A Panel Discussion from the Total Health 2023 Best of Lung Conference
At the Total Health 2023 Best of Lung conference held in Manalapan, Florida Dr Shayma Kazmi from The University of Pennsylvania moderated a panel discussion featuring a clinical case in non-small cell lung cancer (NSCLC) utilizing targeted therapy as component of the patient’s treatment plan. The expert panel also included Dr Jaime Schneider from Massachusetts General Hospital Cancer Center, Dr Theresa Boyle from Moffitt Cancer Center, and Dr Coral Olazagasti from The University of Miami.
The use of targeted therapies in NSCLC relies on the identification of a specific molecular alteration (or mutation) in the tumor’s genetic profile which it is dependent upon for its uncontrolled growth, and which can therefore be targeted with a highly selective small molecule drug. These molecular alterations, also known as ‘driver mutations’ can be identified by using a next-generation sequencing (NGS) analysis of the patient’s tumor sample, which is usually obtained with a biopsy. There are a range of effective and generally well-tolerated targeted treatments now approved and available for use in NSCLC that are specifically designed to inhibit the growth of tumor cells that harbor a given driver mutation. As such, targeted treatments represent an important advance in treatment, and their use may offer a substantive benefit for NSCLC patients over chemotherapy, which had been the standard of care treatment in lung cancer in decades past. Another component in the current treatment landscape for lung cancer is immunotherapy, which enables tumor cells to be more effectively targeted and killed by the patient’s immune system. Like targeted therapy, the use of immunotherapy in patients with lung cancer also requires testing patient’s tumors for expression of a specific immune system modulating protein called programmed death ligand 1, or PD-L1.
Clinical Case – Variation 1
The clinical case which Dr Kazmi presented to the panel was that of a 58 year-old, non-smoking woman who presented with symptoms of shortness of breath (dyspnea) and cough, and was subsequently found to have a 4 cm left upper lobe mass in her lung with swelling of her left hilar lymph node (lymphadenopathy). She underwent a bronchoscopy and endobronchial ultrasound (EBUS), and upon biopsy, was found to have a lung adenocarcinoma staged as IIB disease with lymph node involvement (N1) and no evidence of cancer spread (metastasis) outside of the thorax (MX), as assessed with positron emission tomography (PET) imaging. There is also no evidence of cancer in the brain upon brain magnetic resonance imaging (MRI). She undergoes a surgical excision of her tumor, which confirms the clinical tumor stage (IIB), and the areas around the tumor excision site are microscopically clear of cancer cells (‘clear surgical margins’). The patient’s tumor is also assessed using full NGS panel testing, and it is found to have an epidermal growth factor receptor (EGFR) driver mutation known as L858R, and her PD-L1 level is found to be 60%. Dr Kazmi asked the panel how they would treat this patient in the adjuvant (post-surgery) setting.
Dr Schneider thought, since the patient is relatively young and otherwise well, without comorbid conditions, she would be a candidate for adjuvant chemotherapy (after an appropriate discussion of risks and benefit s with the patient) based on her tumor stage, as clinical evidence indicates there is a small but significant benefit in survival. She also noted that, following chemotherapy, the patient would be a candidate for subsequent targeted therapy with Osimertinib for three years, based on the results of the ADAURA trial. Dr Kazmi agreed, noting that 4 cycles of a platinum-based chemotherapy regimen would be appropriate in this patient, based on her age and good performance status.
Asked whether she would screen this patient for brain, or central nervous system (CNS) metastases, based on the presence of her L858R driver mutation, Dr Olazagasti noted she would be inclined to obtain a brain MRI at baseline, in addition to a PET scan. Dr Kazmi raised the issue of insurance coverage for this kind of testing in a stage II patient, but Dr Olazagasti indicated she had not had problems getting coverage in this setting.
