Karen L. Kelly, MD, a professor, associate director for Clinical Research, and Jennifer Rene Harmon Tegley and Elizabeth Erica Harmon Endowed Chair in Cancer Clinical Research at the University of California Davis, discusses overcoming osimertinib (Tagrisso) resistance in patients with non–small cell lung cancer through the use of bispecific antibodies.

Amivantamab-vmjw (Rybrevant) is a bispecific to EGFR and MET that has demonstrated activity in patients who have developed osimertinib resistance, yielding a promising objective response rate as a monotherapy, according to Kelly. However, the concern with utilizing a monoclonal antibody in this setting is that it will not cross the blood brain barrier, she says. As such lazertinib (YH25448), a third generation TKI that is fairly similar to osimertinib, is a highly efficacious option that is capable of crossing the blood brain barrier with a low toxicity profile.

The theory is that by combining the 2 agents, further activity may be achieved, Kelly says. This formed the rationale for the phase 1 CHRYSALIS study (NCT02609776), which examined the combination in patients who had progressed on osimertinib but had not received standard of care chemotherapy. Findings from the study indicated that patients achieved a response rate of approximately 36% and a median progression-free survival of 4.9 months. When patients were stratified based on 

 dependence, the response rate increased to 47%, Kelly concludes.

Videos

Karen L. Kelly, MD, discusses overcoming osimertinib resistance in patients with non–small cell lung cancer through the use of bispecific antibodies.

Dr. Kelly on Overcoming Osimertinib Resistance in NSCLC With Bispecific Antibodies

Karen Kelly, MD, associate director for Clinical Research at the University of California (UC) Davis Comprehensive Cancer Center, Jennifer Rene Harmon Tegley and Elizabeth Erica Harmon Endowed Chair in Cancer Clinical Research, and a professor of medicine at UC Davis Health, discusses the experimental window-of-opportunity studies with monotherapies in lung cancer.

Right now, window-of-opportunity studies remain very experimental, says Kelly. Two small phase 2 trials examining monotherapy in lung cancer. A larger trial, LCM3, enrolled 180 patients with locally advanced non–small cell lung cancer who underwent treatment with atezolizumab (Tecentriq); however, the rest of the studies reported have been very small.

The field did see some evidence of major pathologic response, although this is a surrogate that needs to be validated in this setting of neoadjuvant therapy because that is the earliest time point for efficacy, explains Kelly.

The next time point would be disease-free survival and finally overall survival (OS), but the wait for OS read-outs is very long, says Kelly. Major pathologic response has been the primary end point for most of these window-of-opportunity studies, concludes Kelly.

Karen Kelly, MD, discusses the experimental window-of-opportunity studies with monotherapies in lung cancer.

Dr. Kelly on Window-of-Opportunity Monotherapy Trials in Lung Cancer

Karen Kelly, MD, associate director for clinical research, University of California (UC) Davis Comprehensive Cancer Center, and professor of medicine, UC Davis Health, discusses encouraging preliminary data with neoadjuvant immunotherapy in lung cancer.

Immunotherapy works by recognizing tumor antigens and creating specific cytotoxic T cells, says Kelly, which, from available research, appears to be more feasible in the neoadjuvant setting. Notably, in this setting, the highest number of tumor antigens are available to create, activate, and expand cytotoxic T cells.

In preclinical research, it was found that mouse models that received neoadjuvant immunotherapy experienced improved survival. Ultimately, these research efforts resulted in several window of opportunity trials for neoadjuvant immunotherapy in this space, Kelly concludes.

Karen Kelly, MD, discusses encouraging preliminary data with neoadjuvant immunotherapy in lung cancer.

Dr. Kelly on Preliminary Data With Neoadjuvant Immunotherapy in Lung Cancer

Karen Kelly, MD, associate director for clinical research, University of California (UC) Davis Comprehensive Cancer Center, and professor of medicine, UC Davis Health, discusses challenges with choosing when to start immunotherapy in patients with lung cancer.

When to start immunotherapy in lung cancer is an important topic of discussion in the real-world setting, says Kelly. Data from 8 trials examining immunotherapy/chemotherapy combinations and 3 trials evaluating immunotherapy alone support the use of immunotherapy as the first line of treatment for patients with advanced disease who do not have an oncogenic driver. However, some real-world situations do not necessarily allow for the use of up-front immunotherapy, says Kelly.

For example, 1 patient that Kelly treated was supposed to begin chemoimmunotherapy but fell, broke his hip, and required surgery. Because he was symptomatic, Kelly decided to treat him with chemotherapy alone in the hospital. For another patient who was younger, very symptomatic with a lot of disease burden, who may have had an actionable mutation, but could not wait for results to return, Kelly decided to begin chemotherapy alone.

