Worth The Wait? Genomic Testing Delays Initiation of Advanced NSCLC Therapy

NON–SMALL CELL LUNG cancer (NSCLC) has seen the most advanced and varied impacts from the use of genomic testing for actionable mutations compared with other cancer types. Because the National Comprehensive Cancer Network (NCCN) recommends a broad molecular panel–based next-generation sequencing (NGS) approach, there is a pressing need for comprehensive results so the optimal treatment can be found.

A number of targeted therapies are available as first- or second-line treatment options, making quick NGS results a high priority. Testing for EGFR and ALK mutations, as well as PD-L1 testing, has a category 1 recommendation from the NCCN for this reason,¹ but it’s important to have the results of testing even for less common mutations that may not directly influence frontline therapy.

In 2 separate Case-Based Roundtable discussions, participants were surveyed on their experiences with molecular testing and how it affected their treatment practice as medical oncologists immediately following diagnosis of NSCLC. All participants said they perform NGS testing at diagnosis, as opposed to after the disease fails to respond to immunotherapy or not routinely testing all patients.

When discussing the case of a nonsmoking Asian woman newly diagnosed with stage IVB TTF1 positive adenocarcinoma, who was anxious to start therapy as soon as possible, the participants were presented with multiple approaches, including starting chemotherapy, immunotherapy, or both. In both events, a significant percentage of participants chose to wait for NGS results rather than start therapy immediately [Polls].

RATIONALE FOR WAITING FOR NGS

Broad molecular panel testing offers the ability to detect the widest range of actionable mutations in lung cancer. “You want testing in all patients up front, because you want to match patients to the best possible therapy,” said Joshua K. Sabari, MD, thoracic medical oncologist at NYU Langone Health’s Perlmutter Cancer Center in New York, and moderator of one of the events.

However, he observed that not all patients get comprehensive testing. “When I see second opinions from community practice, I would say…30% of patients have incomplete molecular testing done. They might have EGFR and ALK by [immunohistochemistry], and PD-L1, and they stop at that. Or they may have EGFR, ALK, ROS1, and RET by [fluorescence in situ hybridization], and then stop at that.

“When you look at the notes from your patients and it says negative testing for molecular [biomarkers], you want to dig deeper than that and find out what testing was done and whether it’s sufficient enough for you to make [the] conclusion that there really is no driver in that patient population,” Sabari said.

The time to receiving test results varies depending on circumstances: One participant estimated it takes 10 days to 2 weeks, whereas others said it can take 3 to 4 weeks for a tissue biopsy–based NGS panel. One participant noted the obstacle of the 14-day rule impacting the billing of patients with Medicare, which may require oncologists to wait up to 14 days after a patient is discharged from a hospital to send an NGS panel.²

Plasma-based liquid biopsies can be done more quickly but are more likely to lead to false negatives, meaning tissue-based testing is eventually needed if oncologists want to consider all available targeted treatments and potential clinical trial access. Several participants said they used plasma-based molecular testing for some results and received them in less than a week.

Alexander Spira, MD, PhD, codirector of the Virginia Cancer Specialists Research Institute in Fairfax and clinical assistant professor at Johns Hopkins University in Baltimore, Maryland, who was the other event’s moderator, asked participants whether they would start frontline therapy without NGS results.

“There are some occasions where the patient is really symptomatic, and I think you have to treat. It’s rare, but there have been situations where I have,” said Beverly J. Drucker, MD, PhD, of Yale School of Medicine in New Haven, Connecticut, in Spira’s event.

Sabari noted that patients can be unsatisfied with waiting. “A lot of our patients are in psychological crisis when we meet them, and they want to start therapy as soon as possible. When we tell them we’re going to wait, they’ll go down the block to another [cancer] center for therapy.”

IMPACT OF FRONTLINE DECISIONS

The preferred frontline regimens for advanced lung adenocarcinoma not otherwise specified in patients with an ECOG performance status of 0 or 1 include carboplatin or cisplatin with pemetrexed chemotherapy plus the addition of pembrolizumab (Keytruda) or other chemoimmunotherapy combinations.¹ In patients with an ECOG performance status of 2, carboplatin/pemetrexed is preferred and no immunotherapy is recommended.

In the poll, the oncologists who said they would treat the patient without NGS results generally selected a platinum-containing chemotherapy doublet without immunotherapy. Another key factor shaping this choice is that EGFR mutations are not only associated with lower responses to immunotherapy, but the EGFR tyrosine kinase inhibitor (TKI) osimertinib (Tagrisso) is also associated with pulmonary toxicity in patients who received prior or concurrent immune checkpoint inhibitor therapy.^3,4 For this reason, oncologists would avoid giving frontline immunotherapy to a patient who could potentially have an EGFR mutation in exon 19 or exon 21. Immune checkpoint inhibitors also appeared to have less efficacy in patients with the less common EGFR exon 20 insertion.⁵

“I would avoid use of immunotherapy and just give traditional chemotherapy in case the patient is symptomatic from the disease burden and wait for the NGS…and the PD-L1 testing before we incorporate immunotherapy,” said Prabhsimranjot Singh, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, in Spira’s event. Spira acknowledged that it is difficult to wait before treating some patients, saying that in the real world, oncologists will treat a number of patients without NGS results, particularly those who are very symptomatic.

