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Division of Hematology/Oncology
Department of Internal Medicine
Henry Ford Cancer Institute
Henry Ford Health System
Shirish M. Gadgeel, MD, has disclosed that he has received consulting fees from AstraZeneca, Blueprint, Boehringer Ingelheim, Bristol-Myers Squibb, Daichii-Sanyko, Janssen, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, and Takeda; fees for non-CME/CE services from Merck Sharp & Dohme and Xcovery; and other financial or material support from AstraZeneca and Roche/Genentech.
The International Association for the Study of Lung Cancer World Conference on Lung Cancer (WCLC) 2021 highlighted important new research on thoracic cancers. Below, Shirish M. Gadgeel, MD, discusses some noteworthy studies that focused on immuno-oncology (IO) for lung cancer. Clinical Care Options also offers other valuable insights from its conference coverage of WCLC, including expert insight on the plenary studies for IMpower010 and POSEIDON.
IO in Special Populations
Pembrolizumab in Combination With Platinum-Based Chemotherapy in Recurrent EGFR- or ALK-Positive NSCLC
Although there have been significant advances in the management of metastatic EGFR-mutant and ALK-rearranged non-small-cell lung cancer (NSCLC), all patients progress after standard-of-care tyrosine kinase inhibitor (TKI) therapy and many will eventually need chemotherapy. However, the benefits of platinum-based chemotherapy in patients with TKI refractory EGFR- or ALK-positive disease have been modest, with a median progression-free survival (PFS) of 5 months and a response rate of 30%. Furthermore, single-agent immune checkpoint inhibitors have not been very effective in patients with advanced NSCLC and these driver alterations. Thus, the search for better alternatives continues.
My colleagues and I reported a single-arm phase II study of carboplatin plus pemetrexed and pembrolizumab in patients with TKI refractory EGFR- or ALK-positive NSCLC. Although slow enrollment caused discontinuation of the study, the results are informative. We enrolled 33 patients in 2 parallel cohorts, 26 in the EGFR cohort and 7 in the ALK cohort. The primary endpoint was overall response rate (ORR), and we observed an ORR of 42% in the EGFR cohort and 29% in the ALK cohort. PFS and overall survival (OS) were secondary endpoints, and here we saw notable differences between the EGFR and ALK cohorts. Median PFS was 8.3 months (12-month PFS: 29%) for the EGFR cohort and 2.9 months (12-month PFS: 14%) for the ALK cohort. Likewise, we saw a median OS of 22.2 months (12-month OS: 76%) for the EGFR cohort and 2.9 months (12-month OS: 14%) for the ALK cohort. No significant toxicity was observed in either group.
We concluded that the benefits of carboplatin plus pemetrexed and pembrolizumab therapy in patients with TKI refractory EGFR-positive NSCLC were encouraging enough to warrant further exploration in this patient population. By contrast, the results for the ALK cohort were very modest. However, with only 7 patients in this cohort, the utility of this regimen in patients with TKI refractory ALK-positive NSCLC remains an open question. Fortunately, there are randomized phase III studies evaluating the combination of chemotherapy and immunotherapy in patients with EGFR-positive NSCLC after progression on EGFR TKI therapy, and the results of those studies are awaited.
Most clinical trials that have evaluated immunotherapy, either as single agent or in combination with chemotherapy, excluded patients with untreated brain metastases. Thus, we are less confident that immunotherapy can benefit patients with brain metastases. However, the ATEZO-BRAIN study sheds light on the potential efficacy of immunotherapy in these patients, especially those who are asymptomatic, as well as suggests that we may be able to treat them with just systemic therapy instead of in combination with local therapy.
ATEZO-BRAIN was a nonrandomized, single-arm phase II clinical trial of atezolizumab combined with carboplatin plus pemetrexed. It enrolled 40 patients with stage IV nonsquamous NSCLC without EGFR and ALK alterations who had untreated brain metastases. Enrolled patients could be receiving steroids, but the steroid dose had to be ≤4 mg/day of dexamethasone. All participants were treated with carboplatin and pemetrexed at their standard doses with atezolizumab administered every 3 weeks for 4-6 cycles, followed by maintenance pemetrexed and atezolizumab for up to 2 years.
