Leveraging Immunotherapy and Targeted Therapy for Cure in Lung Cancer

Benjamin P. Levy, MD

Efforts to leverage targeted therapy and immunotherapy, which have been approved modalities in advanced non–small cell lung cancer (NSCLC), are leading to improved survival in patients with advanced and earlier-stage disease, said Benjamin P. Levy, MD, in a virtual presentation during the 2nd Annual Precision Medicine Symposium, a program developed by Physicians’ Education Resource® LLC.

EGFR-Mutant NSCLC

The leading edge of this era of precision medicine has been EGFR, said Levy, citing the phase 3 FLAURA trial as the first robust demonstration of the potency of wedding a genomic alteration to a targeted therapy. In the trial, patients with locally advanced or metastatic EGFR-mutant NSCLC were randomized to frontline treatment with the third-generation EGFR TKI osimertinib (Tagrisso) versus first-generation EGFR TKIs erlotinib (Tarceva) or gefitinib (Iressa).

Progression-free survival (PFS) served as the primary end point of the study and favored osimertinib in the entire population (HR, 0.46; P < .001), in patients with central nervous system (CNS) metastases (HR, 0.47; P < .001), and those without CNS metastases (HR, 0.46; P < .001).1

Moreover, overall survival (OS), which served as one of the secondary end points of the study was 38.6 months with osimertinib versus 31.8 months with erlotinib or gefitinib (HR, 0.80; 95.05% CI, 0.64-1.00; P = .046).¹

“The question is: We have these great data in the advanced setting, but can we bring it forward to earlier-stage disease,” said Levy, associate professor of oncology and clinical director of Medical Oncology at Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital.

The phase 3 ADAURA trial was designed to answer this question, evaluating the role of adjuvant osimertinib in resected EGFR-mutant NSCLC. In the trial, patients with completely resected stage IB, II, and IIIA NSCLC with an EGFR exon 19 deletion or L858R mutation were randomized to 80 mg of osimertinib once daily versus placebo.

At only 29% maturity, disease-free survival (DFS), which served as the primary end point of the study, was not reached with osimertinib versus 28.1 months with placebo (HR, 0.21; 95% CI, 0.16-0.28; P < .0001). Additionally, the 2-year DFS rates were consistent across stage IB (87%; HR, 0.50), II (91%; HR, 0.17), and IIIA disease (88%; HR, 0.12), as well as across all prespecified subgroups.²

“At the 2020 ESMO Congress, we saw updated data showing that there are more relapses in the CNS in patients who received placebo versus osimertinib,” said Levy. “Based on ADAURA, I am considering giving [adjuvant osimertinib]. The DFS curves are hard to argue, and the urgent need in an unforgiving cancer is also hard to argue when we’re going for cure.”

For patients with oligometastatic disease, layering locally ablative therapy with targeted therapy could be a way to improve outcomes, said Levy, who pointed to a phase 3 trial that evaluated stereotactic body radiation therapy (SBRT) plus an EGFR TKI versus an EGFR TKI alone in patients with EGFR-mutant NSCLC with no more than 5 sites of metastatic disease.

The results demonstrated that, on a Kaplan-Meier plot, the addition of SBRT led to an improvement in PFS (HR, 0.618; 95% CI, 0.394-0.969; P < .001) and OS (HR, 0.682; 95% CI, 0.456-1.001; P < .001).³

“The questions that arise are: What is the definition of oligometastatic disease? What is the optimal timing of local ablative therapy? Should we give local ablative therapy concurrently, after induction, or at the time of oligoprogression? How will this strategy evolve as frontline treatment combinations emerge for EGFR-positive patients?” asked Levy.

ALK-Positive NSCLC

Encouragingly, the move to cure, even in the advanced setting, is not limited to EGFR, said Levy.

“I don’t think that we can offer cure to every advanced-stage patient, but we are learning about ways to sequenceALK-directed TKIs that are leading to unprecedented outcomes for patients,” said Levy.

For example, long-term data from the phase 3 ALEX trial showed that a median follow-up of 48.2 months, the median OS was not reached with alectinib (Alecensa) versus 57.4 months with crizotinib (Xalkori) in patients with advanced ALK-positive NSCLC (HR, 0.67; 95% CI, 0.46-0.98; P = .0376).⁴

Furthermore, a retrospective analysis showed a median OS of 81 months (range, 3-125) in patients with stage IV ALK-positive NSCLC from the time of diagnosis,⁵ suggesting that the right sequence of genomically directed therapy can lead to long-term survival, if not cure.

