Azzoli Considers Multiple Treatment Options in Early-Stage NSCLC

Christopher G. Azzoli, MD

Director of Thoracic Oncology

Lifespan Cancer Institute, Rhode Island Hospital

Brown University Oncology Research Group

Providence, RI

CASE SUMMARY

• An otherwise healthy White woman aged 60 years presented with a nonproductive cough.
• Social history: never smoker
• Physical examination: ECOG performance status, 0; blood pressure, 120/93 mm Hg; heart rate, 75 beats per minute; body mass index, 22; lungs CT angiography bilaterally
• Laboratory values: within normal limits
• Chest x-ray: 5.5-cm right mass in right upper lobe (RUL)
• CT chest/abdomen: lobulated 5.5 × 5.1-cm mass in RUL
• Biopsy of RUL: adenocarcinoma, TTF-1 positive, consistent with non–small cell lung cancer (NSCLC)
• PET imaging: negative for any lymph nodes or distant metastases
• Brain MRI: negative
• Pulmonary function tests: normal
• She underwent mediastinoscopy with negative lymph nodes on frozen section, followed by right upper lobectomy without complications.
• Pathology: 5.5-cm tumor with negative margins; 0 nodes positive for malignancy
• Pathologic stage: confirmed stage IIB (pT3N0M0) lung adenocarcinoma
• Laboratory values after surgery were within normal limits.
• Current ECOG performance status: 1

Targeted Oncology: Should postoperative radiotherapy (PORT) be part of standard treatment for patients with stage IIIA (N2) NSCLC?

AZZOLI: We were surprised by the LUNG ART study [NCT00410683], which was supposed to be the definitive proof that PORT is helpful. Unfortunately, this prospective randomized trial, which even used 3D conformal high-tech PORT, was unable to demonstrate a statistically significant improvement in disease-free survival [DFS].¹ It showed a 3-fold higher toxic death rate in the PORT arm, mostly cardiovascular death. So they were injuring the heart, which potentially led to a decrement in overall survival [OS] without an improvement in DFS. Ever since these data came out 2 years ago, and after the 2022 manuscript, our radiation oncologists have shied away from PORT, except for patients with multistation N2 disease.

There is a very high risk of local regional recurrence. In patients who already received neoadjuvant therapy and still had residual N2, the local regional recurrence is almost guaranteed, and the cancer is chemotherapy refractory. That’s where my radiation oncology team would do radiation.

What are some recommended adjuvant therapy options in NSCLC?

The NCCN [National Comprehensive Cancer Network] guidelines recommend adjuvant treatment for NSCLC.² For stage II disease, it is chemotherapy and atezolizumab [Tecentriq]. Patients with stage IB disease can be given adjuvant chemotherapy. For stage IB or IIA disease, there are other clinical characteristics that might tip the scales toward giving chemotherapy, such as vascular invasion, very high-grade tumors, and visceral pleural involvement. The NCCN guidelines also list wedge resection, but I hate to use drug therapy to compensate for inadequate surgery. I think you might even consider a complete lobectomy as more likely to help someone who had an inadequate surgery. Unknown lymph node status is also inadequate surgery. I have sent patients back to the operating room who had inadequate surgery or nodal staging. The recommended chemotherapy regimens are cisplatin heavy. Carboplatin can be used if the patient is not eligible for cisplatin.

ASCO [American Society of Clinical Oncology] has guidelines for completely resected stage IB to IIIA NSCLC. For stage IB disease, ASCO recommends osimertinib [Tagrisso], but adjuvant cisplatin and atezolizumab is not recommended for routine use in this group. For stage II disease or higher, it is OK to give chemotherapy, osimertinib, and atezolizumab.³ Deciding on the timing and what to give is complex, especially with the FDA approvals that have been rolling in over the [past] 2 years for adjuvant and neoadjuvant therapy.

What data support the addition of nivolumab to neoadjuvant chemotherapy in patients with resectable stage IB to IIIA NSCLC?

The CheckMate 816 study [NCT02998528] was published by Patrick Forde, MBBCh, in the New England Journal of Medicine in May 2022.⁴ This study randomly assigned about 360 patients with operable NSCLC that was at least 4 cm in size. They were randomly assigned to neoadjuvant chemotherapy plus nivolumab [Opdivo] or chemotherapy alone, which has been and remains difficult and unpopular. I think if the patient is with the surgeon and the surgeon can cure you tomorrow, patients like to be cured tomorrow. They don’t like to spend 3 months getting chemotherapy.

After the randomization they followed these patients postoperatively and showed a 37% reduction in the risk of disease recurrence or death with the addition of nivolumab to neoadjuvant chemotherapy. That’s a clinically significant and statistically significant benefit. What caught my eye was the 24% pathologic complete response rate, which I like to show fellows and trainees as an example of how drugs can cure lung cancer. We’re seeing eradication of disease in the preoperative setting, but certainly, you’re only curing 1 in 4 patients with drugs, but you’re curing all of them with surgery because you’re taking out the cancer. Because it was a neoadjuvant study, it attracted high-risk patients, so 60% of the patients on this study had stage IIIA disease.⁴

What do you think of asking patients to wait for molecular testing results to receive these therapies?

Asking a patient to wait for surgery is one thing. Asking a patient to wait for a diagnostic test for chemotherapy candidacy is another thing entirely. But those patients in CheckMate 816 were negative for EGFR and ALK.

What data support adjuvant atezolizumab following resection and chemotherapy in patients with stage II to IIIA disease?