Primary endpoints were safety and PFS. The predefined boundary for unacceptable toxicity (grade 3/4 toxicity incidence of 27.5%) was not reached, allowing full enrollment. Median PFS was 8.9 months (intracranial median PFS: 6.9 months), with an 18-month PFS rate of 24.9% (18-month intracranial PFS: 10.4%). Best systemic and intracranial responses were also compared: Of the 40 patients enrolled, 4 had discordance between systemic and central nervous system response. Two patients had progressive disease outside the brain and stable disease in the brain, and 2 patients had progressive disease in the brain but a partial response elsewhere. Median OS was 13.6 months.
The investigators concluded that atezolizumab plus carboplatin plus pemetrexed can benefit patients with brain metastases and, of more importance, can control untreated brain metastases to almost the same extent as it can control disease outside the brain. Therefore, as we do with targeted therapy, select patients with asymptomatic brain metastases could be initiated on chemotherapy and immunotherapy combination therapy (with close follow-up on the brain metastases), without requiring any specific local therapy such as surgery or radiation. The advantage of starting with systemic therapy is that you use 1 treatment for control of the patient’s entire cancer burden, as opposed to requiring different treatments for the brain and the rest of the body. This is more efficient, and we are able to deliver therapy more promptly.
I would like to briefly mention another study that looked at immunotherapy in the treatment of patients with advanced NSCLC and brain metastases, but from a different perspective. In a retrospective analysis of the randomized phase III CheckMate 9LA trial, the efficacy and safety of nivolumab plus ipilimumab together with 2 cycles of chemotherapy vs chemotherapy alone were assessed in patients with advanced NSCLC with or without baseline brain metastases. Patients with brain metastases were required to be treated for them and be asymptomatic before enrollment.
Investigators found comparable overall PFS and OS benefits in patients with or without brain metastases. In fact, the HRs looked better in the patients with brain metastases, suggesting that the 9LA regimen can provide comparable clinical benefit in patients with brain metastases. As mentioned, these are patients who had received local treatment for the metastases. However, this chemoimmunotherapy study did not show a rapid progression of the disease in these patients, particularly in the brain, giving us confidence that the combination regimen can control brain metastases as well as the disease outside the brain.
Antibody–Drug Conjugates for Lung Cancer
Antibody–drug conjugates (ADCs) are likely options for patients after disease progression on immunotherapy, with or without chemotherapy, so I would like to discuss 2 ADC studies from WCLC 2021.
Garon and colleagues presented results at an updated cutoff point for the NSCLC cohort on the TROPION-PanTumor01 study. This study evaluated datopotamab deruxtecan, an ADC directed against TROP2, a transmembrane glycoprotein overexpressed and associated with poor prognosis in NSCLC. The study evaluated 3 doses of datopotamab deruxtecan—8 mg/kg (n = 50), 6 mg/kg (n = 50), and 4 mg/kg (n = 80) —and enrolled patients with advanced NSCLC who had received multiple previous therapies. Patients with stable, treated brain metastases were allowed. More than 50% of the patients had received more than 3 previous lines of therapy, more than 90% had received platinum-based chemotherapy, and approximately 80% had received previous immunotherapy, either as single agent or in combination with platinum-based chemotherapy.
The primary objectives were safety and tolerability. The safety profile was considered manageable, with the most common adverse events being nausea, stomatitis, alopecia, and fatigue. Across the 3 doses, antitumor partial responses were observed in approximately 25% of the patients. In the 6-mg/kg group, the response rate was 28%, the median duration of response was 10.5 months, and 40% of the patients had stable disease. These data are quite encouraging, considering that these patients were heavily pretreated. The subsequent phase III TROPION-LUNG01 study (NCT04656652) will use the 6-mg/kg dose of datopotamab deruxtecan for further study based on a comparable response rate with less treatment discontinuation than reported with the higher 8-mg/kg dose.
