Good evening and welcome! Thank you for joining OncLive’s fifth episode of Thoracic Night Live, a program devoted to spotlighting the biggest topics in lung cancer and pivotal studies discussed at medical meetings throughout the year.

Live from New York City, I’m Josh Sabari, MD, an assistant professor in the Department of Medicine at NYU Grossman School of Medicine, and it’s great to be back on this program, again as your host!

But it’s not just me tonight. Virtually joining me tonight is 2 former hosts on Thoracic Night Live: Dr Nick Rohs, an assistant professor in medicine, hematology, and medical oncology at Mount Sinai, and Dr Balazs Halmos, a professor in the Department of Medial Oncology at Albert Einstein College of Medicine. Welcome everyone, and it’s an honor to share this virtual stage with you!

Tonight’s discussion is going to focus on reviewing the year 2021 in lung cancer treatment, and highlighting the breakthroughs with immunotherapy and targeted therapy, which have really revolutionized how we approach our patients in clinical practice.

Videos

Thoracic Night Live is devoted to spotlighting the biggest topics in lung cancer and pivotal studies discussed at medical meetings throughout the year.

Reviewing the Year 2021 in Lung Cancer Treatment

Balazs Halmos, MD, director of Thoracic Oncology, and director of Clinical Cancer Genomics at Montefiore Medical Center, discusses the efficacy of the COVID-19 vaccines in patients with cancer.

Regardless of ongoing treatment with chemotherapy, immunotherapy, or targeted therapy, most patients with a cancer diagnosis have a high chance of responding to the COVID-19 vaccines, as long as they are administered in an appropriate manner with both doses being given, according to Halmos. Responses to the vaccines among patients are measured by examining the SARS-CoV-2 spike protein immunoglobulin arrays from the vaccines, Halmos says.

Overall, 95% of patients with cancer mounted an immune response to the vaccines, which is very similar to the control population, Halmos notes. Additionally, when examining the titer levels of antibodies generated in patients with cancer. Those with solid tumors had similar responses to those seen in patients without a cancer diagnosis, Halmos concludes.

Balazs Halmos, MD, discusses the efficacy of the COVID-19 vaccines in patients with cancer.

Dr. Halmos on the Efficacy of COVID-19 Vaccines in Patients With Cancer

Balazs Halmos, MD, MS, director of the Multidisciplinary Thoracic Oncology Program and director of the Section of Thoracic Medical Oncology for Montefiore Health Systems, first director of Clinical Cancer Genetics and professor of clinical medicine at the Albert Einstein College of Medicine, discusses the emergence of KRAS-targeted therapies in lung cancer.

 mutations in lung cancer is an unfolding story, says Halmos. Efficacy data with KRAS inhibitors as single agents and in combination regimens with conventional first- and second-line options, such as chemotherapy and immunotherapy, will likely emerge in 2021, Halmos explains. 

 mutations are present in a significant proportion of patients with lung cancer, the field is hoping to develop an understanding of which investigational KRAS-directed therapy yields the most significant efficacy and in which specific patient populations, concludes Halmos. 

Balazs Halmos, MD, MS, discusses the emergence of KRAS-targeted therapies in lung cancer.  



Dr. Halmos on the Emergence of KRAS-Targeted Therapies in Lung Cancer

There has been dramatic progress with the introduction of targeted therapies and immune checkpoint inhibitors in the management of advanced non—small cell lung cancer (NSCLC). Biomarker-driven targeted therapy has revolutionized the management of oncogene-driven lung adenocarcinomas. Multiple generations of agents are now available for the treatment of 

-aberrant lung adenocarcinomas. Furthermore, effective agents are either available or rapidly emerging for 

, and ErbB2-positive subsets. In addition, immune biomarkers, such as PD-L1 and tumor mutational burden (TMB) analysis, inform clinicians as to the proper choices of immunotherapies, alone or in combination with chemotherapy, as treatment for the majority of patients without actionable alterations. By now there is very little justification for the use of conventional chemotherapy alone as first-line therapy. We have similarly witnessed a sea change in the management of locally advanced disease. The PACIFIC study has established a new standard with adjuvant durvalumab (Imfinzi) following concurrent chemoradiation, leading to major survival benefits.

