NCCN guidelines for second-line therapy in patients with ROS1 rearrangement after they progress on Crizotinib.
Taletrectinib (AB-106 / DS-6051b) is a new selective ROS1/NTRK inhibitor that showed promising pre-clinical data and is currently undergoing Phase 1 testing in both the US and Japan.22 In the pooled analysis of US and Japanese patients, the ORR was 33% with a median PFS of 14.2 months.23 The compound is exciting to researchers as it has been shown to have activity against the secondary resistance mutation G2032R, which commonly develops after first-line ROS directed targeted therapies such as crizotinib, and also confers resistance to the next-generation inhibitors Lorlatinib and Entrectinib.
Foritinib (SAF-189s) is a potent oral TKI with activity against both ALK and ROS. Importantly, in pre-clinical studies it has demonstrated activity against the G2032R resistance mutation that often develops after initial ROS-1 directed TKI therapy.24 It is currently being studied in a phase I/II trial enrolling both TKI naïve as well as pre-treated patients.25
Ceritinib has been shown to have activity in the front-line setting for lung cancer patients whose tumors have a ROS-1 rearrangement. Unlike for those patients with ALK rearrangement, Ceritinib does not seem to have second-line activity after progression on Crizotinib for ROS1-rearranged tumors. A Phase 2 trial with 32 patients showed a 62% response rate and 81% disease control rate. Activity in the brain was demonstrated, with a 63% disease control rate, although the sample size was small at only 5 patients with brain metastases.26 Common side effects include diarrhea, nausea, vomiting, loss of appetite, and lab value changes including increased liver function enzymes and low phosphate levels.27 Currently Ceritinib is recommended in the NCCN guidelines for first-line use in ROS1rearranged NSCLC, but it does not yet have FDA approval in this indication.
Cabozantinib is a multi-kinase inhibitor with activity against several cell signaling targets including ROS-1 rearrangement. It is being evaluated in lung cancer following progression on Crizotinib and Ceritinib. In particular, it has shown efficacy against the G2032R and L2026M resistance mutations found in ROS-1 rearranged tumors.28-29 Safety and efficacy of Cabozantinib continues to be evaluated in lung cancer, but common side effects when used in other types of cancer included nausea, diarrhea, fatigue, mouth sores, and hand-foot syndrome (redness, pain, tingling and numbness to hands and feet).30
Repotrectinib has demonstrated safety and activity in clinical trials (TRIDENT-1) for patients with advanced ROS-1 fusion NSCLC, with response rates of 91% in the TKI-naïve patient population and 40% in patients who had received previous ROS-1 targeted therapy.31 Repotrectinib also showed a potential to overcome TKI resistance mutations after treatment with Crizotinib. It is generally well tolerated, with dizziness, fatigue, contipaiton, taste changes, dyspnea and hypoxia seen in some patients. It was granted fast track status by the FDA in August 2020.32
BRAF mutations are present in 4-5% of NSCLC patients. They are divided into three main classes – Class I are the V600 mutations, for which dabrafenib and trametinib are approved. Class II and III do not yet have FDA approved targeted therapies. Several combination therapies have appeared promising in the pre-clinical setting, and are just entering human clinical trials. Some of these include Lifirafenib (a RAF dimer inhibitor) plus mirdametinib (a MEK inhibitor) (NCT03905148) as well as combinations of LXH254 with either LTT462 or trametinib or ribociclib in melanoma patients (NCT04417621). Because these compounds are in early stages of clinical trial evaluation little safety, efficacy and response data are available. Encorafenib (Braftovi) is a BRAF inhibitor currently being studied in clinical trial in combination with Binimetinib (a MEK inhibitor) in patients with advanced NSCLC whose tumors have a BRAF V600E mutation. Trial enrollment began in June 2019, no results in lung cancer patients have been published to date. The combination was approved for melanoma patients with this mutation in 2018. Side effects have been shown to include fatigue, nausea, diarrhea, vomiting, abdominal pain, and arthralgia. This combination may be less likely to cause fevers than other BRAF targeted therapies.33
Selumetinib is a small molecule drug that is currently approved for pediatric patients 2 years of age and older who have neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN). It inhibits the mitogen-activated protein kinases MEK-1 and MEK-2. It stops cellular proliferation and induces apoptosis in some cell lines.34 Common side effects include rash, diarrhea, nausea, vomiting, hypertension, visual disturbance, and decreased liver function. It has been evaluated in combination with chemotherapy for KRAS mutant lung cancer, and unfortunately was not found to improve progression free survival when combined with docetaxel in the second-line setting. The TATTON trial showed that when combined with Tagrisso for EGFR-mutant patients Selumetinib does appear to have benefit, with 34-42% of patients having partial response, and disease control rate up to 81%.35 Selumetinib continues to be evaluated in combination with immunotherapy in ongoing clinical trials.36
Bimetinib (MEK162) is being evaluated in combination with other therapeutic agents for lung cancer, including standard of care chemotherapy agents as well as other targeted therapies. Common side effects include diarrhea, fatigue, elevated lipase levels, and rash.37 It continues to be evaluated in Phase 2 clinical trial for BRAF mutant NSCLC in combination with Encorafenib, as well as for ALK-rearranged NSCLC in combination with Brigatinib. It remains available through clinical trials only.
