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Hello, and thanks for joining us for the latest in-between-isode of Anamnesis from 乌鸦传媒.

IASLC [International Association for the Study of Lung Cancer] 2021 was a virtual event this year due to COVID-19, but 乌鸦传媒's reporter, Charles Bankhead, followed all the major developments from the conference.

Bankhead: Over the past decade, immunotherapy has transformed treatment of lung cancer, improving survival and quality of life. Clinical research has continued to explore strategies to build on the success. Melissa Johnson, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee, explained the rationale behind the phase III POSEIDON trial, which she reported at the World Conference on Lung Cancer.

Johnson: Immunotherapies targeting the PD-1 and PD-L1 pathway administered as monotherapy or in combination with chemotherapy have transformed the treatment of lung cancer. While the addition of chemotherapy to anti PD-L1 agents may provide early disease control, adding anti-CTLA-4 to anti-PD-L1 may confer long-term survival benefits for some patients. In the POSEIDON study, we evaluated durvalumab [Imfinzi] with or without tremelimumab in combination with investigator's choice platinum-based chemotherapy for first-line treatment of squamous or non-squamous non-small cell lung cancer (NSCLC).

Bankhead: POSEIDON involved 1,013 patients with untreated metastatic non-small cell lung cancer with no EGFR or ALK mutations. They were randomized to chemotherapy alone or with durvalumab or with the combination of durvalumab and tremelimumab. The primary endpoint was progression-free survival (PFS) and overall survival for the chemotherapy-durvalumab combination versus chemotherapy alone. Key secondary endpoints included progression-free survival and overall survival with durvalumab and tremelimumab versus chemotherapy alone.

Johnson: Progression-free survival was significantly improved for the durva plus chemo versus chemotherapy-alone arm, with a hazard ratio of 0.74, and a median of 5.5 months versus 4.8 months with chemotherapy alone. There was also a trend towards improved overall survival: 13.3 months with durva plus chemotherapy versus 11.7 months with chemotherapy alone, but with a hazard ratio of 0.86, that did not reach statistical significance. Positive PFS in the primary endpoint allowed formal testing of these key secondary endpoints, both statistically significant comparing durvalumab plus tremelimumab plus chemotherapy versus chemotherapy alone, with hazard ratios of 0.72 and 0.77, respectively, for PFS and overall survival.

Most subgroups favored the addition of immunotherapy to chemotherapy. And in particular, there was a leftward trend towards improved survival for all patients treated with durvalumab plus tremelimumab plus chemotherapy, in particular for the non-squamous patients and the patients with TPS [Tumor Proportion Score] level less than 1% benefiting from durva plus treme plus chemotherapy.

The safety profile was similar to previous reports of immunotherapy plus chemotherapy, with no new safety signals identified with the addition of tremelimumab. Therefore, durvalumab plus tremelimumab plus chemotherapy represents a potential new frontline treatment option for metastatic non-small cell lung cancer.

Bankhead: Historically, malignant mesothelioma has had a poor prognosis, associated with poor quality of life and high mortality. Surgery, whenever feasible, offers the best outcomes. The advent of immunotherapy has provided some encouragement, as explained by Boris Sepesi, MD, of the University of Texas MD Anderson Cancer Center in Houston.

Sepesi: We have since then learned that mesothelioma is an immunogenic disease and with the advent and increasing use of immunotherapy, certainly immunotherapy is also now being tested as part of mesothelioma treatment.

The aim of this study was really to test chemotherapy plus immunotherapy in surgically resectable mesothelioma based on the fact that these are occasionally immunogenic tumors, they express PD-L1 expression, which is associated with worse outcomes.

Bankhead: Dr. Sepesi reported findings from a small preliminary study of neoadjuvant chemotherapy plus atezolizumab, followed by surgery, and then maintenance treatment with atezolizumab for up to a year. Eligible patients had no prior treatment and were considered candidates for surgery. The trial involved a total of 28 patients, 18 of whom had surgery, and 15 who received maintenance therapy.

Sepesi: And these are some preliminary survival results, which at this point seem rather encouraging, although the median follow-up is not the same as in some of the previous trials. But when we look at overall survival at this point, the overall survival, the median survival has not been reached, and progression-free survival, the median progression-free survival is at least 18 months. So some of these results are comparable to perhaps slightly better historical cohorts, but we will have to complete the trial, and complete the adequate follow-up to be able to make any conclusions from this regimen.

