Patterns of Failure after PACIFIC: How to Address Disease Recurrence after Chemoradiotherapy and Immunotherapy

The standard of care for patients with unresectable locally advanced non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy followed by consolidative durvalumab, as established in the PACIFIC trial. The addition of durvalumab in this population has produced impressive results, with a 5-year overall survival (OS) of 43% in the durvalumab group compared to 33% in the placebo group.1,2

Unfortunately, most patients experience disease recurrence even with the addition of durvalumab. Understanding the subsequent patterns of treatment failure (POF) is crucial as these data often inform subsequent treatment decisions and can help guide optimal management in this clinically challenging scenario. A post-hoc analysis of the PACIFIC trial was presented in abstract form at the 2019 American Society for Radiation Oncology (ASTRO) meeting and demonstrated that most patients had one to two extrathoracic lesions at time of progression, but did not provide rates of distant and locoregional failures, correlation of disease progression with prior radiation fields, or detailed information on candidacy for further ablative treatments.3

As such, many questions for patients treated with the PACIFIC regimen persist:

• Is chemoradiotherapy providing appropriate local control?
• Are these patients experiencing disease recurrence distantly or locoregionally?
• What is the magnitude and location of disease progression?
• Can recurrence successfully be salvaged with further aggressive therapies?
• Can the known POF be used to identify curative strategies for patients post-PACIFIC?

Our research group recently set out to answer these questions and published our findings in the International Journal of Radiation, Biology, and Physics.4 We analyzed a total of 229 patients with unresectable stage III NSCLC who were treated with definitive chemoradiotherapy and consolidative immunotherapy, of whom 119 (52%) experienced subsequent disease progression.

We identified several important findings. First, chemoradiotherapy provided high rates of locoregional control and low rates of in-field failure within the radiation portal. Second, at the time of disease progression, low-volume relapse (defined as <3 sites of progression) was common and occurred in 54% of patients whose disease progressed. Finally, half of our patients were candidates for further ablative therapies at time of progression.

The most common pattern of progression was isolated distant failure, with a crude rate of 31% (71/229) and 1-year and 2-year cumulative incidence estimates of 32% and 39%, respectively. The crude rate of isolated locoregional failure was 8.7% (20/229) and the rate of synchronous locoregional failure with distant failure was 12.2% (28/229); cumulative incidence estimates of locoregional failure were 13% at 1 year and 19% at 2 years. The rate of in-field failure in relation to the delivered radiation portal was 12.2% (28/229) for all patients evaluated and 23.5% (29/119) for all patients who sustained disease progression.

Of the 119 patients who experienced disease progression, most had disease progression in a single lesion (33%) or in two to three lesions (21%). Overall, 54% of patients were found to have low-volume relapse, of which two groups two could be identified: oligometastatic relapse and isolated, intrathoracic locoregional failure. Most patients (70%) had oligometastatic relapse. On multivariable modeling and immortal-time bias corrected survival analysis, patients with low-volume relapse had significantly better survival compared to high-volume relapse, while oligometastatic relapse had improved survival compared to polymetastatic relapse.

At the time of progression, we assessed if patients would be candidates to receive further ablative therapies, regardless of the actual treatment delivered. We found that of the 119 patients whose disease progressed, 50% were eligible for curative-intent ablative therapy (e.g., stereotactic body radiotherapy, metastasectomy, or interventional radiology-guided ablative techniques) at the time of relapse. Of all ablative candidates, 65% were treated with local therapy alone, without further systemic treatment.

Possible Therapeutic Interventions for Patients with Low-Volume Disease Recurrence

Our data suggest that approximately half of patients who experience disease progression after definitive chemoradiotherapy and immunotherapy have low-volume relapse or oligometastatic relapse and are therefore candidates for further potentially curative therapies. The optimal management of low-volume relapse is complex but is critically important, as ablative therapies have the potential to yield long-term survival in select patients.