Table 1. Key Studies of TKIs in Early-Stage NSCLC

In this context, it is extremely disappointing that for the very population of early-stage patients for whom cure is most likely, and for whom the impact of novel therapies could be the most substantial, little has changed since the acceptance of adjuvant chemotherapy for resected stage IB-IIIA patients as the standard of care about 2 decades ago. Since then, we have only witnessed failed attempts at improving on the status quo, with negative results from postoperative radiation (PORT meta-analysis Trialists Group),

 Furthermore, outside of nodal involvement and tumor size, no validated biomarkers exist in this setting to guide patient management. Adjuvant chemotherapy remains the standard of care for patients with resected NSCLC. Results from the landmark International Adjuvant Lung Cancer Trial showed that cisplatin-based postoperative chemotherapy improved survival, marking a new era in NSCLC management.

 The Lung Adjuvant Cisplatin Evaluation meta-analysis of the 5 key trials of this era echoed these results, showing an overall survival (OS) benefit of 5.4% at 5 years—although adjuvant chemotherapy was found to be harmful in stage IA NSCLC.

 Nonetheless, outcomes remain poor; the modest benefit offered by adjuvant chemotherapy indeed seems to lessen over time due to significant toxicities and other long-term complications of treatment. The time is thus ripe to reenergize research with a focus on improving our curative strategies in this setting.

The introduction of targeted therapies in the adjuvant setting highlights this general disappointment. Over the past 15 years, EGFR tyrosine kinase inhibitor (TKI) therapies have been tested in several adjuvant studies, yielding mixed results—partly due to misguided patient selection and poor trial design (

). The nonmolecularly selected NCIC CTG BR19 trial found no improvement in survival for patients receiving gefitinib (Iressa) compared with placebo in stage IB-IIIA surgically resected patients, even in a subset analysis based on 

 mutation status—although this subset was very small, leading to underpowered analyses.

 The RADIANT study randomized resected stage IB-IIIA 

-positive patients, as defined by immunohistochemistry (IHC) or fluorescence in situ hybridization, to receive erlotinib (Tarceva) or placebo following optional adjuvant chemotherapy, and similarly did not find any difference in disease-free survival (DFS) or OS—not surprisingly, in retrospect, given incorrect biomarker choice.

mutations showed a DFS advantage, the results were not significant owing to the hierarchical study design, and OS appeared identical. The subsequent multicenter phase II SELECT study of erlotinib for 2 years following resection of stage IB-IIIA 

-mutated NSCLC used more scientifically valid biomarker selection and included only patients with 

 The study had excellent overall results and reached its endpoint of improved DFS compared with historical controls, but the results are difficult to interpret in the absence of a true control group. Furthermore, a significant relapse rate soon after stopping adjuvant therapy is worrisome. This highlights the specific concern that adjuvant targeted therapy might lack actual curative effect, possibly leading only to delays in recurrence. The results, therefore, are not viewed as practice changing. The latest major trial to conclude, ADJUVANT, a randomized phase III Chinese study comparing adjuvant chemotherapy with gefitinib, reached its primary endpoint of significant DFS improvement (median DFS of 28.7 vs 18 months).

 However, available OS data argue against a substantial true benefit, and the study was criticized for not offering standard-of-care chemotherapy in the gefitinib arm. Based on these studies, adjuvant EGFR TKIs may be beneficial to delaying recurrence, but clear OS benefits—the key endpoint in such studies&mdash;remain elusive. Erlotinib has also been studied in the neoadjuvant setting (CSLC 0702, ML25444).

 Although well tolerated, it is unclear given the limited data whether neoadjuvant erlotinib holds any meaningful survival benefits.

 Meanwhile, principally through the ALCHEMIST study, there is a continued effort in the United States to demonstrate the value of TKIs for early-stage NSCLC. ALCHEMIST was originally designed to test adjuvant targeted therapy in resected stage IB-IIIA patients following receipt of adjuvant chemotherapy.

 Despite high hopes for ALCHEMIST, a group of trials studying adjuvant erlotinib and crizotinib (Xalkori), accrual has been slow, leading to concerns about whether it can be successfully completed and, of more concern, whether it is becoming obsolete as more effective EGFR- and ALK-targeted agents have shown great success in the advanced setting. The potential of another first-generation TKI, icotinib (Conmana), as adjuvant therapy for stage II-IIIA NSCLC is currently being investigated in a number of phase III studies in China, including ICWIP (NCT02125240), EVIDENCE (NCT02448797), and ICTAN (NCT01996098).

