Role of Molecular Biology and Evolution of Immunotherapy Discussed at Lung Cancer Conference

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Horn cancer, traditionally labeled as having poor outcomes, has abandoned its old outlook and looks to the future with hope thanks to 2 strategies that have changed the fate of patients with chest malignancies, says Solange Peters, MD, PhD , in an interview with Targeted therapies in oncologyMT before the 23rd Annual International Conference on Lung Cancer®.1 A better understanding of molecular biology and the role of immunotherapy in lung cancer has ushered in a new era of understanding the disease which has led to the development of an extensive portfolio of targeted therapies.

Molecular characterization, oncogene dependence (that is, the dependence of certain tumor cells on a single protein or oncogenic pathway activated to maintain their malignant properties) and targeted therapies have contributed to the first strategy, according to Peters. “Now we have identified mutations that we can treat not with chemotherapy or radiation, but with first- and second-line targeted therapies,” said Peters, a keynote speaker who is chief of the medical oncology department and chairman of thoracic oncology in the Department of Oncology at the Center Hospitalier Universitaire Vaudois. She is also President of the European Society for Medical Oncology.

As researchers discover new compounds and targets, improvements in the pharmacology of these agents are emerging. “We’ve developed more potent and broader drugs that overcome and prevent resistance,” Peters said.

The second strategy, immunotherapy, has led to long-term survival in some lung cancer patients, despite the presence of metastatic disease. “When I started in oncology, I couldn’t conceive that a patient with metastatic disease could survive for years,” Peters said. “We now have strong data showing that immunotherapy should be used alone or in combination in all patients with metastatic disease.”

Monotherapy and in combinations

Nivolumab (Opdivo) was the first FDA-approved immune checkpoint inhibitor to treat patients with advanced non-small cell lung cancer (NSCLC), followed by pembrolizumab (Keytruda).2.3 Nivolumab as a single agent was supported by results from CheckMate 017 (NCT01642004) and CheckMate 057 (NCT01673867), which led to agent approval. Pembrolizumab was approved based on results from KEYNOTE-010 (NCT01905657), which evaluated previously treated patients with advanced/metastatic NSCLC whose tumors expressed PD-L1 in at least 1% of cells.

The role of combined immunotherapy with nivolumab and ipilimumab (Yervoy) was elucidated by the results of CheckMate 012 (NCT01454102).4.5 CheckMate 227 (NCT02477826) also assessed the role of nivolumab and ipilimumab in treatment-naïve patients with stage IV or recurrent NSCLC with a PD-L1 DST of 1% or greater. Investigators noted that in patients with a TPS of less than 1%, the combination conferred better overall survival (OS) than platinum-based chemotherapy, with a median OS in the treatment arm of 17.2 months versus 12.2 months in the control arm (HR, 0.62).

CheckMate 568 (NCT02659059) evaluated nivolumab plus ipilimumab every 6 weeks as first-line treatment for advanced/metastatic NSCLC. This single-arm phase 2 trial examined the association of efficacy with PD-L1 expression and tumor mutational load (TMB).

Patients with PD-L1 expression greater than 1% had higher progression-free progression

survival (PFS) compared to individuals with negative tumor PD-L1 expression (median PFS, 6.8 months versus 2.8 months, respectively). The researchers noted that TMB was a superior predictive biomarker when compared to PD-L1 expression. In patients with elevated BMR, the objective response rate was 48% and 47% for patients with PD-L1 TPS greater than 1% and PD-L1 TPS less than 1%, respectively. Patients with low BMR had an objective response rate of 18% and 5% with a PD-L1 TPS of 1% or greater and a PD-L1 TPS less than 1%, respectively.

Use in prior diseases

After its success in advanced/metastatic disease, researchers turned to earlier stage disease to determine the effectiveness of immunotherapy. Although perioperative chemotherapy is the standard of care in stage IB to IIIA resectable disease, the strategy provides only modest benefit.

Shu et al6 tested the activity of atezolizumab (Tecentriq) with carboplatin and nab-paclitaxel (Abraxane) as a potential neoadjuvant treatment. The single-arm phase 2 trial (NCT02716038) was conducted at 3 US hospitals that evaluated 39 patients, 30 of whom were enrolled in the study. Patients received neoadjuvant treatment with intravenous atezolizumab (1200 mg) on ​​day 1, nab-paclitaxel (100 mg/m2) on days 1, 8, and 15, and carboplatin (area under the curve 5; 5 mg/mL per min) on day 1 of each 21-day cycle. The primary endpoint was major pathologic response, defined as the presence of 10% or less residual viable tumor at the time of surgery.