Patients without an actionable genetic alteration who have progressed on immunotherapy and chemotherapy currently have limited approved therapy options with modest activity. With further development of datopotamab deruxtecan and good efficacy results in future trials, this agent may be another option for treating patients with advanced NSCLC following progression on immunotherapy.
Telisotuzumab Vedotin Monotherapy
Another potentially useful ADC is telisotuzumab vedotin, which is directed against c-Met, a receptor tyrosine kinase. MET is altered in approximately 1% to 2% of patients with advanced NSCLC, with the primary alterations including MET exon 14–skipping mutations and MET amplification. MET amplification can also occur in patients with EGFR, ALK, or other gene-altered tumors after they are treated with appropriate TKIs and experience disease progression.
This small, single-arm phase II study assessed the safety and efficacy of telisotuzumab vedotin monotherapy in patients with previously treated, locally advanced or metastatic NSCLC with overexpression of the c-Met protein. Patients were enrolled in 1 of 3 cohorts and received 1.9 mg/kg of telisotuzumab vedotin every 2 weeks. The ORR was highest in the EGFR wild-type cohort (35.1%; n = 37) compared with the EGFR mutant cohort (13.3%; n = 31) and the squamous cohort (14.3%; n = 22). The median durations of response for these groups were 6.9 months, not available, and 4.4 months, respectively. The investigators concluded that telisotuzumab vedotin demonstrated promising ORR and a tolerable safety profile in patients with nonsquamous EGFR wild-type NSCLC, and stage II studies are underway.
Although the numbers in this study are small and preliminary, it is important to continue the search for ADCs that can provide better efficacy than standard second-line chemotherapy. This is particularly critical for patients who do not have other options following immunotherapy (with or without platinum-based chemotherapy). Additional trials are planned for telisotuzumab vedotin, and although more data are needed before firm conclusions can be drawn, this is another promising treatment for patients who have immunotherapy refractory disease.
Analysis of Patients With Lung Cancer Receiving SARS-CoV-2 Vaccines
There have been many challenges posed by the COVID-19 pandemic. Some data suggest that the number of patients diagnosed with lung cancer was lower in 2020 than in 2019 and that a greater proportion of the patients diagnosed had stage IV disease. Other data show that fewer people were screened for lung cancer during the pandemic. These pandemic-related behaviors affect diagnosis rates and severity, and the disease poses a greater threat to patients with lung cancer as compared with the general population. But how effective are SARS-CoV-2 vaccines for people living with lung cancer?
A study presented by Gomez and colleagues at WCLC 2021 evaluated the antibody response to the mRNA SARS-CoV-2 vaccines in patients with lung cancer at least 14 days after their second doses of the vaccine. This control-matched longitudinal study reported that most vaccinated patients mounted adequate spike antibody titer. However, even after being fully vaccinated, some patients with lung cancer had significantly lower antibody titers than their healthy counterparts, and investigators did not find a correlation between titer levels and types of cancer treatment. The research team is currently looking at the influence of specific lung cancer treatments on antibody levels in serial samples collected over 2 years. Prospectively, they will study the response to booster vaccines in this population.
I think the take-home message from this study is the importance of vaccination against SARS-CoV-2 for patients with lung cancer, whether or not they are on active treatment. Although most of the study’s cohort showed an adequate immune response, a subset did not. Thus, patients with lung cancer are warned to err on the side of caution and get vaccinated.
These immunotherapy studies from WCLC 2021 provide encouraging early data for healthcare professionals treating challenging cases of NSCLC. We look forward to future studies that will give us more definitive results as we strive to improve the management of NSCLC.
Which of the results reported at WCLC 2021 did you find most interesting or most promising for your patients? Join the conversation by leaving a comment below.