NTRK 1/2/3 are oncogenic driver mutations that are present in many types of solid tumors. They are identified in approximately 1% of NSCLC patients.
Selitrectinib (LOXO-195) is a selective TRK inhibitor evaluated in an ongoing phase 1 clinical trial. Early results form 29 patients showed an overall response rate of 34%, with 45% of patients harboring an acquired NTRK mutation that developed during prior TRK directed therapy having a response to LOXO-195. Comon side effects included dizziness, ataxia, nausea, fatigue, lab abnormalities and abdominal pain. The estimated trial completion date is July 2024.38
Repotrectinib (TPX-005) is a TRK inhibitor that was granted fast-track status by the FDA for NTRK + cancers after prior first line TRK inhibitor. It continues to be evaluated in the TRIDENT-1 clinical trial for patients with either NTRK 1-3, ALK or ROS1 gene rearrangements. In the NTRK mutated cohort 6 patients were evaluable, with an overall response rate of 50%. It is generally well tolerated, with dizziness, fatigue, constipation, taste changes, dyspnea and hypoxia seen in some patients.32
Additional Small Molecule Inhibitors
Multiple other targets continue to be discovered for NSCLC as science advances and the ability to test patients for multiple gene targets becomes a reality. These additional gene targets include HER2, MET amplification, MET exon 14 mutation, KRAS, RET, PIK3CA, AXL and MAP2K1 (also known as MEK1). Numerous drugs are currently being investigated that show activity against one or more of these targets. Interestingly, many of these drugs have more than one intra-cellular target and are being evaluated for application in different types of cancer as well as potentially being useful for multiple different tumor mutations. As the science of tumor genetic sequencing progresses more drug-gene targets will be established in an effort to truly personalize treatment to the genetic fingerprint of an individual patient’s cancer, with continued improvement in treatment options and therapeutic outcomes for lung cancer patients.
Savolitinib is a MET inhibitor currently being evaluated in combination with Osimertinib for use in patients who progress on first-line EGFR TKI therapy and demonstrate a MET exon 14 deletion as a resistance mechanism. In the TATTON trial the safety and efficacy of the combination of Savolitinib with Osimertinib was established. Results showed a response rate of 28% – 52%, depending on what treatment the patient had received in the front-line setting.13-14 Side effects were somewhat more severe than observed with single agent dosing, with the most frequent side effects being nausea, diarrhea, fatigue, fevers, decreased appetite, and decreased blood cell counts (white blood cells and platelets). The combination of Savolitinib with Osimertinib continues to be evaluated in the Phase 2 SAVANNAH trial which began enrollment in early January 2019.15
TPX-0046 is a next-generation RET inhibitor. Pre-clinical data demonstrated that this compound has the ability to overcome some of the more common resistance mechanisms identified following treatment meth currently available RET inhibitors. A phase I/II clinical trial (NCT04161391) is currently enrolling, but data from human studies are not yet available.39 Several additional compounds are in early stages of development, including TAS0953/HM06 (NCT04683250) and BOS172738 (NCT03780517). No safety or efficacy data have been published at this time.40-41
KRAS mutations are among the most commonly found oncogenic drivers of tumorigenesis in lung cancer, however KRAS has historically been considered an “undruggable” mutation due to a lack of a traditional small-molecule binding pocket on the protein. Sotorasib was approved in the spring of 2021 for patients with KRAS G12C mutations. However, this is only one of the multiple oncogenic KRAS mutations that have been identified.