Investigators determined that the neoadjuvant regimen followed by surgery was safe and feasible, with no treatment-related delays for surgery. Ninety percent (27 of 30) of enrolled patients underwent R0 resection, and there was no apparent increase in serious postoperative complications. Efficacy was promising, with a downgrade from N2 to N0 in 11 of 19 patients (58%), a major pathologic response rate of 57%, and a pathologic complete response in 33%.

Another study evaluated neoadjuvant nivolumab in patients with newly diagnosed stage IA-IIA resectable NSCLC (NCT02259621). Twenty-two patients were recruited and 21 were deemed eligible for the study. Of the 21 per-protocol patients, 18 patients (85%) had stable disease and 2 patients (10%) had a partial response while one patient had progressive disease. Notably, CT imaging underestimated the extent of response to nivolumab, as multiplanar reconstruction imaging was reported in 9 of 21 cases (43%; 95% CI, 24% to 63%). With a median follow-up of 12 months, 2 of the 20 resected patients experienced a recurrence. Based on these encouraging data, this trial expanded to examine neoadjuvant therapy combined with nivolumab and ipilimumab.

The FDA has approved durvalumab (Imfinzi) for unresectable stage III NSCLC based on results from the PACIFIC trial (NCT02125461).7.8 In PACIFIC, the median PFS was 16.8 months (95% CI, 13.0-18.1) for the durvalumab arm versus 5.6 months (95% CI, 4.6-7.8) with the placebo arm (HR, 0.52; 95% CI, 0.42-0.65; P

International Lung Cancer Congress®

As for the congress, Peters says the faculty and international colleagues that the conference brings together are a plus. “It sheds light on the perspective of different practices,” Peters said. Clinicians draw on their experience in their respective countries, but by bringing together international faculty, “we can review the evidence for the treatment options we routinely use based on the experience of our international colleagues.”

She noted that some international colleagues implement immunotherapy early in the disease, unlike other colleagues who have not considered it. “By sharing these insights, you can improve your own approach to treating your patients,” she said.

“I may know the data explaining why we treat a disease in a certain way, but I want to know what my colleagues think of this data, because it is the only way to improve myself. Sometimes I learn a little nuance about the data or the limitations of the data – or maybe there’s a piece of data that I haven’t taken into account. It’s very important,” Peters said.

Peters will make 2 presentations at the conference: a presentation that focuses on relevant biomarkers in perioperative immunotherapy and a presentation on the role of sequencing treatment agents in ALK– Rearranged NSCLC.

REFERENCES

1. 23rd Annual International Congress on Lung Cancer. PER®. Accessed April 27, 2022. https://bit.ly/3kiX9Sq


2. FDA approves Opdivo (nivolumab) for treatment of patients with previously treated metastatic non-small cell squamous cell lung cancer. Press release. Bristol Myers Squibb; March 4, 2015. Accessed April 27, 2022. https://bit.ly/3OIhKgK

3. FDA approves Keytruda (pembrolizumab) for the treatment of patients with metastatic non-small cell lung cancer whose tumors express PD-L1 with disease progression during or after platinum-containing chemotherapy. Press release. Merck; October 2, 2015. Accessed April 27, 2022. https://bit.ly/3vl2jDD

4. Hellmann MD, Rizvi NA, Goldman JW, et al. Nivolumab plus i ilimumab as first-line treatment for advanced non-small cell lung cancer (CheckMate 012): results from a multicohort phase 1 open-label study. Lancet Oncol. 2017;18(1):31-41. doi:10.1016/S1470-2045(16)30624-6

5. Hodi FS, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab combined versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival results in a phase 2 multicenter, randomized, controlled trial. Lancet Oncol. 2016;17(11):1558-1568. doi:10.1016/S1470-2045(16)30366-7

6. Shu CA, Gainor JF, Awad MM, et al. Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small cell lung cancer: an open-label, multicenter, single-arm, phase 2 trial. Lancet Oncol. 2020;21(6):786-795. doi:10.1016/S1470-2045(20)30140-7

7. FDA extends approval of Imfinzi to reduce risk of progression of non-small cell lung cancer. Press release. Accessed April 28, 2022. https://bit.ly/3vnUAoi


8. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small cell lung cancer. N Engl J Med. 2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937


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