The important ADAURA study being conducted in a similar setting utilizes adjuvant osimertinib (Tagrisso), a third-generation EGFR TKI with greater central nervous system penetrance that targets the T790M resistance mutation. Osimertinib has become the standard-of-care frontline option in advanced disease, thereby making ADAURA the most relevant of ongoing targeted adjuvant trials. In general, the lack of investment in adjuvant studies has led to a series of missed opportunities over the past decade and a half, hopefully informing us about the next wave of studies ahead.

Immunotherapy represents the next frontier of oncology, with the FDA already approving checkpoint inhibitors for a growing variety of cancer types, including 2 anti—PD-1 and 2 anti–PD-L1 agents for the management of advanced and locally advanced NSCLC.

 Although checkpoint inhibitors are in widespread use for treatment-refractory advanced NSCLC, they remain investigational for early stages, which is when their efficacy would likely be the most robust and their impact could be the most significant. Clearly, great efforts urgently need to be expanded to assess these agents. To this end, a variety of studies are ongoing in both the adjuvant and neoadjuvant settings. The latter has been speculated to be particularly attractive (

Table 2. Key Studies of Immunotherapy in Early-Stage NSCLC

The administration of immunotherapy prior to surgical resection might be particularly advantageous, as larger tumors are thought to generate greater immune activity than micrometastatic disease. Furthermore, the pathologic specimen allows for an early and robust readout of therapeutic activity, which might be particularly helpful in the selection of combination regimens for further studies. Completed efforts investigating this theory include TOP1201 and the pilot study by Forde and colleagues. Results of the phase II TOP1201 study by Yi et al demonstrated significant activation of CD4/CD8 lymphocytes after chemotherapy and ipilimumab (Yervoy) in stage II-IIIA NSCLC, although it did not meet the primary endpoint of detecting a significant increase in circulating T cells with specificities against tumor-associated antigens.

 Yang et al subsequently demonstrated the safety and feasibility of surgical resection in this study population.

 Forde and colleagues treated a cohort of 22 patients with resectable stage I-IIA NSCLC with 2 cycles of nivolumab (Opdivo) prior to surgical resection.

 The neoadjuvant nivolumab was not only safe and feasible but also associated with a 45% pathologic response rate in 9 of 20 patients who underwent resection, and 3 patients had a complete response. In addition, biomarker analysis of this cohort yielded remarkable data as to neoantigen discovery and identification of activated T-cell clones, providing an excellent platform for future studies.

The single-arm nature of the above pilot studies limits further interpretation of the data. Notable ongoing neoadjuvant studies include a series of now-pivotal and potentially practice-changing phase III trials. IMpower030 is studying the role of neoadjuvant atezolizumab in resectable II, IIIA, or select IIIB NSCLC. KEYNOTE-671 (PEARLS) is investigating the combination of both neoadjuvant doublet chemotherapy and neoadjuvant/ adjuvant administration of pembrolizumab (Keytruda) in patients with resectable stage IIB or IIIA NSCLC. Finally, CheckMate-816 is studying whether either combined nivolumab and ipilimumab or nivolumab plus platinum doublet chemotherapy is superior to doublet chemotherapy alone in the neoadjuvant treatment of stage IB-IIIA NSCLC.

 Another immune checkpoint inhibitor, durvalumab, was recently approved for treatment of unresectable stage III NSCLC.

 This agent is now being investigated in a number of phase II neoadjuvant studies, including IONESCO, NCT02572843, and NCT02904954. In addition to studying durvalumab therapy, NC02904954 is examining whether there is an added benefit from the administration of stereotactic body radiation therapy (SBRT) prior to, or concurrently with, durvalumab therapy. Another ongoing trial, NCT03148327, examines this combination as adjuvant therapy in patients who are medically inoperable or who decline surgery. The investigation of SBRT in conjunction with durvalumab could further expand treatment options for early-stage patients who are undergoing immunotherapy, thanks to the abscopal effect, through which local irradiation of the primary tumor is followed by regression of disease at nonirradiated metastatic sites—a phenomenon hypothesized to occur due to generation of a systemic immune response following the release of neoantigens from the irradiated tumor.

 Within the past decade, as the use of immunotherapy has risen, there has been a growing consensus that a combination of radiotherapy and immunotherapy is superior to either modality alone, which certainly warrants further investigation in earlier-stage NSCLC. With the expanding use of curative radiation-based strategies in lung cancer management, these studies will provide key data for large groups of patients.

