Presentation by Dr. Melissa Johnson, Tennessee Oncology
Written By Bailey Mars, NP | Saint Luke's Health System
At the 2023 West Oncology conference, Dr. Melissa Johnson of Tennessee Oncology discussed neoadjuvant and adjuvant treatments for patients with non-small cell lung cancer (NSCLC), and addressed several new “paths” to cure for early-stage NSCLC patients (i.e., stages 1-3). Previously, patients had generally been receiving chemotherapy and immunotherapy in the metastatic setting (stage 4), however, a number of studies are now looking at the benefits of combining these agents as part of neoadjuvant and adjuvant treatments. Dr. Johnson reviewed the importance of biomarkers, programmed death ligand-1 (PD-L1) expression, and epidermal growth factor receptor (EGFR) mutations in selecting patients for the correct strategy, even for patients with early stages of NSCLC. Dr Johnson noted that, because it has relevant treatment implications, it is important to know about patient’s PD-L1 status as soon as possible in order to choose the most appropriate therapy for patients.
Adjuvant Chemotherapy Followed by Immuno-Oncology (IO) Agents
Dr Johnson first described the Impower010 study, which examined patients with resected stage IB to IIIA NSCLC, who received at least one dose of a platinum-based chemotherapy, who were randomized to receive one year, or 16 cycles, of the IO atezolizumab or best supportive care (BSC). The results showed the greatest benefit for adjuvant atezolizumab in stage II and III patients. This study also showed the importance of PD-L1 expression as a prognostic indicator, as patients with a PD-L1 of >1% at 36 months were noted to have a disease-free survival (DFS) rate of 60%, versus 48.2% in the placebo arm. Because of this, on October 15, 2021, the US Food and Drug Administration (FDA) approved the use of atezolizumab in patients with stage II to III disease and positive PD-L1 expression. Of note, Dr. Johnson mentioned that the patients who received the most benefit with atezolizumab were those with a PD-L1 of >50%; whereas overall survival (OS) was not significantly different with atezolizumab versus placebo in the overall population (i.e., all PD-L1 levels), there was an OS benefit for those with >50% PD-L1.
Another IO drug Dr. Johnson discussed in the setting of adjuvant therapy was pembrolizumab. The Keynote 91 trial examined the impact of adjuvant IO in patients with stage IB to IIIA disease, irrespective of their PD-L1 status. In this study, there was an improvement in DFS in all-comers and no apparent increase in benefit in patients with PD-L1 high status, and as a result of these findings, the FDA approved pembrolizumab for all-comer NSCLC patients. Dr. Johnson thus suggested using atezolizumab if the patient was PD-L1 high, and using pembrolizumab in PD-L1 low patients.
Lastly, in the adjuvant setting, Dr. Johnson discussed the ADAURA trial, which examined the use of adjuvant osimertinib in patients with stage IB to IIIA disease with an EGFR mutation. The study showed a statistically significant benefit in DFS when adding osimertinib to treatment. Dr. Johnson emphasized the clear separation is survival curves with Osimertinib versus placebo and contrasted these findings with the smaller, albeit significant differences seen with adjuvant immunotherapy.
Neoadjuvant Chemotherapy and IO
Dr Johnson then discussed another decision that needs to be made with the patient prior to surgical resection, that is, whether to use chemotherapy with an IO in the neoadjuvant setting. Citing a case of a 53-year-old patient with a 60-pack year smoking history, Dr. Johnson described the benefits and implications of neoadjuvant chemotherapy with an IO. The patient in question presented with abdominal pain and was noted to have a right lower lobe (RLL) mass. A bronchoscopy was performed, and pathology revealed squamous cell lung cancer with a PD-L1 level of 25%. In this regard, Dr Johnson cited results from the CheckMate 816 trial, utilizing 3 cycles of combined chemotherapy and the IO nivolumab prior to surgery in patients with stage IB to IIIA disease, which showed an increase in pathologic complete response (pCR) rate from 2.2% with chemotherapy alone to 24% with the nivolumab addition. Notably, patients with stage III disease showed the most benefit from this approach, whereas patients with stage IB to II disease showed minimal benefit. When looking at PD-L1 status, however, patients with PD-L1 >1% showed greater benefit. It was also noted that patients who achieved a complete remission at the time of resection (i.e., a pCR “at the time of surgery… there is no cancer left”) had an increased event-free survival (EFS) rate. Lastly, patients in the trial had a better prognostic outlook if they had negative circulating tumor DNA (ctDNA) status post-resection, as compared to those who had a positive ctDNA status. OS was also superior in patients receiving nivolumab and chemotherapy versus chemotherapy alone.
