Oligoprogression in Non-Small Cell Lung Cancer

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1		Daijiro Harada	+ 1704 word(s)	1704	2021-11-22 08:55:09	\|
2	The format is correct	Lindsay Dong	+ 411 word(s)	2115	2021-12-22 07:54:19	\|

This entry is adapted from the peer-reviewed paper 10.3390/cancers13225823

Oligometastatic disease (OMD) is cancer in an intermediate state between the localized early stage and the advanced metastatic stage.

non-small cell lung cancer oligometastatic disease oligoprogressive disease

1. OPD in NSCLC with Driver Mutations

The progression pattern can be classified into three categories: (1) progression of CNS metastasis alone; (2) systemic progression with or without CNS; and (3) OPD ^[1]. The frequency of OPD varies depending on its definition and is estimated to be between 15–47% ^[1]^[2]^[3].

For the treatment of OPD in patients with NSCLC with driver mutation, the addition of LAT, such as stereotactic body radiotherapy (SBRT), while continuing the previous tyrosine kinase inhibitor (TKI) may be adopted. This is because SBRT is preferred over conventional radiotherapy (RT) or invasive surgical treatment as it requires less time for interruption of TKI. As for other LATs, surgery is an important treatment modality for resection of primary and metastatic lesions in OMD, and retrospective studies have revealed beneficial results of LATs in patients with OPD ^[4]. However, surgical invasion and acute complications may increase the risk of prolonged resumption time for subsequent TKI therapy beyond PD. A retrospective analysis reported that radiofrequency ablation (RFA) was applied to lung lesions in 2 of 46 OPD cases ^[5]. Furthermore, a retrospective analysis of cryotherapy for OPD showed survival benefits ^[6]. However, RFA and cryotherapy tend to have high incidences of complications, such as hemoptysis and pneumothorax/pleural effusion requiring drainage ^[7]^[8]. Thus, to standardize surgery, RFA and cryotherapy as LAT for OPD, issues such as the relatively high possibility of prolonging resumption time of subsequent therapy beyond PD and the bias in treatment outcomes among different physicians and facilities need to be considered and resolved ^[9].

In retrospective analysis, the addition of LAT to OPD, mainly during treatment with molecularly targeted agents, is expected to improve local control, suppress secondary metastasis, and prolong progression-free survival (PFS) and overall survival (OS) (Table 1) ^[10]^[2]^[5]^[11]^[12]^[13]^[14]^[15]^[16]^[17]^[18]. The median PFS in patients with NSCLC with driver mutation treated with LAT is generally expected to be 6 months or more, and there are reports of significantly longer overall survival than in patients who are not eligible for LAT.

Table 1. Outcomes of local ablative therapy for oligoprogressive disease.

