Role of Molecular Biology, Evolving Immunotherapy Addressed in Lung Cancer Conference

Solange Peters, MD, PhD

Lug cancer, traditionally labeled as having poor outcomes, has shed its former outlook and looks to the future with hope because of 2 strategies that have changed the fate of patients with thoracic malignancies, said Solange Peters, MD, PhD, in an interview with Targeted Therapies in Oncology^TM ahead of the 23rd Annual International Lung Cancer Congress®.¹ A greater understanding of molecular biology and the role of immunotherapy in lung cancer has ushered in a new era of understanding the disease that has led to the development of an extensive targeted therapy portfolio.

Molecular characterization, oncogene addiction (ie, the dependency of certain tumor cells on a single activated oncogenic protein or pathway to maintain their malignant properties), and targeted therapies have contributed to the first strategy, according to Peters. “Now we have identified mutations we can treat not with chemotherapy or radiation, but with targeted therapies in the first and second line,” said Peters, a key presenter who is head of the medical oncology service and chair of thoracic oncology in the Department of Oncology at the Centre Hospitalier Universitaire Vaudois. She is also the president of the European Society for Medical Oncology.

As investigators discover new compounds and targets, improvements in the pharmacology of these agents emerge. “We have been developing more potent and broader drugs that overcome and prevent resistance,” Peters said.

The second strategy, immunotherapy, has led to long-term survival in some patients with lung cancer, despite the presence of metastatic disease. “When I first started in oncology, I could not conceive that a patient with metastatic disease could survive 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 immune checkpoint inhibitor approved by the FDA 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 findings from CheckMate 017 (NCT01642004) and CheckMate 057 (NCT01673867), which led to the agent’s approval. Pembrolizumab was approved based on the results of KEYNOTE-010 (NCT01905657), which evaluated previously treated patients with advanced/metastatic NSCLC whose tumors expressed PD-L1 on at least 1% of cells.

The role of combination immunotherapy with nivolumab and ipilimumab (Yervoy) was elucidated by results from CheckMate 012 (NCT01454102).^4,5 CheckMate 227 (NCT02477826) also evaluated the role of nivolumab and ipilimumab in treatment-naive patients with stage IV or recurrent NSCLC with a PD-L1 TPS of 1% or greater. Investigators noted that among patients with a TPS less than 1%, the combination conferred superior overall survival (OS) compared with platinum-based chemotherapy, with a median OS in the treatment arm of 17.2 months compared with 12.2 months in the control arm (HR, 0.62).

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

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

survival (PFS) compared with individuals with negative tumor PD-L1 expression (median PFS, 6.8 months vs 2.8 months, respectively). Investigators noted that TMB was a superior predictive biomarker compared with PD-L1 expression. In patients whose TMB was high, 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 TMB had an objective response rate of 18% and 5% with PD-L1 TPS 1% or greater and PD-L1 TPS less than 1%, respectively.

Use in Earlier Disease

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

Shu et al6 tested the activity of atezolizumab (Tecentriq) with carboplatin and nab-paclitaxel (Abraxane) as a potential neoadjuvant treatment. The phase 2 single-arm trial (NCT02716038) was conducted in 3 US hospitals that assessed 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 end point was major pathological 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 received R0 resection, and there was no apparent increase in serious postoperative complications. Efficacy was promising, with downstaging from N2 to N0 in 11 of 19 patients (58%), a major pathologic response rate of 57%, and a complete pathologic response in 33%.

Another study evaluated neoadjuvant nivolumab in patients with newly diagnosed resectable stage IA-IIA NSCLC (NCT02259621). Twenty-two patients were enrolled and 21 were deemed eligible for study. Among the 21 per protocol patients 18 patients (85%) demonstrated stable disease, and 2 patients (10%) demonstrated a partial response whereas 1 patient had progressive disease. Notably, CT imaging underestimated the extent of nivolumab response, as multiplanar reconstruction imaging was reported in 9/21 cases (43%; 95% CI, 24%–63%). With a median follow-up of 12 months, 2 of 20 resected patients had experienced recurrence. Based on these encouraging data, this trial has expanded to examine combination neoadjuvant therapy with nivolumab and ipilimumab.

The FDA approved durvalumab (Imfinzi) for unresectable stage III NSCLC based on findings 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 vs 5.6 months (95% CI, 4.6-7.8) with the placebo arm (HR, 0.52; 95% CI, 0.42-0.65; P < .001). The 12- and 18-month PFS rates also favored durvalumab over placebo, with investigators reporting 55.9% vs 35.3% for the 12-month rates and 44.2% vs 27.0% for the 18-month rates, respectively.

International Lung Cancer Congress®

Turning to the congress, Peters says the international faculty and colleagues that the conference brings together is a benefit. “It brings to light the perspective of different practices,” Peters said. Clinicians draw on their experience within their respective country, but by bringing together a international faculty, “we can revisit the evidence for the treatment options we regularly use based on our international colleagues’ experience.”

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

“I may know the data for why we treat a disease a certain way, but I want to know what my colleagues think about the data, because that’s the only way I can improve. Sometimes I’ll learn a little nuance about the data or the limitations of the data—or maybe there is a piece of data I haven’t considered. It’s very important,” Peters said.

Peters will make 2 presentations during the conference: a presentation that focuses on the relevant biomarkers in perioperative immunotherapy and a presentation about the role of treatment agent sequencing in ALK-rearranged NSCLC.

_REFERENCES

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

_{2. FDA approves Opdivo (nivolumab) for the treatment of patients with previously treated metastatic squamous non-small cell lung cancer. News 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 on or after platinum-containing chemotherapy. News 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 of an open-label, phase 1, multi-cohort 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. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 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, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2020;21(6):786-795. doi:10.1016/S1470-2045(20)30140-7}

_{7. FDA expands approval of Imfinzi to reduce the risk of non-small cell lung cancer progressing. News 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}