Some of the discussion around this first clinical scenario included whether three years of adjuvant Osimertinib is needed (as opposed to a shorter duration such as 2 years). The panelists agreed that based on the ADAURA trial, three years of treatment is what is currently indicated, although they admitted that tolerability and financial toxicity (i.e., costs of the treatment) remain a concern. Dr Boyle noted that monitoring for minimal residual disease (MRD), an indicator of an impending cancer recurrence, using circulating tumor DNA (ctDNA) assessment (a simple blood test), could be one means of reassuring the patient wishing to stop therapy (de-escalation of treatment). By comparison, those patients found to have evidence of an impending cancer recurrence (as indicated by an ‘MRD positive’ result from ctDNA testing) might be more inclined to continue therapy, or possibly escalate their anti-cancer treatment.
BOX 1. Case Variation 1 – Stage IIB/N1/MX Adenocarcinoma of the Lung
Clinical Case – Variation 2
A second iteration of the same case that was presented for discussion by the panel was, what if the same patient (with an L858R driver mutation) was not a candidate for surgery (unresectable) for their lung cancer, and instead, their disease was staged as IIIB or IIIC, with a high risk for recurrence. Dr Kazmi noted that patients with unresectable disease are generally treated with chemotherapy and radiation (chemoradiation). She asked the panelists whether, based on the results of the PACIFIC trial, would they consider using adjuvant immunotherapy with durvalumab (which has been shown to improve both progression-free and overall survival after chemoradiation, or would they consider using adjuvant Osimertinib in this patient (for which there is presently no data available for stage IIIB and IIIC patients treated with chemoradiation).
Dr Kazmi favored using Osimertinib in this setting, particularly if the patient was found to be MRD positive (and therefore at high risk for recurrence). Dr Olazagasti agreed with the approach of offering Osimertinib to this patient, as did Dr Schneider, who also noted it is not currently the policy at her center to offer consolidative durvalumab to a patient with an EGFR mutation after chemoradiation, and Osimertinib would be discussed with the patient as an off-label option. Dr Kazmi also highlighted the risk for immunotherapy-related adverse events like pneumonitis with durvalumab, which could impair the use of a TKI therapy like Osimertinib at the time of progression. At least one of the meeting participants disagreed, and expressed that he would rather save Osimertinib until the time of progression for this patient. Dr Kazmi disagreed, noting that, for a young patient at a high risk for recurrence, use of the CNS penetrant Osimertinib could be beneficial for a patient to prevent brain metastases.
BOX 2. Case Variation 2 – Stage IIIB or IIIC Unresectable Lung Adenocarcinoma After Chemoradiation
Clinical Case – Variation 3
A third iteration of the same case that was presented for discussion by the panel was, what treatment options would they consider for the same patient who, having received 2 years or more of targeted therapy with adjuvant Osimertinib, now presents with radiologic evidence of disease recurrence (a 4 cm liver mass) on a routine PET scan. The principal concerns for such a patient would then be that 1) their cancer has developed another mutation which now is resistant to Osimertinib therapy, or 2) the patient has had what is known as a ‘histologic transformation’ of their cancer, from a non-small cell to a small cell lung cancer phenotype, with additional therapy-resistant molecular alterations, and a likely more aggressive disease course.
Dr Boyle thought a ‘liquid biopsy’ would be a reasonable course of action in such a patient (entailing a ctDNA blood test to determine if the patient’s tumor has acquired an altered molecular profile or a different driver mutation). If another driver mutation was detected, the patient could be a candidate for a different targeted treatment. If no actionable results were found from the liquid biopsy, Dr Boyle noted she would then opt for a tissue biopsy. Dr Kazmi expressed her concern about possibly missing a histologic transformation to small cell by using only a liquid biopsy, without examining the tissue. Dr Boyle agreed, and noted that while tissue is preferable, it would depend on the patient’s overall clinical status and ability to tolerate a biopsy. Treatment options discussed for this patient included continuing the Osimertinib (assuming the patient has not had the full three years), and/or chemotherapy treatment for oligometastatic disease. Dr Schneider thought adding immunotherapy to chemotherapy in this setting (as in the Impower150 trial) would not be beneficial, as immunotherapy has shown limited benefit in patients such as this with EGFR driver mutations.
BOX 3. Case Variation 3 – Patient Progressing on Osimertinib Adjuvant Therapy
Speaker Disclosure Information: The panelists reported no disclosures for this case discussion.
You can see the full presentation from the Total Health 2023 Best of Lung Conference here: