Increasingly Specialized Clinical Trials Accelerate Advances in NSCLC Management

Konstantinos Arnaoutakis, MD

Subgroup analyses from non–small cell lung cancer (NSCLC) clinical trials, such as the phase 3 POSEIDON (NCT03164616) and FLAURA2 (NCT04035486) trials, can help personalize treatment decisions with immunotherapy and targeted therapy based on individual mutational profiles, according to Konstantinos Arnaoutakis, MD.

During an OncLive^® Institutional Perspectives in Cancer webinar on lung cancer, Arnaoutakis and colleagues highlighted immunotherapy developments in NSCLC, updated data with osimertinib (Tagrisso) in EGFR-mutated disease, considerations for future research targeting KRAS mutations in NSCLC, the evolving role of antibody-drug conjugates (ADCs) in this disease, and radiation therapy clinical trials coming down the pike.

“Regarding the current state of biomarkers in stage IV disease, we have a plethora of molecular biomarkers that are helping us decide if a patient will require targeted therapy,” Arnaoutakis said of the NSCLC treatment paradigm during his presentation.

Arnaoutakis, who chaired the event, is an associate professor in the Department of Internal Medicine in the Division of Hematology and Oncology at the University of Arkansas for Medical Sciences (UAMS) Winthrop P. Rockefeller Cancer Institute in Little Rock.

Arnaoutakis was joined by his colleagues:

• Sajjad A. Bhatti, MD, assistant professor, Department of Internal Medicine, Division of Hematology and Oncology, the Winthrop P. Rockefeller Cancer Institute at UAMS
• Ahmed Mazen Safar, MD, MS, associate professor, medicine, the Winthrop P. Rockefeller Cancer Institute at UAMS
• Sarah W. Jewell, MD, hematologist/oncologist, Highlands Oncology, Fayetteville, Arkansas
• Sanjay Maraboyina, MD, associate professor, Department of Radiation Oncology, UAMS, clinical director, UAMS-Baptists Radiation Oncology Network

Below, Arnaoutakis, Bhatti, Safar, Jewell, and Maraboyina summarize key points from their presentations.

Immunotherapy for Advanced NSCLC

Arnaoutakis: We have only 1 immunotherapy biomarker: PD-L1. Evolving biomarkers in stage IV disease include high-level MET amplification, where you can use a MET inhibitor, and 3 other biomarkers: STK11, KEAP1, and SMARCA4.

There are several immunotherapy options for the treatment of [patients with] lung cancer. PD-L1, although it’s an imperfect biomarker for a variety of reasons, is still the best approach we have [for determining patient eligibility for immunotherapy]. There is a need to personalize immunotherapy beyond PD-L1 and therefore overcome primary and secondary resistance.

The overall survival [OS] update [of the POSEIDON trial, which was presented] at the 2022 European Society for Medical Oncology Congress, showed a durable long-term OS benefit with combined immune checkpoint blockade and chemotherapy vs chemotherapy [alone in patients with metastatic NSCLC], with a HR of 0.75 and an estimated 25.0% [of patients] alive at 3 years vs 13.6% [of patients who received chemotherapy alone]. In the subgroup analysis, there was a benefit [with durvalumab (Imfinzi) and tremelimumab-actl (Imjudo) plus chemotherapy] across PD-L1 expression levels. There was, as expected, more of a response in the [subgroup of patients with] high PD-L1 expression compared with the [subgroup of patients with] low PD-L1 expression, but all groups seemed to benefit from [the combination therapy].

In a subgroup analysis [that stratified patients by STK11 and KEAP1 mutation status], patients with STK11 mutations seemed to benefit when they received chemotherapy and [immune checkpoint] blockade [vs chemotherapy alone]. The same results [were seen in patients with] KEAP1 mutations. Although the patients with KEAP1 mutations [comprised] a smaller sample size, there was still a benefit with combined immune checkpoint blockade compared with chemoimmunotherapy or chemotherapy alone. [Patients with] KRAS mutations were also analyzed, and similar results were seen.

Targeting EGFR in Lung Cancer

Bhatti: I gave an overview of EGFR-mutated NSCLC. Then I reviewed the results of the [phase 3] FLAURA trial [NCT02296125], which established osimertinib as the preferred first-line treatment option for patients with metastatic EGFR-mutated lung cancer. I provided a brief summary of some trials that are potentially challenging osimertinib for its coveted place as the first-line preferred option. I also explored the results of the FLAURA2 trial, which built on the osimertinib platform by adding chemotherapy [for the first-line treatment of patients with EGFR-mutated NSCLC]. In the adjuvant setting, I talked about the [phase 3] ADAURA trial [NCT02511106] of adjuvant osimertinib [in patients with stage IIB to IIIA NSCLC].

[In FLAURA2 trial findings], the progression-free survival [(PFS) benefit with osimertinib] is there. The median PFS was 25.5 months with chemotherapy plus osimertinib vs 16.7 months with osimertinib alone. All subsets of patients did appear to benefit from chemotherapy in terms of PFS. Patients with and without central nervous system [CNS] metastases seemed to benefit. The patients with CNS metastases seemed to benefit a little more.

