Summary:
Durvalumab after concurrent chemoradiation has significantly improved survival in stage III non-small cell lung cancer (NSCLC). However, there is limited data evaluating the utilization and challenges to deliver durvalumab consolidation in the real world. We assessed the use of consolidative durvalumab at a large academic center to examine clinical limitations to delivery of this practice-changing regimen. We found that despite incorporating consolidative durvalumab into standard practice for stage III unresectable NSCLC, 27% patients did not initiate this treatment, largely due to disease progression or toxicity from chemoradiation.
Keywords: Non-Small Cell Lung Cancer, Consolidative Durvalumab, Chemoradiation
Introduction:
Prior to the publication of the PACIFIC trial, the efficacy of standard chemoradiation in unresectable stage III NSCLC had reached a plateau, with studies evaluating radiation dose-escalation and consolidative chemotherapy strategies failing to improve outcomes1–3. Presented initially in 2017, the PACIFIC trial found consolidative durvalumab after chemoradiation to significantly improve progression-free and overall survival, and now represents a current standard of care for the treatment of unresectable stage III non-small cell lung cancers (NSCLC)4,5. However, given that the design of this trial allowed for enrollment only after the completion of chemoradiation, the proportion of patients unable to receive durvalumab, and the reasons precluding its utilization remain mostly unknown. To inform the needs of future treatment strategies, we assessed the utilization of consolidative durvalumab and identified reasons precluding its delivery at a high-volume tertiary cancer center.
Methods:
Patients and Treatment:
Eligible patients had AJCC 8th edition stage III non-small-cell lung cancer (NSCLC) at the time of treatment initiation. Patients underwent pre-treatment staging with magnetic resonance brain imaging and whole-body positron emission tomography-computed tomography. PD-L1 immunohistochemistry was routinely evaluated using the E1L3N antibody (Cell Signaling Technology, Danvers, MA). Patients were planned to receive curative intent concurrent chemoradiation therapy with radiation prescription doses ranging from 54Gy – 66Gy in 2 Gy fractions using intensity modulated radiation planning, and at least two cycles of platinum-based chemotherapy. Patients were evaluated post-chemoradiation with follow-up visits along with computed tomography (CT) imaging of the chest, abdomen and pelvis to determine disease status and to assess appropriateness for consolidative durvalumab.
Analysis:
The first patient to receive consolidative durvalumab was identified, and all consecutive patients treated thereafter were retrospectively assessed to determine the frequency of initiation of durvalumab and factors precluding its use. The potential plan for consolidative durvalumab was noted in the medical record of all patients in this analysis. Toxicity grading was based off common terminology criteria for adverse events (CTCAE) v. 5.0. This retrospective study was completed under an institutional review board approved protocol.
Baseline patient characteristics including sex, age, Eastern Cooperative Oncology Group (ECOG) performance status, smoking history, history of diabetes, PD-L1 expression level, albumin level (g/dl), hemoglobin level (g/dl), overall AJCC 8th edition stage, and stage per AJCC 8th edition were compared between patients who did and did not initiate durvalumab. Treatment characteristics including the chemotherapy regimen, radiation planning volume (cc), percent of lung volume receiving at least 20 Gy, and mean lung and heart dose (Gy) were also evaluated. The Mann-Whitney and T-test were used for comparisons. A p-value < 0.05 was considered significant.
Results:
Patient Characteristics and Durvalumab Utilization
Ninety-seven patients with stage III NSCLC treated with definitive-intent chemoradiation therapy between August of 2017 and April of 2019 were identified. The median patient age was 66 years, 53% (n=51) were male, 72% (n=70) had stage IIIB or IIIC disease, 95% (n=92) were ever smokers, and 53% (n=51) had an ECOG 0 performance status. PD-L1 expression testing was available for 77% (n=75) of patients of which 61% (n=46) had PD-L1 expression of ≥1%. Most patients (93%, n=90) underwent CT imaging a median of 6.1 weeks (interquartile range: 3.9 – 7.5 weeks) after the end of radiation therapy to assess disease response and appropriateness for consolidative durvalumab. In total, 73% (n=71) of patients started consolidative durvalumab treatment while 28% (n=23) did not. The first cycle of durvalumab was administered a median of 6.7 weeks after the end of radiation therapy (interquartile range: 4.4 – 9.4 weeks). There was no statistical difference in gender, age, baseline albumin, hemoglobin, PD-L1 expression, ECOG performance status, smoking history, history of diabetes mellitus II, stage distribution, nodal stage distribution, tumor stage distribution, between patients that started and did not start consolidative durvalumab. Additionally, no statistical difference was found in chemotherapy regimens and the evaluated radiation therapy planning parameters (Table 1).