In Sabari’s group, Parth V. Khade, MD, of Texas Oncology in Plano, said, “I’ll typically wait for the results of the NGS. If a patient is more critical and has signs of end organ dysfunction, then sometimes I’ll use chemotherapy as a bridge without immunotherapy. But that would only be in really critical cases where they just have to start treatment as soon as possible.”

The participants discussed whether PD-L1 expression being 100% would lead to starting chemoimmunotherapy without NGS results. “If the patient has an actionable mutation and you give the immunotherapy, they’re going to have a risk of toxicity, so I would still prefer to wait for the NGS,” said Giancarlo Moscol, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Sabari agreed, saying that before NGS testing was available, he had a younger nonsmoking patient with 100% PD-L1 expression whose disease failed to respond to pembrolizumab. After an EGFR mutation was discovered, his patient had immune-mediated colitis when given an EGFR TKI. “Not only did the patient get the wrong therapy up front, [but they also] couldn’t get the right therapy in the second-line setting,” he said.

TARGETING RARE ACTIONABLE MUTATIONS

In the patient case presented, the disease was negative for PD-L1 expression, and the patient began receiving carboplatin/pemetrexed before DNA-based NGS results were returned. Despite a partial response to chemotherapy, the patient reported worsening back pain and dyspnea on mild exertion 4 months after initiation.

The NGS showed an EGFR exon 20 insertion mutation (V769_D770insASV), which is a rare driver mutation that can be targeted with amivantamab-vmjw (Rybrevant). Amivantamab has received accelerated approval as second-line treatment following chemotherapy. A second targeted therapy, mobocertinib (Exkivity), also received accelerated approval but it was voluntarily withdrawn in October 2023.⁶

Most participants said they would be comfortable using amivantamab in the second line. Sabari noted that docetaxel with or without ramucirumab (Cyramza) is an alternative second-line option, though it would likely only offer modest survival improvement.

Although the exon 20 insertion would not have been actionable in the front line in this case, the moderators discussed how it will become relevant soon. The phase 3 PAPILLON trial (NCT04538664) investigated the combination of carboplatin, pemetrexed, and amivantamab in comparison with carboplatin/pemetrexed alone in this population. At a median follow-up of 14.9 months, the median progression-free survival (PFS) by blinded independent central review was 11.4 months with amivantamab vs 6.7 months without it (HR, 0.40; 95% CI, 0.30-0.53; P < .001), with an 18-month PFS rate of 31% vs 3%, respectively.⁷

ANTICIPATING FUTURE DEVELOPMENTS

Should the combination become a frontline option, getting NGS panel results will be crucial in this population, as an estimated 50% of EGFR exon 20 insertions found by NGS would have been missed by polymerase chain reaction tests.⁸ However, Sabari acknowledged that this leaves no preferred second-line therapy option in patients who already received amivantamab in the front line. He also said that targeted therapies have shown promise in early-phase trials as an adjuvant treatment for patients with NSCLC and an EGFR exon 20 insertion, similar to osimertinib in EGFR exon 19 and 21.

According to the PAPILLON investigators, 43 patients in the amivantamab/chemotherapy arm received subsequent therapy: 12 received an EGFR-targeted or TKI monotherapy or combination, 23 received chemotherapy or immunotherapy-based regimens, and 8 received antineoplastic agents.⁷

“By the time people are going through the second regimen for lung cancer, they’re [less fit] already, so it’s a lot of shared decision-making, given that there’s increased toxicity and the overall survival [is poor],” said Shail Maingi, MD, of Dana-Farber Cancer Institute, in Spira’s group.

Because finding the right therapy in the first line offers the most opportunity to benefit patients, prompt NGS results are all the more essential, but obstacles persist. “Even if I have a patient [who] was at a hospital across the street from our hospital, sometimes it takes a week or 2 just to get the tissue— then from that point, another 2 to 3 weeks,” Sabari said. “It’s not uncommon for our patients to wait, on average, 3 to 4 weeks for their results of their DNA-based assays. One way to improve upon that is to get reflex testing…at all institutions, and the results come with the patient when you see them. Wouldn’t that be amazing if we [could] have the results up front?”

_REFERENCES

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_{2. Laboratory date of service policy. Centers for Medicare & Medicaid Services. Updated September 6, 2023. Accessed January 5, 2024. https://go.cms. gov/3rp440t}

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_{4. Schoenfeld AJ, Arbour KC, Rizvi H, et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. Ann Oncol. 2019;30(5):839-844. doi:10.1093/annonc/mdz077}

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_{6. Takeda provides update on EXKIVITY (mobocertinib). News release. Takeda. October 2, 2023. Accessed January 5, 2024. http://tinyurl.com/2reykxdn}

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_{8. Viteri S, Minchom A, Bazhenova L, et al. Frequency, underdiagnosis, and heterogeneity of epidermal growth factor receptor exon 20 insertion mutations using real-world genomic datasets. Mol Oncol. 2023;17(2):230-237. doi:10.1002/1878-0261.13327}