Adagrasib (MRTX849) is an inhibitor of KRASG12C that irreversibly and selectively binds to KRASG12C, preventing downstream cell signaling. The KRYSTAL-1 trial evaluated 51 patients with previously treated KRAS G12C mutated NSCLC, and 45% had at least a partial response to adagrasib therapy. In those patients with a concomitant STK11 mutation, the response rate was 64%.42 Side effects included GI upset (nausea, vomiting, diarrhea) fatigue and lab abnormalities.42 Additional trials are ongoing to better understand the efficacy of this drug, including combining it with immunotherapy and other targeted therapies.43
EGFR / HER2 Exon 20 insertion
EGFR exon 20 insertion are a unique group mutations. Unlike the majority of EGFR mutations which are “sensitizing” mutations, exon 20 insertions tend to confer resistance to the typical first generation EGFR TKIs. Thus, addressing this unique oncogenic target has required development of its own set of therapies. Amivantamab is an infusion therapy that was approved in May 2021 for this mutation subtype, but several additional agents continue to be evaluated in clinical trials. CLN-081 is an oral EGFR inhibitor with high selectivity to mutant form of EGFR with exon 20 mutations. Although the overall response rate is not yet available, preliminary trial data showed a reduction in tumor size in 76% of patients. The safety data suggest that CLN-081 is better tolerated than some of the other exon 20 targeting therapies, with fewer than 20% having grade 3 or severe side effects. Typical side effects were rash, diarrhea, lab abnormalities and stomatitis.44
Poziotinib is an oral tyrosine kinase inhibitor that is being evaluated in the Phase II ZENITH20 trial for lung cancer patients with EGFR or HER2 Exon 20 insertion mutations. Poziotinib irreversibly blocks signaling through the HER family of receptors, including HER1 (ErbB1/EGFR), HER2 (ErbB2), and HER4 (ErbB4). Response rates were encouraging, with tumor reduction seen in up to 28% of patients treated. Unfortunately, side effects have been problematic, with over 50% of patients experiencing moderate to severe symptoms, including rash, diarrhea, paronychia, mucositis, and fatigue. These side effects often require dose reduction or treatment discontinuation. Splitting the dose into twice daily dosage appears to decrease the risk for severe toxicity by up to 52% while maintaining response rates of approximately 30%. The ZENITH20 trial continues enrolling patients to better understand the efficacy of the twice daily dosing schedule.45
Mobocertinib (TAK788) is an oral inhibitor of tumors with EGFR/HER2 exon 20 insertion mutations. In a phase 1/2 clinical trial it demonstrated a response rate of 43%, and PFS of 7.3 months.46 The extent of CNS penetration is not yet well characterized, and additional data is needed to better understand the degree to which this compound can cross the blood brain barrier. Common side effects reported were diarrhea, nausea, vomiting, decreased appetite and rash. Mobocertinib was granted breakthrough status designation by the FDA in April 2020, and the Phase 3 EXCLAIM-2 trial continues to evaluate efficacy and safety in the first line setting.
Pyrotinib is another TKI with irreversible binding and pan-HER activity (i.e. it has activity against HER1 (EGFR), HER2 and HER4. It has been evaluated in several Phase 2 trials, in one case after patient had received at least one prior line of chemotherapy, with almost 60% having had at least 2 prior lines of chemotherapy.47 Overall response rate was 30% with a median PFS of 6.9 months.48 Side effects were reported to be diarrhea as well as lab abnormalities.
Tarloxotinib is a pan-ErbB kinase inhibitor that was shown in pre-clinical studies to have activity against EGFR exon 20 and HER2 mutant NSCLC. The RAIN-701 study showed positive results in their first presentation of initial data analysis in September of 2020. At the time 23 patients (of a planned 60) had been enrolled onto the trial with evaluable results. Two patients had a partial response, with a demonstrated disease control rate of 60% (at least stable disease). Side effects seen included changes to heart rhythm, rash, diarrhea, nausea and lab abnormalities.49
AXL is a cell membrane receptor that has been identified new drug target in lung cancer. High AXL expression is thought to suppress the body’s immune response to cancer cells, and promotes resistance to anti-PDL1 immunotherapies.50 Further, high AXL expression is thought to confer a poor prognosis in most cancers. Currently there are no FDA approved therapies targeting AXL.