Scenarios like these create a dilemma regarding when immunotherapy should be added to treatment, says Kelly. Should immunotherapy be used in combination with the second cycle of chemotherapy? Both of Kelly’s patients responded to their first cycle of chemotherapy in terms of symptom improvement; therefore, could immunotherapy wait until the second-line setting? These are important questions to address in this space, concludes Kelly.

Karen Kelly, MD, discusses challenges with choosing when to start immunotherapy in patients with lung cancer.

Dr. Kelly on Challenges With Starting Immunotherapy in Lung Cancer

Karen Kelly, MD, associate director for clinical research, University of California (UC) Davis Comprehensive Cancer Center, professor of medicine, UC Davis Health, discusses how to determine treatment after patients with lung cancer progress on TKIs.

Patients receiving TKIs for lung cancer have a range of progression-free survival (PFS) achieved; an exceptional PFS for patients on ALK inhibitors is around 35 months, according to Kelly. Although patients enjoy a prolonged PFS provided by TKIs compared with chemotherapy, all patients eventually fail their TKI due to developed resistance, explains Kelly.

When patients fail their TKI, it is important to determine why. Kelly’s goal when treating patients with TKIs is to keep them on a TKI as long as possible, whether that be in the first- or second-line setting. When choosing a TKI for the second-line setting, Kelly suggests gathering information from a tissue or liquid biopsy to help guide selection for a TKI.

View more from the 2019 New York Lung Cancers Symposium

Karen Kelly, MD, discusses how to determine treatment after patients with lung cancer progress on TKIs.

Dr. Kelly on Determining Second-Line TKI in Lung Cancer

Karen Kelly, MD, associate director for Clinical Research, Jennifer Rene Harmon Tegley and Elizabeth Erica Harmon Endowed Chair in Cancer Clinical Research, professor of Medicine, UC Davis Comprehensive Cancer Center, UC Davis Health System, discusses the toxicity profile of the therapies used in the CheckMate-227 trial.

The study assessed nivolumab (Opdivo), nivolumab plus ipilimumab (Yervoy), nivolumab plus platinum-doublet chemotherapy, and platinum-doublet chemotherapy alone as different treatment options for patients with non-small cell lung cancer (NSCLC).

The biggest concerns for toxicity lie in the ipilimumab arm, says Kelly. Some of the adverse events with this drug included colitis and hepatitis. Given the fact that these drug combinations have been evaluated in other cancer types, physicians already have an idea of how to manage such toxicities. However, Kelly emphasizes that it is important to note that patients with lung cancer are often older and have more comorbidities. Therefore, there is still a bit of a learning curve in managing adverse events in this particular patient population.

Dr. Kelly on the Toxicity Profile in CheckMate-227 in NSCLC

Karen Kelly, MD, associate director for Clinical Research, Jennifer Rene Harmon Tegley and Elizabeth Erica Harmon Endowed Chair in Cancer Clinical Research, professor of Medicine, UC Davis Comprehensive Cancer Center, UC Davis Health System, discusses the potential of immunotherapy combinations as treatment for patients with non—small cell lung cancer (NSCLC).

Much research lies ahead regarding combinations of immunotherapy agents in the field of lung cancer, Kelly explains. However, prior studies in melanoma demonstrate that PD-1 and CTLA-4 inhibitors do demonstrate significant survival benefits when combined. Data reported for nivolumab (Opdivo) and ipilimumab (Yervoy) in NSCLC have shown promise; however, the associated adverse events are concerning.

Practitioners hope that these combinations produce deep, durable responses that translate into prolonged survival. Nevertheless, it is not yet determined whether two-drug combinations will be more effective versus monotherapy with an immune agent, she adds.

Karen Kelly, MD, associate director for Clinical Research, Jennifer Rene Harmon Tegley and Elizabeth Erica Harmon Endowed Chair in Cancer Clinical Research, professor of Medicine, UC Davis Comprehensive Cancer Center, UC Davis Health System, discusses the potential of immunotherapy combinations as treatment for patients with non–small cell lung cancer (NSCLC).

Dr. Kelly on Immunotherapy Combinations for Patients With NSCLC

Karen Kelly, MD, associate director for Clinical Research, Jennifer Rene Harmon Tegley and Elizabeth Erica Harmon Endowed Chair in Cancer Clinical Research, professor of Medicine, UC Davis Comprehensive Cancer Center, discusses the results of the phase Ib JAVELIN Solid Tumor Trial.

This international trial has multiple expansion cohorts with a 3+3 design, Kelly explains. The trial set the 10 mg/kg bi-weekly dose of avelumab as the recommended phase II dose, before going onto 16 selected to solid tumor cohorts. In the phase Ib analysis, a safety update of avelumab was examined in the first 900 patients.

Results showed that there were minimal differences in toxicity observed. Patients who were enrolled in the first-line non—small cell lung cancer cohort experienced slightly less toxicity versus patients in the other cohorts, she adds.

Karen Kelly, MD

Articles