The randomized SABR-COMET and Gomez phase II trials as well as recent guidelines from the American Society for Therapeutic Radiology and Oncology (ASTRO)5,6,7 suggest that local therapy may benefit patients with low-volume metastatic disease; however, no such study has been performed specifically in patients with relapse after definitive treatment for locally advanced NSCLC. Phase III trials such as NRG LU-002 (NCT03137771) and SABR-COMET 10 (NCT03721341) continue to accrue and may provide more confirmatory data for the benefit of local therapy in these patients.

Importantly, the management of isolated locoregional recurrence significantly varies from oligometastatic relapse. In oligometastatic relapse, clinicians are likely to feel more comfortable delivering curative-intent ablative treatment, as the prescription of such local therapies are part of routine practice. For isolated locoregional recurrence, our institution prefers proton beam reirradiation with concurrent chemotherapy with or without consolidative pembrolizumab,8 a manner in which many of the patients in this series were treated.

As clinicians, we are often eager to suggest further ablative treatment in patients with low-volume relapse, but we must consider that in patients with relapsed disease, the standard of care remains systemic therapy alone. While our data demonstrate that low-volume relapse is a strong prognostic marker of long-term survival, they do not suggest the optimal treatment strategy for this population. Multidisciplinary discussion is crucial for these patients and treatment strategies need to be individualized, often requiring the use of local therapies alone or in combination with systemic treatments.

Guiding Future Therapies with Known Patterns of Failure

These results also demonstrate the need to further optimize the treatment paradigm for unresectable NSCLC where distant failure has been the most common pattern of progression. Recently, the randomized phase II COAST trial demonstrated improved progression-free survival with the addition of an anti-CD73 monoclonal antibody oleclumab or anti-NKG2A monoclonal antibody monalizumab to durvalumab, compared to durvalumab alone.9 Future phase III studies such as PACIFIC-8, PACIFIC-9, and SKYSCRAPER-03 aim to improve survival and the cure rate for patients with unresectable disease by reducing the number of distant failures.

As distant disease control improves, strategies to enhance locoregional control continue to rise in importance. Clearly, chemoradiotherapy can provide cure in select patients, as evidenced by a low locoregional failure and in-field failure rate, as well as multiple long-term survivors in the cohort. However, for those with local failure, how can outcomes be improved?

Our study reported a locoregional failure rate at 2 years of 19%, which is considerably lower than historical rates (2-year locoregional failure rate of 31% on RTOG 0617).10 It remains unknown if the addition of durvalumab during chemoradiotherapy improves locoregional control compared to chemoradiotherapy alone. This may be answered by the upcoming EA5181 (NCT04092283) randomized phase III trial. Regarding radiotherapy techniques, the NRG LU-008 (NCT05624996) phase III trial is investigating if upfront SBRT to the primary tumor followed by chemoradiotherapy to mediastinal nodes can improve tumor control and survival compared to conventional chemoradiotherapy.

Finally, it is feasible to consider a clinical trial in which patients who were initially technically unresectable because of bulky disease are treated with a “neoadjuvant PACIFIC approach” (i.e., chemoradiotherapy followed by short course immunotherapy) followed by surgical resection after disease response. The INCREASE study reported at the 2023 World Conference on Lung Cancer showed that neoadjuvant nivolumab-ipilimumab in addition to chemoradiotherapy for borderline resectable tumors produced a pathologic complete response in 63% of patients without an increase in surgical morbidity.11

Although previous trials have not demonstrated the superiority of trimodality intervention for survival, surgical resection has been shown to increase local control,12 and surgical intervention after full dose chemoradiotherapy can be administered safely.13 The window for intensifying local therapies may be ripe in the future with improved systemic control.

Conclusion

While much of the contemporary excitement in locally advanced NSCLC surrounds the use of neoadjuvant therapies and the continued refinement of consolidative immunotherapy, many patients will still experience disease relapse. Even when PACIFIC fails, this pattern of failure analysis demonstrates that many patients have low-volume relapses and a favorable prognosis, allowing for further ablative treatments. This promising treatment approach may benefit patients with relapsed disease. Ideally, these patients should be discussed in a multidisciplinary fashion to optimize their treatment recommendations.

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