Additional studies are ongoing into the use of immunotherapy in the adjuvant setting. The pivotal ANVIL trial is a component of the phase III ALCHEMIST trial, which is studying the effects of adjuvant nivolumab versus observation for 

negative patients, while the KEYNOTE-091 trial is investigating the adjuvant use of pembrolizumab versus placebo, with or without standard adjuvant chemotherapy, in resected NSCLC. Additional adjuvant studies currently recruiting participants with stage IB-IIIA NSCLC are NCT02273375 (investigating durvalumab vs placebo) and IMpower010 (comparing adjuvant atezolizumab [Tecentriq] vs best supportive care following 4 cycles of doublet chemotherapy). Another study currently in the recruitment phase, NCT03447769, aims to evaluate the role of canakinumab (Ilaris) as adjuvant therapy in patients with stage II-IIIA and completely resected stage IIIB NSCLC. Canakinumab, a monoclonal antibody against the pro-inflammatory cytokine IL-1ß, was originally approved for treatment of a spectrum of autoinflammatory conditions. Analysis of the results of the 2017 CANTOS cardiovascular study incidentally revealed a highly significant reduction in lung cancer incidence and mortality in the canakinumab group relative to placebo, prompting further interest in its potential as a lung cancer therapy and opening novel avenues into the exploration of the role of the myeloid cell compartment in the tumor microenvironment.

As the role of targeted therapies and immunotherapy in early-stage lung cancer continues to be explored, it is crucial that further investments be made in the development of better biomarkers to facilitate patient selection and risk stratification. Research continues into additional biomarkers beyond 

 that represent actionable therapeutic targets or are associated with risk of progression of earlystage NSCLC. For instance, the myPlan Lung Cancer proprietary prognostic test developed by Myriad Genetics measures cell cycle progression genes; it has been validated in a cohort of 650 patients with stage I-II NSCLC and found to be a more significant indicator of mortality than pathologic cancer stage.

 Another important biomarker being explored is TMB, a measure of the number of mutations in a given tumor, as well as a surrogate marker for a tumor’s potential to generate an immune response via neoantigens. Initial studies in NSCLC have demonstrated an association between higher TMB and better response to immunotherapy; it appears that TMB might serve as a complementary biomarker to PD-L1 IHC in patient selection.

 Further studies will be necessary in the setting of early-stage NSCLC as this biomarker is further elucidated and refined. Finally, plasma-derived circulating tumor DNA (ctDNA) holds the potential to further expand the role of personalized therapy—making it available to those patients not amenable to tissue biopsy and enabling noninvasive repeat sampling so that therapy can be modified as needed over the course of treatment, as the molecular profile of an individual’s cancer changes.

 Its most promising role in the definitive setting might be as a biomarker of residual microscopic disease, allowing patient enrichment in adjuvant studies following delivery of definitive surgery or radiation-based therapy. The recently published study by Chaudhuri et al highlights the potential tremendous utility of ctDNA testing for risk stratification in this context.

 Among the outcome measures of the ALCHEMIST Screening Trial (NCT02194738) are the identification of new mutations at time of cancer recurrence and the correlation of ctDNA level with survival measures in these patients. Another study that recently started recruitment (NCT03465241) is investigating the role of ctDNA dynamic monitoring of stage II-IIIA NSCLC to verify its prognostic predictive effect.

In summary, following a 2-decade, significant lull in this critical area of research, we are now seeing much better-designed neoadjuvant and adjuvant studies based on proper biomarker selection, as well as optimized treatment choices founded upon recent advances in the metastatic setting. There is real hope that in the coming years, we will see tremendous changes in the management of early-stage lung cancer. The only way this can be achieved is through support by all relevant thoracic disciplines to allow timely completion of important studies whose results could hold the key to improving cure rates for the large number of patients with early-stage lung cancer worldwide.

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Articles

Following a 2-decade lull in early-stage lung cancer, we are now seeing much better-designed neoadjuvant and adjuvant studies based on proper biomarker selection, as well as optimized treatment choices founded upon recent advances in the metastatic setting.

Early-Stage NSCLC Is Ripe for Change

Balazs Halmos, MD, director, Thoracic Oncology, director, Clinical Cancer Genomics, Montefiore Medical Center, discusses the prevalence of 

 mutations in patients with non—small cell lung cancer (NSCLC).

In the last 2 years, there have been a flurry of developments recognizing that a subset of patients with NSCLC have recurrent genetic abnormalities affecting the 

 amplification which is not very common and is difficult to define, Halmos explains. There needs to be specific thresholds to understand what level of amplification is a key driver event. Lately, high-driver MET amplification has been identified as an area where MET inhibitors will show promise, such as crizotinib (Xalkori) and cabozantinib (Cabometyx).