Authors	Driver Mutation	Design	n	Induction Tx	Intervention	Mainte. Tx	mPFS1 (m)	TTP from Intervention (m)	Duration of Treatment (m)	MST (m)	MST from Intervention (m)	Comment	Ref
Gan et al.	ALK fusion+	retro	14	crizo	local ablative Tx (RT or OP)	crizotinib	14	5.5	28	NA	NA		^[16]
Gan et al.	ALK fusion+	retro	13	crizo	not eligible for LAT		7.2	NA	NA	NA	NA		^[16]
Yu et al.	EGFR m+	retro	18	gef or erlo	local ablative Tx (RT or OP)	gefitinib or erlotinib	19	10.0	NA	NA	41.0	TTF from intervention: 22 m	^[10]
Weickhardt et al.	ALK fusion+ (n = 38) EGFR m+ (n = 27)	retro	ALK rearrange (n = 15) EGFR m+ (n = 10)	crizo erlo	local Tx (RT or OP)	crizotinib erlotinib	9.0 12.0	6.2	NA	NA	NA		^[2]
Weickhardt et al.	ALK fusion+ (n = 38) EGFR m+ (n = 27)	retro	26	crizo or erlo	Pts without LAT		12.8	NA	NA	NA	NA		^[2]
Qiu et al.	EGFR m+	retro	46	EGFR-TKI	local ablative Tx (RT or RFA)	EGFR-TKI	NA	7.0	NA	35.0	13.0		^[5]
Chan et al.	EGFR m+	retro	25	EGFR-TKI	local ablative Tx (RT)	same TKI	NA	7 *¹	NA	NA	28.2 *²	¹: p = 0.0017. ²: HR:0.4 4[95%CI:0.21–0.92], p = 0.030	^[11]
Chan et al.	EGFR m+	retro	25 (matched cohort)	EGFR-TKI	chemotherapy		NA	4.1	NA	NA	14.7	¹: p = 0.0017. ²: HR:0.4 4[95%CI:0.21–0.92], p = 0.030	^[11]
Rossi et al.	EGFR m+	retro	30	EGFR-TKI	local ablative Tx (RT)	same TKI	13.8	6.7 *³	NA	37.3 *⁴	NA	³: HR: 0.54 [95%CI:0.24–1.18], p = 0.06. ⁴: p < 0.0001. *⁵: p = 0.0015	^[12]
			13		same TKI		12.3	3.1		20.1
			88		2nd line treatment or BSC		8.9	NA		15.1
	EGFR m+ without intrinsic resistance to EGFR-TKI	retro	29	EGFR-TKI	local ablative Tx (RT)	same TKI	NA			37.3 *⁵	NA
			12		same TKI			NA	NA	20.1
			64		2nd line treatment or BSC					21.9
Santarpia et al.	EGFR m+	retro	36	EGFR-TKI	high-dose radiation therapy	EGFR-TKI	12.5	6.3		38.7			^[13]
Schmid et al.	EGFR T790M+	retro	13	osim	local ablative Tx (RT or OP)	osimertinib	NA	6.7	19.6	28.0	NR *⁶	*⁶: p = 0.2	^[18]
Schmid et al.	EGFR T790M+	retro	13	osim	osimertinib		NA	6.7	19.6	28.0	20.2	*⁶: p = 0.2	^[18]
Weiss et al.	EGFR m+ at least 6 m without PD	P2	25	erlo	SRT	erlotinib	NA	6.0	NA	NA	29.0		^[14]
Xu et al.	EGFR m+	retro	206	EGFR-TKI	local ablative Tx (RT or OP)	EGFR-TKI	10.7		18.3	37.4			^[15]
Friedes et al.	NSCLC	retro	253	chemo or TKI	definitive RT	same systemic Tx	NA	7.9	NA	NA	NA	TTF from intervention was 8.8 months.	^[17]
Kagawa et al.	NSCLC	retro	10	ICI	local ablative Tx (RT or OP)	ICI beyond PD (n = 6)	10.4	NA	NA	NA	NR *⁷	*⁷: p = 0.456	^[19]
Kagawa et al.	NSCLC	retro	28	ICI	no local therapy		NA	NA	NA	NA	NR	*⁷: p = 0.456	^[19]

BSC: best supportive care; chemo: chemotherapy; CNS: central nervous system; crizo: crizotinib; erlo: erlotinib; gef: gefitinib; ICI: immune checkpoint inhibitor; NA: not available; NR: not reached; NSCLC: non-small cell lung cancer; m+: mutation; m: month; mainte.: maintenance; MST: median survival time; OP: operation; osim: osimertinib; P2: phase II study; PD: progression disease; retro: retrospective study; RT: radiation therapy; TKI: tyrosine kinase inhibitor; TTF: time to treatment failure; TTP; time to progression; Tx: treatment; WT: wild type. The * superscript numbers indicate the test of comparison of each outcome in the corresponding clinical trials.