[Patients with] both subsets of EGFR mutations [EGFR exon 19 deletions and EGFR L858R mutations] appeared to benefit [from the addition of chemotherapy]. Interestingly, [those with] EGFR L858R mutations didn’t benefit as much from osimertinib alone in [FLAURA]. Here they appeared to have a longer PFS, so in this subset of patients, you may want to consider chemotherapy up front.

However, in the absence of [mature OS data], I am not ready to change my practice [based on these findings]; I would rather use chemotherapy in sequence [instead of using] a combination treatment at the start. We’ll follow up on these trial results. These results need more time to mature, but in the absence of an OS benefit [with osimertinib plus chemotherapy], I wouldn’t want to [give] chemotherapy up front for these patients; I would still stick with osimertinib alone. [I may give up-front chemotherapy to patients with] EGFR L858R mutations, but I would discuss the pros and cons with the patient.

Controversies in KRAS

Safar: I’m not too impressed [with the findings from the phase 1/2 KRYSTAL-1 trial (NCT03785249)]. A 35.1% overall response rate [ORR] in the solid tumor [population] is a response, but it’s not dramatic. However, I wonder whether measuring the size of the tumor is always the right way to assess the tumor. RECIST 1.1 criteria are the convention, but one wonders, what could be the biologic impact of shutting off KRAS? I would argue that [KRAS] is the oncogene, and if the drug does its job, the PET scan should become negative, but we don’t know whether that has been done. That would tell me: Did the drug do its job?

One can ask more detailed questions about what happened to the KRAS pathway [in KRYSTAL-1]. Did we shut it off? What was the cellular fate? Maybe we induced senescence, and senescence is not cell death, but [this result] would not be reflected in the size measure. These [questions] are for future investigation: Did the drug do its job? Did it manifest the benefit differently, or is it a pharmacologic problem?

Combining a KRAS inhibitor with an EGFR-targeted drug is interesting because EGFR-targeted drugs were considered useless [in patients with] a KRAS mutation. That was in situations where we didn’t have [any drugs targeting RAS]. Now we have a RAS-targeted drug, and a recent publication indicates that [an EGFR inhibitor combined with a RAS inhibitor] is effective. This is changing our paradigm. KRAS mutations make us not use cetuximab [Erbitux] or panitumumab [Vectibix] alone, but if you are using them with KRAS-targeted drugs, the story is different.

KRAS as a gene finally has drugs. There is more than 1 [drug targeting] KRAS G12C mutations, and there is a lot of activity in the pharmaceutical companies about other non–KRAS G12C–targeted drugs. There is more in the pipeline for KRAS(on) and KRAS(off), which is a new concept [where we are] trying to attack KRAS before it turns on. It is a worthy goal to attack KRAS because [KRAS mutations are] common, [occurring in approximately] one-third of patients [with NSCLC]. We need to think about different end points for our future studies beyond RECIST 1.1 criteria.

ADCs in Lung Cancer

Jewell: ADCs are an exciting class of drugs, and they have an emerging role in NSCLC. Fam-trastuzumab deruxtecan-nxki [Enhertu] received an FDA accelerated approval for subsequent therapy or second-line therapy in HER2-mutated NSCLC, but there are a couple [of] other [ADCs with] FDA breakthrough designations and multiple ongoing trials [with ADCs], so I expect to see more coming in the future with these ADCs.

The TROPION-PanTumor01 trial [NCT03401385] was a phase 1 dose-escalation/dose-expansion trial [of datopotamab deruxtecan] in [patients with] advanced or metastatic NSCLC. The maximum tolerated dose was 8 mg/kg, and the recommended dose [for further development] ended up being 6 mg/kg. We saw a fair amount of nausea which occurred in 64% [of patients]. Stomatitis was more of a significant issue with this ADC compared with some of the others. Alopecia [was observed in] 42% of patients, and we saw [drug-related] interstitial lung disease in 6% of patients. The ORR was 26%. There was a median PFS of 6.9 months and a median OS of 11.4 months.

Radiation Oncology Clinical Trials in NSCLC

Maraboyina: The main objectives I discussed were stereotactic body radiation therapy [SBRT] and immunotherapy in early-stage NSCLC. I also touched on proton therapy in locally advanced NSCLC and discussed SBRT as local consolidative therapy in oligometastatic disease.

The RTOG 1308 trial [NCT01993810] is a phase 3 randomized trial comparing OS [after photon chemoradiotherapy vs proton chemoradiotherapy in patients with] locally advanced NSCLC. The chosen dose [of photon or proton chemoradiotherapy] is 70 Gy. When we’re [investigating] radiation, we don’t typically look at OS as a main end point, but [based on findings from] the [phase 3] RTOG 0617 trial [NCT00533949], there is a possibility that decreasing the radiation dose to the heart with proton [chemoradiotherapy] may improve OS. Some of the secondary outcomes [of RTOG 1308] are PFS and toxicity. This trial has been open [since 2014] and just completed its accrual, so we eagerly await the results.