Multifaceted Approach Remains a Linchpin for Stage IIIB NSCLC Therapy

Heather A. Wakelee, MD

Although emerging strategies are expanding options for treating patients with early-stage non–small cell lung cancer (NSCLC), stage IIIB disease continues to pose challenges. A multimodality approach may help overcome current barriers to care.

The paradigm for treating patients with stage IIIB disease was among the topics discussed by a panel of experts participating in a recent OncLive Peer Exchange® program. The discussion spanned the spectrum of care for patients with stages I to III NSCLC. “There are so many different trials coming forward, I’m really excited about where we are in the management of NSCLC,” moderator Heather A. Wakelee, MD, said.

In general, staging patients with NSCLC is clinically challenging. Although the sensitivity and specificity of individual diagnostic modalities are high, the accuracy of comparing the clinical stage and pathological stage is typically low, ranging from 50% to 60%. Nevertheless, correct clinical staging is crucial because it affects initial therapy options and, potentially, treatment outcomes. A multidisciplinary team should classify patients into 1 of 3 categories before beginning any treatment: potentially resectable, potentially resectable with a higher risk of incomplete resection, or definitely unresectable.¹

Stage III NSCLC is defined as a locally advanced lung cancer within the primary tumor (T) based on size and location and/or metastatic disease present only in regional lymph nodes (N), and no distant metastasis (M), according to the American Joint Committee on Cancer TNM staging system, which was updated in 2017.²

The stage III classification encompasses a heterogenous group of tumors characterized as stage IIIA, IIIB, and IIIC.³ Whereas surgery with neoadjuvant and/or adjuvant therapy is frequently an option for patients with stage IIIA disease, most patients with stage IIIB or stage IIIC NSCLC are not candidates for surgery.⁴

An estimated 17.6% of patients have received diagnoses of stage IIIB NSCLC. The estimate 5-year survival rate ranges from 3% to 7% for most patients, although it has reached 20% for selected patients with T4, N0-1 disease (Figure).⁴

Figure. Illustration of Lung Cancer at Stage IIIB⁴

Within stage IIIB, there are 2 unresectable subgroups: T1 to T2, N3 tumors; and T3 to T4, N2 tumors. For patients with confirmed N3-positive disease, the standard of care is definitive concurrent chemoradiation (cCRT) followed by durvalumab (Imfinzi), a PD-L1 inhibitor, according to National Comprehensive Cancer Network guidelines. The immunotherapy agent also is recommended as consolidation therapy for eligible patients with unresectable stage III NSCLC whose disease has not progressed after definitive cCRT.²

Although surgery is not advised for patients with T4, N2 to N3 disease (stages IIIB and IIIC), the N3 and N2 nodes are biopsied during the initial work-up. The same treatment options as for stage IIIA (T4, N0-1) disease may be considered if these biopsies are negative. Durvalumab is recommended for patients with unresectable tumors who have received definitive cCRT if either the contralateral or ipsilateral mediastinal node is positive.²

Recommending Surgery

During the Peer Exchange program, panelists discussed which patients with early-stage NSCLC should be considered for neoadjuvant chemoimmunotherapy, including some patients whose tumors might be downstaged for subsequent surgery with earlier intervention.

“For stage III disease, it’s clear—nodal disease, that patient who is at high risk of occurrence, over 50% to 70%, depending on which literature you read, in 5 years,” Joshua K. Sabari, MD, said. “So that’s the patient population, and there’s no argument in our tumor boards. I would even argue the stage II patients should get neoadjuvant therapy. It’s the IB/IIAs that become controversial in tumor board. I think that’s going to be an ongoing discussion until we see real survival benefit that’s long term.

“Patients with stage IIIA NSCLC are the ones to be resected,” Sabari added. “With stage IIIB NSCLC patients, I’m on the fence.”

Billy W. Loo Jr, MD, PhD, FASTRO, FACR, sounded a note of caution about embracing neoadjuvant approaches too quickly. In answer to a question about patients with stage IIIB NSCLC, he said he was concerned about “trying to expand the indications [to] patients who really would not have been considered resectable up front, and the idea is that now we’re going to try and make them resectable with induction therapy. That’s a risky extrapolation.”

Wakelee agreed that the prospect of surgery for these patients could be problematic. “That’s what we always say—the tumor never really shrinks away from the mediastinum; it always shrinks into it.”