Bemcentinib (BGB324) is a novel AXL inhibitor which seemed to enhance anti-PD1 therapy in pre-clinical studies. A phase 2 trial involving 38 patients have been dosed with the combination of bemcentinib and pembrolizumab, with 29 evaluable for response to treatment. 28% of patients showed a partial response, and 40% of the AXL-positive patient responded to therapy.51 The FDA has granted bemcentinib fast track status, and clinical trial enrollment is ongoing.50
Cancers develop and spread in part because they evade detection by the immune system. The goal of immunotherapy is to make cancer cells recognized as abnormal or “non-self” by the immune system, enabling natural immune defense mechanisms to eliminate the cancer. With immunotherapy, side effects are typically mild because the drugs affect only certain types of cells, and they use the body’s own defenses (not cytotoxic drugs) to kill cancer cells. However, in some cases the immune system may become over-engaged, creating auto-immune inflammatory side effects. These side effects can be severe and may require treatment with immune suppressant medications.
Several antibodies have been developed that target immune checkpoints, which play a role in cell signaling and driving cancer growth. Some of the most promising developments in treating lung cancer have been seen with drugs that target the Programmed Death 1 (PD-1) receptor pathway, including Opdivo (Nivolumab), Keytruda (Pembrolizumab), Tecentriq (Atezolizumab), and Imfinzi (Durvalumab). Currently all four of these have been approved by the FDA for at least one indication in lung cancer treatment.
Ipilimumab and Tremelimumab are monoclonal antibodies that inhibit the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immune checkpoint pathway. Although these agents have been used extensively in the treatment of melanoma, they are now being evaluated in NSCLC, typically in combination with the Anti-PD1 class of drugs. They have a similar side effect profile to the Anti-PD1 antibodies, including rash, diarrhea/colitis, hepatitis, iritis/uveitis, hormonal changes and pneumonitis. However, side effects tend to be more common with Anti-CTLA-4 drugs compared to Anti PD-1 and Anti-PD-L1 compounds.52-53
NKTR-214 (Bempegaldesleukin) is a CD122-preferential IL-2 pathway agonist that was designed to enhance the patient’s own immune response in order to fight their cancer. In the PIVOT-02 trial BEMPEG showed an overall response rate of 60% in the NSCLC cohort.54 It is currently being evaluated in clinical trials in combination with Nivolumab or with Nivolumab and Ipilimumab, as well as with Pembrolizumab. Common side effects are fatigue, fevers, chills, and flu-like symptoms. Enhancing the immune response is felt to be particularly important for those patients whose tumors do not express PD-L1.
APX005M is a CD40 Agonistic Antibody being studied in combination with Nivolumab and Cabiralizumab. This drug was designed to stimulate the immune system and enhance the anti-cancer immune response. There is limited data for NSCLC, however a Phase 1 trial reported on four patients of whom one had a partial response, two had stable disease and the fourth progressed.55 Side effects include fatigue, malaise, nausea, fevers, chills and flu like symptoms. The Phase 2 trial continues to enroll patients, with results forthcoming.
NC318 is a novel monoclonal antibody targeting Siglec-15. It was designed to function in the tumor microenvironment and enhance t-cell function, thereby restoring the ability of the immune system to recognize and fight off cancer cells. Currently only pre-clinical data have been published and suggest a tolerable safety profile with less risk of serious immune-related toxicity than the anti-PD-1 and anti-CTLA4 targeted antibodies have previously demonstrated.56 The initial Phase1/2 clinical trial is currently enrolling patients and has an expected completion date 2021.