Table 1:
Patient and Treatment Characteristics
| Durvalumab (n=71) |
No Durvalumab (n=26) | p-value | |
|---|---|---|---|
| Sex | 0.44 | ||
| Female | 45% (n=32) | 54% (n=14) | |
| Male | 55% (n=39) | 46% (n=12) | |
| Age (years) | 0.96 | ||
| Range | 49 – 86 | 28 – 84 | |
| Median | 66 | 68 | |
| Performance Status | 0.76 | ||
| ECOG 0 | 54% (n=38) | 50% (n=13) | |
| ECOG 1 | 46% (n=33) | 50% (n=13) | |
| Smoking History | 0.10 | ||
| Yes | 97% (n=69) | 88% (n=23) | |
| Diabetes Mellitus II | 0.53 | ||
| Yes | 25% (n=18) | 19% (n=5) | |
| Stage | 0.57 | ||
| IIIA | 29% (n=21) | 23% (n=6) | |
| IIIB | 54% (n=38) | 65% (n=17) | |
| IIIC | 17% (n=12) | 12% (n=3) | |
| Nodal Stage | 0.71 | ||
| N0/N1 | 7% (n=5) | 12% (n=3) | |
| N2 | 49% (n=35) | 42% (n=11) | |
| N3 | 44% (n=31) | 46% (n=12) | |
| Tumor Stage | 0.46 | ||
| T0/T1 | 24% (n=17) | 38% (n=10) | |
| T2 | 25% (n=18) | 20% (n=5) | |
| T3 | 25% (n=18) | 14% (n=4) | |
| T4 | 25% (n=18) | 27%(n=7) | |
| PD-L1 Expression | 0.93 | ||
| Unavailable | 23% (n=16) | 23% (n=6) | |
| ≥ 1% | 50% (n=35) | 42% (n=11) | |
| ≥ 50% | 27% (n=19) | 27% (n=7) | |
| Albumin (g/dl) | 0.23 | ||
| Range | 2.9 – 5.2 | 3 – 4.6 | |
| Median | 4.0 | 4.3 | |
| Hemoglobin (g/dl) | 0.56 | ||
| Range | 8.5 – 16.8 | 9.7 – 16 | |
| Median | 13.2 | 12.7 | |
| Chemotherapy | 0.45 | ||
| Carboplatin/Paclitaxel | 38% (n=27) | 31% (n=8) | |
| Cisplatin/Pemetrexed | 22% (n=16) | 31% (n=8) | |
| Carboplatin/Pemetrexed | 30% (n=21) | 24% (n=6) | |
| Cisplatin/Etoposide | 10% (n=7) | 7% (n=2) | |
| Carboplatin/Etoposide | (n=0) | 7% (n=2) | |
| Radiation Planning Target Volume (cc) | 0.55 | ||
| Range | 90.1 – 1234.4 | 122.4 – 1904.8 | |
| Median | 562.8 | 494.5 | |
| Lung Volume Receiving ≥ 20Gy | 0.23 | ||
| Range | 6.4 – 38.5 % | 9.2 – 39.8 % | |
| Median | 30.1 % | 31.3 % | |
| Mean Lung Dose (Gy) | 0.28 | ||
| Range | 5.8 – 21.4 | 6.9 – 21 | |
| Median | 17.1 | 18.9 | |
| Mean Heart Dose (Gy) | 0.19 | ||
| Range | 0.4 – 38.2 | 1 – 31.1 | |
| Median | 10.8 | 15.84 |
Patient characteristics are from time of initiation of radiation therapy
Factors Impacting Receipt of Durvalumab Consolidation
Among the 26 patients in whom durvalumab consolidation was forgone, 27% (n=7) had persistent ≥ grade 2 chemoradiation toxicity, and 19% (n=5) did not receive treatment due to concerns regarding durvalumab tolerability given baseline toxicities and recovery after chemoradiation. Additionally, 42% (n=11) had new metastatic disease progression outside the radiation field on post-chemoradiation restaging. Other factors identified included preexisting autoimmune disease (n=1) and treatment with investigational therapies (n=2). (Figure 1). Radiation pneumonitis (n=5) accounted for the majority of chemoradiation toxicities precluding the use of consolidative durvalumab of which four cases were grade 2 and one case was grade 3. Other precluding chemoradiation toxicities included grade 3 radiation esophagitis (n=1) and grade 3 febrile neutropenia (n=1).