This trial highlights the challenging nature of the neoadjuvant therapy because of the heterogeneity of the disease, as well as how patients react, as well as the difficult and complex surgical therapy. However, I think this is a step forward in terms of complex treatment of mesothelioma.

Bankhead: Another featured study at the conference focused on small cell lung cancer, which accounts for about 15% of all lung cancers and has proven especially difficult to treat. Luis Paz-Ares, MD, of the Hospital Universitario 12 de Octubre in Madrid, provided some context about the disease.

Paz-Ares: This is a very aggressive cancer, very often metastatic already. And something on the good side is that it's very sensitive to chemotherapy, very responsive also to traditional therapy, but typically response lasts very short because relapse is typically coming after some few months.

Unfortunately, we have learned a lot about the biology, the genomics of this disease. We were not that successful over the last 2 decades in having new treatment options in this disease -- some effect of immunotherapy, but it's still particularly for relapsing patients, very few treatment options.

Bankhead: Dr. Paz-Ares reported findings from the phase III ATLANTIS study evaluating lurbinectedin, a transcription factor inhibitor that received accelerated FDA approval for relapsed or refractory small cell lung cancer on the basis of a phase I trial involving about 100 patients. ATLANTIS involved 613 patients with previously treated small cell lung cancer. They were randomized to receive lurbinectedin plus doxorubicin or standard-of-care chemotherapy. The primary endpoint was overall survival.

Paz-Ares: The trial didn't meet the primary endpoint. There were no differences in survival between the two treatment arms, as you see by those superimposable curves. The hazard ratio being 0.97, that was not statistically significant. There was, however, some improvement in PFS, with a hazard ratio of 0.83 -- that means a decrease in the risk of progression over the time [of] about 17%, but of course, [this] was not enough to actually impact on survival.

Bankhead: Despite the negative outcome, Dr. Paz-Ares remains optimistic that lurbinectedin combination therapy has a role in treating small cell lung cancer.

Paz-Ares: In terms of combinations, we are now trying a number of combinations. Particularly my group has been involved in two combos, one with irinotecan, the initial data are really promising, [with a] response rate [of] 62%.

And of course the combination with atezolizumab [Tecentriq], another PD-L1 inhibitor, is also very attractive. The drug itself is able to reshape the microbiome element to a more immunogenic one. And the initial data with PD-L1 inhibition in combination are really good, and those data will be released within the next few months.

Bankhead: The brain is one of the most common sites of metastasis in patients with lung cancer. Brain metastases are associated with deterioration of cognitive function and quality of life and poor prognosis. Radiation therapy has been the mainstay of treatment but can also affect cognitive function and delay the start of systemic treatment for lung cancer. Immunotherapy has shown promise as a potential alternative, according to Ernest Nadal, MD, of the Catalan Institute of Oncology and the University of Barcelona.

Nadal: Patients with brain metastasis ... and patients receiving corticosteroids have been excluded or underrepresented in many trials conducted that were studying the combination of immunotherapy and chemotherapy. And we have data coming from some studies that demonstrated that immunotherapy and chemotherapy could yield promising intracranial efficacy, and are safe treatments in patients with non-small cell lung cancer.

Bankhead: The study included 40 patients with stage IV non-small cell lung cancer and untreated brain metastases. They received four to six cycles of chemotherapy plus atezolizumab, followed by maintenance treatment with chemotherapy and atezolizumab for up to a year. The primary endpoints were safety and progression-free survival.

Nadal: In terms of safety, we didn't have fatal adverse events and most of the adverse events were grade 1 or 2. That means that they were mild or moderate. In terms of efficacy, this combination of chemo plus immunotherapy in this specific population yields promising systemic and intracranial PFS. The median PFS in the body was 8.9 months, while in the brain intracranial PFS was 6.9 months. The median overall survival was 13.6 months. And the 2-year overall survival rate was 32%, which is promising survival for this specific population.

For more coverage from IASLC 2021, you can visit 乌鸦传媒's meeting page online. Be on the lookout for our next Anamnesis feature coming later this week, entitled Resilience. And stay tuned for our next in-between-isode featuring the latest meeting coverage.

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