In an effort to try to both improve first line response rates to immunotherapy as well as to overcome resistance to first line immunotherapies, multiple trials are being conducted evaluating novel combinations of immunotherapy with targeted therapies. Some of these include PARP inhibitors, VEGF inhibitors, novel anti-CTLA-4 antibodies, anti-CD137 antibodies, ICOS agonists and antagonists
While the compounds noted above and the majority of lung cancer clinical trials continue to be designed to help patients diagnosed with stage IV disease, many immunotherapy drugs are also being tested for use in patients diagnosed with earlier stage lung cancers because of their potential for considerable clinical benefit. In stage III unresectable disease Durvalumab was FDA approved for use as maintenance therapy and other immunotherapies are now being used in combination with chemotherapy and radiation. In stage Ib, II and resectable stage III patients, the LCMC3 trial is investigated the use of 2 cycles of atezolizumab prior to surgery. This approach has demonstrated major pathologic response with less than 10% viable tumor remaining after 2 cycles of atezolizumab in 21% of patients, and complete response in 7% of patients.57 Another trial evaluating response to combination immunotherapy prior to surgery is the NEOSTAR trial, which is enrolling stage I – IIIA patients and is using a combination of Nivolumab and Ipilimumab. In this trial major pathologic responses were seen in 22% of patients in the nivolumab arm and 50% of patients in the Nivolumab plus ipilimumab arm following resection.58
Another type of cancer treatment that has received a lot of attention recently is CAR-T therapy. It is currently approved for several types of blood cancers, but its utility in solid tumors, and in lung cancer in particular remains unclear. Part of the challenge in lung cancer is identifying a target unique to the cancer cells that is not present elsewhere in the body. Too much overlap between the presence of the target in the tumor and healthy tissues will result in the patient suffering severe side effects due to off target impacts of the treatment. Rather than CAR-T cells, a perhaps more promising avenue in solid tumor is to develop specific tumor infiltrating lymphocytes (TILs) that are unique to a particular patient and will recognize and eliminate their specific cancer cells. Trials are currently enrolling patients where researchers collect a tumor specimen from a patient and then isolate the active TILs, increase their number exponentially in a lab, and then infuse them back into the patient. The TIL therapy regimen is quite intense, almost like a mini bone marrow transplant. First the patient undergoes a biopsy to collect tumor tissue. If adequate tissue is obtained, then the patient is admitted to the hospital for several weeks of chemotherapy. During this time the TILs are being isolated and grown in the lab. If the patient is clinically stable after the chemotherapy, they will then receive the infusion of TILs along with other immune stimulatory agents, after which they a monitored closely for potentially severe side effects.
Tumor Mutational Burden
Immune Checkpoint Inhibitors have become a mainstay of lung cancer treatment. In patients without targetable mutations immunotherapy continues to show improved efficacy either as monotherapy or in combination with chemotherapy in comparison with chemotherapy alone in the first- and second-line setting. Unfortunately, only about 20% of patients demonstrate durable long-term responses to these drugs, while a significant proportion of patients experience disease progression within the first months of treatment. PD-L1 expression level is currently the only biomarker approved by the FDA, yet it is not perfect, and seems to correlate with treatment response in some but not all patients. One cannot ignore the high cost of these immunotherapy medications (as much as $150,000/year), and from a purely economic perspective a better marker to identify response is needed to avoid wasteful spending of healthcare dollars. For these reasons, a new set of biomarkers must be developed that will better guide clinicians and help identify those patients who will benefit from immune checkpoint inhibitors.
Tumor mutational burden (TMB) is one potential marker of response to immunotherapies. TMB is defined as the number of mutations per DNA megabase. It continues to be studied as a potential biomarker to predict response to immune checkpoint inhibitors in NSCLC. To date, responses from clinical trials have been mixed, with some trials showing a predictive association between high TMB and treatment response, while others not finding the same predictive relationship.59-60
Because of the potential for long-term durable responses with immunotherapies, any marker selected to guide treatment selection will have to be well validated with extensive clinical support. Limiting treatment options and potentially preventing patients from the benefit of these novel therapies needs to be considered with the utmost caution.
Corticosteroids and ICI
Recent research has brought into question whether or not steroid use affects clinical outcomes during treatment with immunotherapies. Some studies have demonstrated that patients who received corticosteroids prior to starting ICI therapy experienced lower overall response rates, worse progression free survival, and poorer overall survival.61
One large retrospective study looked to determine the effect of corticosteroid use specifically in the treatment of immune-related adverse effects and found that there was no significant difference in overall survival (median; 14.5 vs 30.0 months), progression-free survival (median; 7.8 vs 9.6 months), and objective response rate (46% vs 41%) in patients who required steroids (>10mg per day) vs those who did not. They concluded that steroids should not be avoided in patients with moderate to severe immune-related adverse effects due to concerns over reduced efficacy.62
Gut Microbiome and Cancer Treatment
Another avenue of research in cancer treatment is the effect of the gut microbiome on overall health, promotion of pathogenic conditions including tumor development and treatment outcomes. A recent report documented stark differences in gut flora of patients following cancer treatments compared to their healthy peers. It has long been understood that antibiotics can change the gut microbiome, and it has become clear that use of antibiotics can impact response to immune checkpoint inhibitor therapy. Several studies have demonstrated significant reduction in progression free and overall survival when antibiotics are administered in the 30 days prior to initiation of immunotherapy treatment.63-65 Methods for how best to restore gut balance and enhance the positive effects of the microbiome on health are currently under investigation.