Figure 1:
Factors precluding the initiation of durvalumab after chemoradiation in stage III NSCLC were identified among the 26 patients (27%) in whom durvalumab consolidation was forgone.
Discussion:
The addition of durvalumab to the treatment paradigm of stage III NSCLC patients after chemoradiation has produced the largest improvement in disease-control and survival since the recognition of the advantage of concurrent chemoradiation over sequential treatment6. In this study we found that these data have, as expected, have changed our practice to incorporate consolidative durvalumab after chemoradiation in most patients. Still, 27% of patients did not initiate durvalumab consolidation, primarily due to rapid disease progression or chemoradiation toxicity. These data demonstrate that a substantial percentage of patients will have outcomes after chemoradiation that preclude the delivery of durvalumab. Notably, these results occur in the setting of a tertiary cancer center with highly specialized care and substantial supportive resources for patients.
In total, the combination of chemoradiation toxicities and concerns regarding the tolerability of additional toxicities accounted for most patients not initiating durvalumab consolidation. These data highlight the delicate balance in maintaining a positive therapeutic ratio in the management of stage III unresectable disease. Furthermore, it was found in the PACIFIC trial that grade 3 or 4 events occurred in 30.5% of the patients randomized to consolidative durvalumab, and that durvalumab treatment was discontinued in 15.4% of patients due to adverse events5. This suggests that upwards of a third of patients may not initiate or will discontinue durvalumab treatment due to toxicities of chemoradiation alone or in combination with durvalumab.
There remains a need for treatment intensification as the two-year progression-free survival in patients randomized to consolidative durvalumab in the PACIFIC trial was still estimated to be less than 50%4. We additionally found metastatic disease progression during chemoradiation to account for many patients that did not initiate durvalumab. This finding of early-disease progression is consistent with the 3-month progression rate found in standard chemoradiation patients treated on cooperative group trials and supports the need for earlier treatment intensification before the adjuvant setting2,7. However, our data also suggests that intensification strategies that add additional toxicities may imbalance the therapeutic ratio. We found pneumonitis to be the most frequent adverse event precluding the initiation of durvalumab. Similarly, pneumonitis was the most frequent adverse event leading to the discontinuation of durvalumab treatment in the PACIFIC trial5. Therefore, future intensification strategies should reevaluate the chemoradiation backbone, as chemotherapy agents and radiation volume design can impact the incidence of pneumonitis8,9.
The interpretation of the study is constrained by its retrospective nature and its inclusion of a single high-volume tertiary cancer center with institutional standards for the management of NSCLC. The timing of durvalumab consolidation was not consistently within 42 days, which may have impacted durvalumab initiation by allowing for greater recovery from chemoRT or conversely for more time to develop radiation pneumonitis. Additionally, over 70% of patients in this study were stage IIIB or IIIC, suggesting a higher risk population than in the PACIFIC trial, in-line with being a tertiary referral center and our institutional standard for surgery for low-volume N2 disease. However, our findings are supported by a recent retrospective evaluation of patients treated prior to the approval of durvalumab that similarly estimated 30% of patients to be ineligible for durvalumab10. Overall, this data provides a necessary assessment to guide the development of future treatment strategies and supports the need for earlier treatment intensification and to investigate novel approaches with the potential to decouple toxicity and efficacy in stage III unresectable NSCLC11.
Acknowledgments
This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748
Footnotes
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