Although most retrospective studies suggested that a strategy of controlling TKI-resistant OPD by aggressive LAT is clinically beneficial, the following theoretical basis can be considered. LAT will aid in the prevention or treatment of symptoms and complications caused by growing tumors in the near future, may prevent secondary dissemination of TKI-resistant clones, and may allow the continuation of current TKI maintenance therapy ^[20]. For example, SBRT to asymptomatic brain metastasis in OPD may delay cranial symptoms and allow continuation of TKI therapy until systemic metastases, resulting in a survival benefit.

Based on the retrospective studies mentioned above, the U.S. National Comprehensive Cancer Network guidelines currently recommend a strategy of employing LAT for OPD ^[21]. A prospective study in this regard is also underway, and the results will clarify the evidence in the future ^[14]. HALT (NCT03256981) is a multicenter phase II/III study of 110 patients with advanced NSCLC with driver mutations who developed OPD after induction of TKI therapy ^[13]. The study design was to randomize patients to receive SBRT with continued TKI therapy or standard chemotherapy for up to three extracranial sites of OPD and to compare PFS as the primary endpoint.

2. OPD in NSCLC without Driver Mutations

There are few reports on the efficacy of continuing treatment beyond the PD after the addition of LAT for OPD in NSCLC without driver mutations. The ongoing STOP-NSCLC (NCT02756793) is a randomized, multicenter, phase II trial with a primary endpoint of PFS in patients with OPD (up to three lesions in a single organ, including the brain, for a total of up to five lesions) in NSCLC without driver mutations, comparing SBRT for OPD and continuation of current systemic therapy versus standard chemotherapy ^[22].

NCT03808662 is an open-label, randomized phase II study in patients with triple-negative breast cancer and stage IV NSCLC without EGFR/ALK mutation. The primary endpoint was the PFS, and the secondary endpoint was the OS. Characteristically, this trial is open to patients with medical conditions that preclude participation in other systemic therapies or drug trials. The purpose of this study was to determine whether receiving SBRT, when the subject’s metastatic tumor (up to five lesions, excluding the brain) is just beginning to grow, will prolong the time until the worsening of the disease. STOP-NSCLC, HALT, and NCT03808662 trials examined the efficacy and safety of SBRT of all progressions in patients with OPD after response to systemic chemotherapy, and the results of these trials may allow us to evaluate the efficacy and safety of a strategy of continuation of treatment beyond PD with the addition of LAT in OPD, with and without driver mutations.

3. OPD in NSCLC Patients Treated with Immune Checkpoint Inhibitor

Patients with EGFR and ALK mutations have been excluded from the clinical trials of combination therapy of immune checkpoint inhibitor (ICI) with cytotoxic chemotherapy due to their low efficacy, and the development of treatment has been mainly focused on patients with NSCLC without driver mutations. ICI with and without cytotoxic chemotherapy has also been reported to have a favorable prognosis in patients with OPD.

Rheinheimer et al. defined OPD as a localized treatment failure at one or two anatomic sites, with one to five progressive measurable lesions (according to RECIST 1.1). As for the characteristics of the development of OPD, when ICI monotherapy was compared between first- and second-line therapy, it was shown to be more frequent in first-line therapy (20 vs. 10%, p < 0.05), to occur at a later time (median 11 vs. 5 months, p < 0.01), to affect fewer organs (mean 1.1 vs. 1.5, p < 0.05), and to have fewer lesions (1.4 vs. 2.3, p < 0.05). The frequency by organ was 42% for mediastinal LNs, 39% for the brain, and 24% for the lung. Compared with multiple PD, OPD had a later onset (9 vs. 2 months, p < 0.001), a better prognosis (mean 26 vs. 13 months, p < 0.001), and more cases with high PD-L1 expression (p < 0.001) ^[23].