Vaccines are also being used to treat lung cancer and as maintenance therapy with the goal of decreasing or preventing the risk of recurrence. Analogous to vaccines that may prevent the spread of communicable diseases, these cancer vaccines stimulate the immune system to identify and attack cancer cells without damaging normal cells.
CIMAvax-EGF is also known as the “Cuban Vaccine” and is currently available in the US through clinical trials. Multiple trial have shown that it is safe and does elicit an immune response.66 Side effects have been reported to include fevers, injection site irritation, vomiting, and headache.67 A phase III trial evaluating use of the vaccine after completion of platinum chemotherapy did not find overall survival benefit.67 Further studies are needed to determine whether this vaccine can benefit lung cancer patients.
TG4010 is targeted immunotherapy based on a pox virus (the Modified Vaccinia Ankara virus) that codes for the MUC1 tumor-associated antigen and interleukin-2. TG4010 has been assessed in combination with first-line chemotherapy in advanced NSCLC and has shown an improvement in progression-free survival.68 Common side effects include injection site reaction and flu-like symptoms.69 TG4010 continues to be evaluated in Phase 2 and 3 clinical trials, and is now being combined with chemotherapy as well as Opdivo (Nivolumab).70 Additional data on this combination of drugs is expected to be published in late 2021.
BI 1361849 (CV9202) is a vaccine that is made up of six mRNAs that code for six different NSCLC-associated antigens. Phase 1 trials have demonstrated safety and tolerability of the compound, as well as an enhanced anti-tumor effect when combined with radiation.71 Collection of survival data remains ongoing. The most common side effects were injection site reactions and mild to moderate flu like symptoms. As it is thought that this compound may increase tumor infiltrating lymphocytes, a trial combining it with an immunotherapeutic agent targeting Anti-PD-1 was performed with modest responses seen in the 26 enrolled patients, including one partial response and 46% of patients with stable disease.72 A trial is ongoing combining BI1361849 with both Anti-PD-L1 and Anti-CTLA-4 antibodies.73
Although much research is focusing on new approaches to lung cancer treatment, research also is being done to develop new drugs for chemotherapy or improve existing chemotherapy regimens. Combination therapy has long been the hallmark of cancer treatment. As promising new agents are identified, they are evaluated in clinical trials in an effort to identify novel treatment modalities that will improve quality of life and prolong survival. Multiple trials evaluating the addition of small molecules, monoclonal antibodies, as well as immunotherapy are currently underway.
Multiple studies have been conducted to identify compounds that might prevent the development of lung cancer. Unfortunately, to date none have been identified that have demonstrated a dramatic decrease in cancer rates.74 Antioxidants and anti-inflammatory drugs like COX-2 inhibitors did not ultimately show a decreased cancer incidence, but aspirin seemed to slightly decrease risk in several studies, particularly in those at highest risk for developing lung cancer.75 A better understanding of features of pre-malignant lesions continues to develop, and a personalized “cocktail” may ultimately offer the best protection against developing lung cancer in high risk individuals.76 Unfortunately no compound has been identified that has protective effects against lung cancer. Smoking cessation remains the best approach available to prevent an individual from developing lung cancer.
Lung Cancer Screening Programs
Because 1 in 9 smokers will go on to develop lung cancer, avoiding exposure to tobacco smoke and smoking cessation remain the best defense against lung cancer.76 See Chapter 13: How to Quit Smoking Confidently and Successfully. However, novel screening algorithms are being developed for use of low-dose screening CT scans in order to identify both those individuals at highest risk for lung cancer, as well as to identify cancers in an early, asymptomatic, surgically resectable and thus more treatable stage. The best lung cancer screening programs are comprehensive, and include the services of pulmonary experts, as well as oncologists and counselors who can educate patients regarding their risk of developing cancer as well as interpret and appropriately act on any screening test results.
Lung cancer is a devastating diagnosis, but research is improving both the options for treatment of this disease as well as patient outcomes. Chemotherapy has been the mainstay of treatment for most advanced lung cancers for many years. However, new targeted therapies and immunotherapies are changing the treatment landscape for lung cancer, with several new drugs demonstrating remarkable improvement in patient outcomes in terms of both progression free and overall survival. Additional novel agents used both alone and in combination with existing agents are being studied in clinical trials, with the goal of further improving patient outcomes and survival. More therapies will become available in the near future. With advances in lung cancer treatment, patients will benefit from treatments that have fewer side effects and provide long term responses to treatment, such that even if lung cancer remains incurable, it may be treated as a chronic disease and managed for many years.
Questions to Ask About Clinical Trials
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