Spicer noted promising findings for patients who participated in the INCREASE trial (NL8435), a small study conducted in the Netherlands, with results reported at the European Society for Medical Oncology Congress 2022 in September 2022. Patients with T3 to T4, N0 to 2, M0 NSCLC were treated with combination immunotherapy with ipilimumab (Yervoy), a CTLA-4 inhibitor, plus nivolumab (Opdivo), a PD-1 inhibitor, along with platinum-doublet chemotherapy and radiotherapy, followed by surgical resection.⁵

Among 24 participants who received induction therapy and subsequent surgery, 15 patients (63%) had a pathological complete response and 19 (79%) had a major pathological response, defined as residual viable tumor cells of 10% or less. The pathological complete response compared favorably (P < .001) with a historical reference point of 30%, investigators said.⁵

Wakelee noted that most INCREASE participants had Pancoast tumors, defined as tumors of the superior sulcus that occur infrequently but are sometimes tackled with curative therapy.⁴ She also pointed out that patients received chemoradiation plus immunotherapy.

“They were mostly Pancoast [tumors], but there was some invasion of the mediastinum,” Sabari agreed. “It’s a controversial study, don’t get me wrong, but [there was] 100% resection in that sampling. So, again, we need prospective trials to drive this.”

New Data on Immunotherapy

During 2022, new data were reported for durvalumab therapy in patients with unresectable stage III NSCLC that solidify its place in the treatment paradigm and suggest a broader role in this population.

PACIFIC Study: Durvalumab Following cCRT

In February 2018, the FDA approved durvalumab for patients with unresectable stage III NSCLC whose disease had not progressed following concurrent platinum-based chemotherapy and radiation therapy.⁶

The agency based its decision on an interim analysis of data from the phase 3 PACIFIC trial (NCT02125461), in which 713 patients who had completed at least 2 cycles of cCRT were randomly assigned 2:1 to receive durvalumab at 10 mg/kg or placebo intravenously every 2 weeks for up to 12 months. In all, 476 patients were treated with durvalumab and 237 were given placebo; 53% of the participants had stage IIIA disease and 45% had stage IIIB.⁷

After a prespecified number of events, the findings showed that median overall survival (OS) was not reached (NR) for patients who received durvalumab (95% CI, 34.7 months-NR) compared with 28.7 months (95% CI, 22.9-NR) for participants treated with placebo (HR, 0.68; 95% CI, 0.53-0.87; P = .0025). Median progression-free survival (PFS) also was longer with durvalumab at 16.8 months (95% CI, 13.0-18.1) vs 5.6 months (95% CI, 4.6-7.8) with placebo (HR, 0.52, 95% CI, 0.42-0.65).⁷

Five-year data from PACIFIC show “robust and sustained OS and durable PFS benefit” with durvalumab therapy, investigators reported in the Journal of Clinical Oncology in February 2022. The median OS was 47.5 months (95% CI, 38.1-52.9) for patients who received durvalumab compared with 29.1 months (95% CI, 22.1-35.1) for those on placebo (HR, 0.72; 95% CI, 0.59-0.89). The median PFS was 16.9 months (95% CI, 13.0-23.9) with durvalumab vs 5.6 months (95% CI, 4.8-7.7) with placebo (HR, 0.55; 95% CI, 0.45-0.68).⁸

In a subgroup analysis, the benefit with durvalumab therapy was greater for patients with stage IIIA disease (HR, 0.61; 95% CI, 0.470.80) than for participants with stage IIIB (HR, 0.86; 95% CI, 0,63-1.17).⁸

Overall, the estimated 5-year OS rate was 42.9% (95% CI, 38.2%-47.4%) with durvalumab and 33.4% (95% CI, 27.3%-39.6%) with placebo. The corresponding PFS rates were 33.1% (95% CI, 28.0%-38.2%) and 19.0% (95% CI, 13.6%-25.2%), respectively.⁸

The objective response rate also was higher with durvalumab therapy compared with placebo (29.8% vs 18.3%, respectively), and approximately half of the durvalumab respondents had continuing responses at 5 years.⁸