These retrospective analyses suggest that the incidence of OPD in patients with ICI is approximately 20%, the median time of onset is 7–9 months, and the prognosis in OPD is better than that in MPD. OPD sites were reported relatively frequently in the primary tumor, mediastinal LN, brain, and intrapulmonary and abdominal LNs and tended to be more frequent in patients with response to ICI, patients with PFS longer than 6 months, males, patients with EGFR wild-type mutation, and patients with a smoking history. However, the impact of the LAT on the OS is uncertain. In addition, these data are from retrospective observational studies and should be interpreted with caution, keeping in mind that there are various biases and differences in the definition of OPD (number of OPD, response to ICI, and minimum duration of treatment). Since the efficacy of ICI is higher in the first-line than in the later-line regimens, evidence from standard first-line treatment including ICI should be emphasized for OPD ^[24]^[25].

As for the mechanism by which radiation for OPD may enhance the clinical efficacy of ICI, as well as the evidence for the efficacy of LAT in patients with driver mutation, it has been shown that besides prolonging PFS2 by controlling OPD, radiation may also contribute to this strategy by modifying cell surface molecules to enhance the efficacy of immunotherapy, activating the innate immune system to produce an abscopal effect, and enhancing the efficacy of ICI by reducing the tumor volume ^[26]^[27]^[28].

Currently, there are several prospective clinical trials of LAT for OPD after ICI therapy in NSCLC and for continuation of ICI therapy beyond the PD. For example, the OLCSG 2001 [UMIN000041778] study is a single-arm phase II study that evaluates the efficacy and safety of adding localized radiation as LAT and continuing maintenance therapy beyond the PD in patients who develop OPD after initial immune-chemotherapy. The primary endpoint is 1-year survival rate, and the secondary endpoints are OS, PFS, safety, and post-treatment status. NCT04767009 is an open-label, multicenter, phase II study to evaluate the efficacy and safety of SBRT in patients with OPD, who were defined as those not requiring palliative irradiation and whose numbers of OPD are based on the opinion of the investigator, in NSCLC without driver mutation after an anti PD-1 inhibitor, followed by PD-1 inhibitor maintenance beyond the PD. The primary endpoints are safety and 1-year new lesion-free survival rate, and the secondary endpoints are PFS and OS. NCT04549428 is a multicenter, open-label, single-arm phase II study to evaluate the preliminary efficacy, safety, and tolerability of atezolizumab in combination with 8-Gy single-dose radiation therapy in patients who were diagnosed with stage IV NSCLC with OPD. The study considered patients who had up to four OPD lesions in up to three organs, excluding the brain and bone, with both anti-PD-1 agents and first-line cytotoxic chemotherapy, regardless of PD-L1 status. The primary endpoint is the ORR. NCT04517526 is a multicenter, phase II study to evaluate the efficacy and safety of platinum-based chemotherapy + bevacizumab + durvalumab and salvage SBRT for patients with stage IV NSCLC with EGFR mutations after the failure of first-line osimertinib. The primary endpoints are the PFS and OS.

4. Summary

Currently, ICI treatment has become the standard of care, and radiation therapy is expected to improve the efficacy of ICI by producing an abscopal effect and reducing tumor volume. This mechanism is expected to have a beneficial effect on LAT and subsequent continuation of the ICI beyond PD for OPD. Long-term survival in patients treated with ICI plus chemotherapy has been observed at a certain percentage. Hopefully, a multidisciplinary treatment strategy using ICI, cytotoxic agents, molecular-targeted agents, and radiation will reveal the possibility of long-term survival or cure in patients with metastatic NSCLC who do not respond adequately to ICI plus chemotherapy. There is also a need to establish clinically useful biomarkers to screen patients with rapid disease progression. Biomarkers in serum/plasma and tumor micro-environment may help detect the disease state ^[26].

In daily clinical practice, some patients meet the definition of OPD in clinical trials. They do not always receive LAT or subsequent continuation of the current therapy beyond PD. This is because established definitions and evidence of OPD are missing. It is important to conduct prospective comparative studies to verify the efficacy and safety, establish appropriate eligibility criteria, identify biomarkers, and determine the optimal dose and timing of LAT.

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