Additionally, 3% to 4% of patients with NSCLC have sarcomatoid carcinoma of the lung, which involves a recurrent abnormality known as 

 exon 14 skipping mutation. This is a unique genetic abnormality caused by a range of genetic abnormalities, he says. This leads to loss of a particular amino acid that is critical to the binding of another protein. The second protein marks the first protein for degradation. This leads to a drive in cancer growth, Halmos explains.

 exon 14 skipping mutations can be identified and potentially treated with MET inhibitors.

View more from the 2016 New York Lung Cancer Symposium

Balazs Halmos, MD, director, Thoracic Oncology, director, Clinical Cancer Genomics, Montefiore Medical Center, discusses the prevalence of MET mutations in patients with non–small cell lung cancer (NSCLC).

Dr. Halmos on MET Mutations in Patients With NSCLC

Balazs Halmos, MD, section chief of Thoracic Oncology at New York-Presbyterian Hospital/Columbia University Medical Center, comments on the detection of actionable mutations in patients with lung cancer.

CO-1686 and AZD9291 represent examples of two drugs that only benefit patients with EGFR mutations, Halmos says, â€‹which is 10-15% of all patients with lung cancer.

For a community oncologist, it is important to look at all patients and classify them by their actionable mutation. This poses a problem, though, as more testing is needed. It is crucial for a community oncologist to be aligned with a comprehensive cancer center for its expertise in medical oncology and treatment, but also for its expertise in pathological genetics.

Dr. Halmos on Detecting Actionable Mutations in Patients With Lung Cancer

Balazs Halmos, MD, section chief of Thoracic Oncology at New York-Presbyterian Hospital/Columbia University Medical Center, discusses the impact of EGFR inhibitors on the treatment of lung cancer.

It is now widely recognized that a proportion of patients with lung cancer (about 10% in the U.S.) carry an 

 mutation. This discovery has transformed the way the disease is treated.

EGFR inhibitors extend survival and are less toxic than chemotherapies, Halmos saysâ€‹. Previously, life expectancy was 12 months in this population; now, it is about 3 years. EGFR inhibitors have changed the entire mindset of how to treat lung cancer.

Dr. Halmos on the Impact of EGFR Inhibitors on the Treatment of Lung Cancer

Balazs Halmos, MD, section chief of Thoracic Oncology at New York-Presbyterian Hospital/Columbia University Medical Center, discusses the variety of immune checkpoint inhibitors that are currently being explored as treatments for patients with non-small cell lung cancer (NSCLC).

Currently, Halmos is involved in the investigation of the PD-1 inhibitor MK-3475. In addition to this agent, several other therapies are being explored in NSCLC that target immune checkpoints, including the PD-1 inhibitor nivolumab and the PD-L1 inhibitor MPDL3280A. These agents have been explored primarily in phase I studies. As a result, it remains unclear whether targeting PD-1 or PD-L1 is superior.

When exploring these agents, it is essential to look at the levels of pneumonitis and other side effects to determine the best approach. At this point, it appears that PD-L1 inhibition could result in fewer side effects, like pneumonitis, Halmos believes. Future research in this space will focus on patient selection, minimizing toxicities, and which class of agents is the most effective.

Balazs Halmos, MD, section chief of Thoracic Oncology at New York-Presbyterian Hospital/Columbia University Medical Center, discusses the anti-PD-L1 antibody MK-3475 and the challenge of integrating immunotherapies into the field of lung cancer.

Dr. Halmos on Checkpoint Inhibitors in Lung Cancer

Balazs Halmos, MD, section chief of Thoracic Oncology at NewYork-Presbyterian Hospital/Columbia University Medical Center, discusses the implication of the IPASS study.

The IPASS study was a key study in the field, Halmos says, as it analyzed the EGFR inhibitor gefitinib compared with standard chemotherapy for patients with advanced lung adenocarcinoma without knowledge of EGFR mutation status.

Results of the study showed that the two groups fared similarly over the long term, but that there was a huge discrepancy between outcomes in patients with EGFR mutated and wild-type tumors. Patients treated with gefitinib demonstrated a 70-fold greater benefit in EGFR mutated tumors compared with wild-type. This group of patients also experienced quality of life benefits.

The IPASS study was the first that concluded there was a need to identify patients early on with EGFR mutations and ensure that they receive an upfront EGFR tyrosine kinase inhibitor.

Balazs Halmos, MD