Incorporating Immunotherapy Into Neoadjuvant and Adjuvant Therapy

When it comes to immunotherapy, there are now 9 FDA-approved regimens for patients with advanced disease who do not harbor an actionable mutation.

“Similar to the genotype space, we have all these great data for immunotherapy in the advanced setting. We have long-term outcomes from the phase 1 trial with nivolumab [Opdivo] showing a 5-year OS rate of 16%. Can we incorporate immunotherapy [into] resectable disease?” said Levy.

Immunotherapy is an attractive option, particularly when the absolute improvement in 5-year OS with chemotherapy ranges from 5% to 15% in patients with resected stage II disease, said Levy.

A number of trials are ongoing, looking at the role of adjuvant immunotherapy. One such trial is the phase 3 EA5142 ANVIL study, which is evaluating 1 year of nivolumab versus observation in patients with stage IB to IIIA resected NSCLC. Chemotherapy will be given per physician discretion prior to randomization.

The trial is not expected to read out until July 2024, explained Levy, stating that the median time from patient enrollment to publication of study results for phase 3 adjuvant studies in NSCLC is 11 years.

Given the data with immunotherapy in the advanced setting, it’s not unreasonable to evaluate its use in the neoadjuvant setting, explained Levy, who added that results would be more timely and potentially more effective.

In a phase 1 neoadjuvant study of nivolumab prior to resection in patients with stage I to IIIA NSCLC, 2 cycles of the PD-1 inhibitor led to a major pathological response (MPR) rate of 43%.⁶

Data published from the phase 2 NADIM trial in September 2020 corroborate the idea that neoadjuvant therapy can lead to improved responses in patients with resectable disease. The difference in this trial was that patients with stage IIIA resectable disease received neoadjuvant chemoimmunotherapy followed by adjuvant immunotherapy.

Earlier findings from the trial demonstrated that the pathological complete response (pCR) rate after neoadjuvant carboplatin, paclitaxel, and nivolumab was 61%, and the MPR rate was 85%.⁷ Updated findings demonstrated that the 2-year PFS rate was 77.1% (95% CI, 59.9%-87.7%).⁸

“It’s tough to believe that 3 cycles of chemotherapy with immunotherapy could elicit that type of response when the historical pCR rate to neoadjuvant chemotherapy is 5%. If this data holds up in phase 3 trial, we’re going to be in a new treatment paradigm where everyone will receive neoadjuvant chemoimmunotherapy,” concluded Levy.

References

1. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50. doi:10.1056/NEJMoa1913662
2. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients with stage IB-IIIA EGFR mutation-positive NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(suppl 18):LBA5. doi:10.1200/JCO.2020.38.18_suppl.LBA5
3. Wang X, Zeng M. First-line tyrosine kinase inhibitor with or without aggressive upfront local radiation therapy in patients with EGFRm oligometastatic non-small cell lung cancer: interim results of a randomized phase III, open-label clinical trial (SINDAS) (NCT02893332). J Clin Oncol. 2020;38(suppl 15):9508. doi:10.1200/JCO.2020.38.15_suppl.9508
4. Peters S, Mok T, Gadgeel SM, et al. Updated overall survival and safety data from the randomized, phase III ALEX study of alectinib versus crizotinib in untreated ALK+ NSCLC. J Clin Oncol. 2020;38(suppl 15):9518. doi:10.1200/JCO.2020.38.15_suppl.9518
5. Pacheco JM, Gao D, Smith D, et al. Natural history and factors associated with overall survival in stage IV ALK-rearranged non–small cell lung cancer. J Thoracic Oncol. 2019;14(4):691-700. doi:10.1016/j.jtho.2018.12.014
6. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med. 2018;378(21):1976-1986. doi:10.1056/NEJMoa1716078
7. Provencio M, Nadal E, Insa A, et al. NEO-adjuvant chemo-immunotherapy for the treatment of STAGE IIIA resectable non-small-cell lung cancer: a phase II multicenter exploratory study––final data of patients who underwent surgical assessment. J Clin Oncol. 2019;37(suppl 15):8509. doi:10.1200/JCO.2019.37.15_suppl.8509
8. Provencio M, Nadal E, Insa A, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2020. doi:10.1016/S1470-2045(20)30453-8