ASCO 2020 Ushers in a Number of New Targeted Therapy Developments in NSCLC

Fam-trastuzumab deruxtecan-nxki (Enhertu) could provide patients with metastatic non–small cell lung cancer (NSCLC) who harbor HER2 exon 20 insertion mutations and high HER2 expression a more specific and less toxic treatment compared with platinum doublet chemotherapy. However, the jury is still out on whether the agent will be pursued as an alternative frontline therapy and in both patient subsets, according to Paul A. Bunn, Jr, MD.

Currently, the agent is under investigation in the phase 2 DESTINY-Lung01 trial in patients with HER2-mutant and high HER2-expressing relapsed/refractory unresectable or metastatic nonsquamous NSCLC.¹

Findings from cohort 2 of the trial, which were presented at the 2020 ASCO Virtual Scientific Program, showed an objective response rate (ORR) of 61.9% in patients with HER2 mutations who had received a median of 2 prior lines of therapy. The majority of patients had received platinum-based chemotherapy (90.5%), followed by anti–PD-1/PD-L1 inhibition (54.8%), and docetaxel (19.0%). At a data cutoff date of November 25, 2019, 45.2% of patients remained on treatment.

“The toxicity profile is so different compared with immunotherapy, but clearly, the toxicity profile is better than chemotherapy. Certainly, if the 62% response rate holds up, the efficacy is going to be enough to outweigh the toxicity,” said Bunn.

In EGFR-mutant NSCLC, the results of the phase 3 ADAURA trial, which were also presented at the 2020 ASCO Virtual Scientific Program, showed that adjuvant treatment with osimertinib (Tagrisso) led to a 79% reduction in the risk of disease recurrence of death in patients with stage IB to IIIA EGFR-mutant NSCLC.²Despite the impressive disease-free survival (DFS) benefit, Bunn stated that an overall survival (OS) improvement should be seen before the agent is incorporated into standard practice. 

In an interview with OncLive, Bunn, distinguished professor, Division of Medical Oncology, James Dudley Chair in Lung Cancer Research, University of Colorado Denver, and a 2014 Giant of Cancer Care® in Lung Cancer, provided his perspective on these trials and their projected impact on the field.

OncLive: Could you discuss the current unmet need for patients with HER2-mutant NSCLC?

Bunn: HER2 exon 20 insertion mutations are fairly common. They’re more common than some of the rare fusions, and there’s no standard TKI or antibody therapy for these patients at the moment. The standard first-line treatment for patients with lung cancer who have HER2 exon 20 mutations is chemotherapy. We would like to give patients molecular therapy in the first-line setting, which is more specific and less toxic.

Nothing has a response rate of over 50%. Some of the drugs that work in EGFR exon 20 mutations also work in HER2 exon 20 mutations, but none of them have a high response rate. A response rate over 60% is what we’re looking for in order for these drugs to be approved and used in the first-line setting. In the second- and third-line settings, [trastuzumab deruxtecan] had a 62% ORR. The duration of those responses seemed to be pretty reasonable. I would say that [trastuzumab deruxtecan] is the lead agent at the moment for the 2% or so of patients with lung cancer who have HER2 insertion mutations.

What was the design of the DESTINY-Lung01 trial?

This was a standard phase 2 trial. There were 2 baskets; 1 basket enrolled patients with HER2 exon 20 mutations. Because [trastuzumab deruxtecan is an] antibody-drug conjugate (ADC), it might also work in patients that have high [HER2] expression by immunohistochemistry (IHC). Therefore, the other basket enrolled patients that don’t have the mutation but have high protein expression on the cell surface by IHC. We expect that patients with HER2 exon 20 mutations would have the best response rate.

What are your thoughts on the safety profile of trastuzumab deruxtecan? Do you think the adverse events that were reported in the trial were manageable?

Yes. Standard chemotherapy is probably the most toxic type of treatment we have. TKIs are probably the least toxic treatment we have. In between, we have ADCs and immunotherapy.

What would you like to see with longer term follow-up?

The best agents should be used up front. [Trastuzumab deruxtecan] seems to be a good drug. Hopefully, the best use of the drug would be in the first-line setting. The standard again is platinum doublet chemotherapy in the first-line setting, so there are 2 approaches. One approach is [to use the drug in the] second- and third-line settings and hope for a response rate in big population over 50% and a PFS of 9 months or more. In that setting, the FDA has frequently given accelerated approval. The other approach would be to [compare] the agent with platinum doublet chemotherapy in the first-line setting and see [which treatment performs] better.

Presumably, [investigators] will [evaluate] both approaches. At the end [of the DESTINY-Lung01 trial], the investigators will have to sort out whether they’re going to have individual trials for patients with mutations and high protein expression, or whether they’re going to have a trial that includes both patient subsets.

What is the significance of these data that were reported from the DESTINY-Lung01 trial?

[Trastuzumab deruxtecan] is probably the lead agent for patients with HER2 exon 20 mutations and probably high protein expression.

What other lung cancer studies caught your eye at the 2020 ASCO Virtual Scientific Program?

The ADAURA trial generated the most interesting controversy. That trial was an adjuvant trial for patients with resected early-stage NSCLC. If patients had stage I disease and didn’t need chemotherapy, they were randomized osimertinib or not. If patients who needed chemotherapy completed chemotherapy, they were randomized to osimertinib or not.

There was a huge benefit in terms of DFS. That DFS benefit was greatest in patients with stage III disease. It was still significant and important in patients with stage II disease, and even those with stage IB disease who got chemotherapy.

However, the goal is to cure patients, and about half of patients are cured with standard treatment, surgery, or surgery post-chemotherapy. Those patients are not going to get any benefit. For 55% of patients, there’s going to be a lot of cost and some toxicity with absolutely no benefit.

In the other 45% of patients who have undetected micrometastatic disease, you’re killing off cells [and expect] to cure some of those patients. However, the DFS benefit doesn’t give the answer to that. At the 2020 ASCO Virtual Scientific Program, we saw the results of another adjuvant trial with erlotinib (Tarceva) with the CT1104 trial. A couple years ago, that trial was big news because we saw a DFS benefit with erlotinib. However, at this’s year meeting, the survival was identical; we didn’t see a survival benefit. Thus far, every adjuvant trial with a TKI has shown no OS benefit. I don’t think adjuvant osimertinib is going to be a standard until we see the survival results.

There are some people who disagree with that, but they should keep in mind that chemotherapy has an [encouraging cure and response rate]. TKIs have a CR rate of essentially 0%. Even though all the cells have the receptor, many of them die in the presence of the drug inhibitor, so all we get are partial responses. If you have systemic disease, it will delay the time to [additional therapy], but you’re probably not curing the disease. [Adjuvant TKIs] have failed in terms of curing people. Time will tell, but I don’t think it’s a standard treatment until we see a survival benefit.

References

1. Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non–small cell lung cancer (NSCLC): interim results of DESTINY-Lung01. J Clin Oncol. 2020;38(suppl 15);9504. doi:10.1200/JCO.2020.38.15_suppl.9504
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