In terms of adverse events (AEs), safety data from PACIFIC were not updated beyond the March 2018 data cutoff because no patients were treated as per trial protocols beyond the 12-month study period. At the time of the primary analysis, the incidence of AEs of grade 3/4 severity was 30.5% among patients who received durvalumab and 26.1% for participants in the placebo group, with fatal events of 4.4% and 6.4%, respectively. AEs that most frequently led to discontinuation of therapy included pneumonitis, radiation pneumonitis, and pneumonia.⁸

DOLPHIN Study: Durvalumab Plus Concurrent Radiation Therapy

Although PACIFIC marks a milestone in the use of immunotherapy with curative intent in NSCLC,⁸ approximately 30% of patients with stage III unresectable disease would not be eligible to receive durvalumab consolidation therapy following definitive chemoradiotherapy because of pneumonitis or disease progression.⁹

Investigators in Japan sought to determine whether introducing durvalumab earlier in the treatment algorithm would be beneficial. The DOLPHIN study (JapicCTI-194840) was the first phase 2 trial to assess the efficacy of immunotherapy plus concurrent curative radiation therapy in patients with PD-L1–positive unresectable locally advanced NSCLC (stage III or postoperative recurrent) without chemotherapy.¹⁰

The study enrolled 35 patients with a median age of 72 years; 54.3% had an ECOG performance score of 0 and 25.7% had postoperative progression, investigators reported at the IASLC World Conference on Lung Cancer in August 2022. Participants were required to have a PD-L1 expression level of 1% or greater. The treatment involved concurrent curative radiation therapy (60 Gy) plus durvalumab (10 mg/kg every 2 weeks), followed by maintenance durvalumab for up to 12 months until disease progression or intolerable toxicity.¹⁰

After a median follow-up of 18.7 months, the 12-month PFS rate, the primary end point, was 72.1% (90% CI, 59.1%-85.1%) in 33 evaluable patients. That result exceeded the prespecified threshold for the study of 28%.¹⁰

The confirmed overall response rate was 90.9% (95% CI, 75.5%-98.1%), including complete and partial response rates of 36.4% and 54.5%, respectively. The median PFS was NR by independent central review and 24.1 months (95% CI, 16.0-NR) by investigator assessment.¹⁰

In terms of toxicities, 47.1% of 34 safety-evaluable patients experienced grade 3 or grade 4 AEs, most frequently lung infection and pneumonitis (11.8% each). Two patients (5.9%) experienced grade 5 AEs from any cause; 1 patient had lung infection and 1 had a broncho-esophageal fistula because of tumor progression. Thirteen patients (39.4%) discontinued durvalumab; 6 because of disease progression and 7 because of AEs.¹⁰

The therapeutic approach is a “promising” strategy for patients with unresectable locally advanced NSCLC suitable for exploration in phase 3 studies, investigators concluded.¹⁰

More Molecular Testing on Horizon

Moving forward, treatment considerations for patients with stage IIIB NSCLC likely will go beyond the current TNM staging system, Peer Exchange panelists noted. Ignacio I. Wistuba, MD, anticipates that “pro-molecular targets” will factor into decision-making. “That’s going to be not just staging but more molecular testing,” he said.

In general, panel members said, the introduction of immunotherapy and targeted therapies into the treatment paradigm in several earlier stages of NSCLC is creating a need for biomarker testing beyond the advanced and metastatic settings currently recommended in National Comprehensive Cancer Network guidelines.²

“I think as much information as possible is useful even for stage I [disease],” Jonathan Spicer, MD, PhD, BSc (Hon), FRCS, said. “The landscape is changing enormously fast, and more and more targets are coming into play even for those very early-stage patients. It's helpful for clinical trial enrollment, but in standard practice, I’d say the bare minimum [for testing] is EGFR, ALK, and PD-L1 [tumor proportion score] to get moving, particularly for any tumor that’s over 4 cm or if you have positive lymph nodes.”

Spicer, a surgeon, said he likes to have cases involving any locally advanced NSCLC, which he defines as stages IB to III disease, discussed at tumor board. “It’s a much more fruitful discussion if we have as much molecular data as possible,” he said.

References

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10. Tachihara M, Tsujino K, Shimokawa M, et al. MA06.04 Phase II study of durvalumab plus concurrent radiotherapy in unresectable locally advanced NSCLC: DOLPHIN study (WJOG11619L). J Thorac Oncol. 2022;17(suppl 9):S64. doi:10.1016/j.jtho.2022.07.107