Returning to the case study described earlier, Dr Johnson noted that the patient received 3 cycles of carboplatin, Taxol, and nivolumab, and that, while the tumor was reduced, there was still evidence of disease on computed tomography (CT) scan noted in the hilum (i.e., a partial response). A surgical resection revealed large regions of fibrosis and necrosis with minimal viable squamous cell carcinoma present in the primary tumor, and all lymph nodes were negative. In view of these clinical findings, Dr. Johnson stated that it is her practice at the present time to ‘combine’ the neoadjuvant and adjuvant data and administer adjuvant treatment in this setting. She noted that 11% of patients in the nivolumab containing arm, and 22% of the chemotherapy containing arm in this study had received adjuvant therapy post-resection in the trial. Dr. Johnson suggested that adjuvant therapy for one year post-operatively would be her go-to treatment strategy in this patient at the current time. She noted that on March 4, 2022, the FDA approved the use of nivolumab with a platinum-based doublet chemotherapy regimen for patients with resectable NSCLC.
Chemo-Radiation Therapy Followed by IO
Dr Johnson then reviewed results from the PACIFIC trial, which revolutionized the field of locally advanced NSCLC and combination therapy for patients with non-resectable, stage III disease. She noted the impressive five-year survival data from the trial, which showed that one year of the IO durvalumab resulted in an increase not only in progression-free survival (PFS), but also OS versus placebo, with approximately one third of patients without progression, and 40% of patients still alive at 5 years. While these are encouraging data, she noted that we are “not out of the woods with durvalumab alone”, as this data also shows that roughly 70% of patients have progression, and that 60% are not surviving. In addition, PD-L1 assessment showed that patients with >25% PD-L1 had better outcomes with durvalumab versus those with a lower-level PD-L1. In fact, the OS of patients with >1% PD-L1 was 63.1 months versus 29.6 months with placebo. PFS was also 24.9 months with durvalumab versus 5.5 months with placebo. In those with PD-L1 <1%, OS was 33.1 months compared to 43 months and PFS was 10.7 months compared to 5.6 months. Dr Johnson noted there are now several PACIFIC trials, and PACIFIC 6 has revealed that, irrespective of performance status after receiving chemotherapy and radiation, all patients still benefitted from durvalumab. She did, however, voice concern about the use of concurrent chemotherapy, radiation and immunotherapy as she has seen an increase in bronchospasms, especially in patients with pre-existing COPD or who were smokers, leading to increased wheezing, coughing, and shortness of breath.
In the final portion of her presentation, Dr. Johnson discussed results from the LAURA trial, examining patients with an EGFR mutation who receive chemoradiotherapy, which is currently ongoing. It is known that patients with EGFRmutation do not respond well to immunotherapy and the question remains as to whether Osimertinib would be a better option in this setting. She noted her interest to see the benefit of Osimertinib versus placebo, and whether the benefit outweighs the risk.
NP Take Away
Overall, Dr. Johnson suggested that standard of care for all patients with NSCLC is currently chemotherapy and immunotherapy combinations. Knowing the stage of NSCLC and PD-L1 status of your patient as soon as possible is helpful to ensure that they are receiving the best and most effective therapy available. Assessing the patient’s EGFR status upfront has become standard practice, as it may be helpful in treatment decisions. NPs should be aware of and be able to discuss PD-L1 status with their patients and communicate the implications of adding immunotherapy to their treatment.
· Chemotherapy and immunotherapy combinations are rapidly becoming the standard of care not only for advanced/metastatic NSCLC, but also for earlier stage patients.
· Because patient’s PD-L1 status has treatment implications for use of immunotherapy, it should be tested for whenever possible, and as soon as possible.
· Patients with higher PD-L1 expression appear to respond better to immunotherapy.
· Both neoadjuvant and adjuvant chemotherapy and immunotherapy have a role in achieving cure for NSCLC patients; options include:
o Adjuvant Chemotherapy followed by IO agents
o Neoadjuvant chemotherapy with IO
o Chemo-radiotherapy followed by IO
· The optimal use of immunotherapy, if at all, in patients with EGFR mutation remains under investigation.