The adjuvant atezolizumab data were from the IMpower010 study [NCT02486718]. Patients were allowed in the study if they had EGFR and ALK mutations. They did a post hoc analysis about how those subgroups did. All patients received adjuvant chemotherapy, 1 to 4 cycles, and then were randomly assigned to 1 year of atezolizumab or best supportive care.⁵

About the same benefit is seen in the stage II to IIIA population who are PD-L1 positive. They had about a 35% reduction in the risk of disease recurrence or death.⁵ So the benefit is similar for adjuvant and neoadjuvant therapy, but certainly they are very different patient experiences in terms of holding up the surgery or getting 1 year of treatment afterward instead of 3 cycles preoperatively, so very different approaches, but similar benefit.

In the update at the 2022 World Conference on Lung Cancer, the PD-L1 positive subgroup benefit held up. The [HR] was refined up to 0.71. They lost a little bit of that risk reduction on longer follow-up. No benefit has been seen in the subsequent subgroups. So PD-L1 positivity and high-risk cancer stage II or greater are needed to see benefit.⁶

CASE UPDATE

Postoperative treatment course:

• The patient has completed 4 cycles of adjuvant chemotherapy with cisplatin plus pemetrexed.
  • ECOG performance status: 1
    
• Molecular testing: EGFR exon 19 deletion

Would you consider an adjuvant EGFR tyrosine kinase inhibitor (TKI) in this patient?

The Chinese trial CTONG 1104 [NCT01405079] looked at adjuvant gefitinib [Iressa] for 2 years and randomized the patients to gefitinib or chemotherapy. So, they were asking the question about whether you need chemotherapy at all in patients with EGFR mutations. Gefitinib was more effective than chemotherapy in keeping the cancer from growing over 2 years, but the curves come back together and then you don’t see an OS benefit in the long run, so you worry that you are leaving survival benefit on the table if you don’t give the chemotherapy. There’s real benefit in preventing the cancer from coming back, but maybe not curing patients. So, I think the standard of care remains that you offer patients chemotherapy and then consider adjuvant TKI after that.⁷

Do you offer the chemotherapy to all patients even if you don’t know whether they have stage IB EGFR-positive disease?

I think it’s important to consider chemotherapy and targeted therapy independently. You ask the chemotherapy question first and you answer yes or no and then you ask the targeted therapy question. Some oncologists would give cisplatin or pemetrexed to a patient with stage IB disease; that’s controversial. But certainly, in stage II or greater you would want to give adjuvant cisplatin. If the patient can’t tolerate cisplatin or is elderly, then you might say no. The next question is TKI. I think that the Chinese study shows that we don’t have the data that say targeted therapy is better than chemotherapy, but chemotherapy does improve OS.

Which trial investigated osimertinib, and what was the efficacy observed?

The ADAURA phase 3 study [NCT02511106] enrolled patients with resected NSCLC stage IB or greater. They could or could not have had adjuvant chemotherapy, but they needed to have EGFR mutations of exon 19 deletion or L858R. They were randomly assigned to 3 years of osimertinib daily therapy, as opposed to 2 years in the prior studies, vs placebo and then they were followed over 3 years for recurrence. The study was well balanced between the 2 arms.⁸

The benefit was enormous, with stage II or greater disease showing an 80% reduction in the risk of recurrence or death. That benefit was also evident in the overall population, which included stage IB disease.⁹

What have updated data of ADAURA shown for this patient population?

The data were updated at ESMO [European Society for Medical Oncology Congress] 2022. The Kaplan-Meier curves held up with longer follow-up, and there was still an 80% reduction in recurrence and death for stage II or greater disease and a similarly excellent [HR] for the overall population.¹⁰

There is greater DFS benefit for higher stages of disease. But still, even the patients with stage IB disease had a 60% reduction in the risk of disease recurrence. As we see with advanced disease, there seemed to be more benefit in patients with exon 19 deletions compared with L858R and about the same benefit whether one got chemotherapy or not. So, the benefit wasn’t dependent on chemotherapy, but additively we think taking chemotherapy has more net benefit.

We still see benefit in stage IB disease. There is the concept of overtreatment because the control arm in the patients with stage IB did well, although still 40% had recurrence. That’s a larger area of patients under the curve of the control arm [whom] you’d be giving 3 years of osimertinib to when they were cured by their surgeon. But based on the updated data at ESMO 2022, these curves stand up to time with real benefit visible in stage IB disease and massive benefit in higher stages.

One of the updates by Masahiro Tsuboi, MD, at ESMO 2022 was that maybe a large part of the benefit of adjuvant osimertinib is protecting the central nervous system [CNS]. The Kaplan-Meier curve of events of CNS progression showed an 80% reduction in these catastrophic events with adjuvant osimertinib. OS trends were favorable, as you would expect.

What are the adverse events (AEs) associated with osimertinib?

For those who have given osimertinib, one AE is rash. Another is diarrhea in a few patients. Most patients can tolerate it. I have seen patients have gastrointestinal AEs that make the drug intolerable, but most [persons] are able to take it continuously and, in fact, only 10% had to discontinue the drug on the study. They did not report any treatment-related deaths.¹⁰

About half the patients had some amount of diarrhea, but mostly low grade. We do see interstitial lung disease from TKIs, so I think for any patient you consent for adjuvant osimertinib, you must warn them about the potential of lung injury. They recorded a 3% rate in the study.

_REFERENCES

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_{2. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 3.2023. Accessed April 18, 2023. https://bit.ly/3KblO83}

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_{7. Zhong WZ, Wang Q, Mao WM, et al. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC: final overall survival analysis of CTONG1104 phase III trial. J Clin Oncol. 2021;39(7):713-722. doi:10.1200/JCO.20.01820}

_{8. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients (pts) with stage IB-IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(suppl 18):LBA5. doi:10.1200/JCO.2020.38.18_suppl.LBA5}

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