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Hideo Kunitoh
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ES21 - Current Strategies to Improve Outcome of Patients with Oligometastatic NSCLC (ID 24)
- Event: WCLC 2019
- Type: Educational Session
- Track: Oligometastatic NSCLC
- Presentations: 1
- Now Available
- Moderators:Ernest Nadal, Francoise Mornex
- Coordinates: 9/09/2019, 15:45 - 17:15, Dublin (1997)
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ES21.04 - Optimal Systemic Treatment of OMD (Now Available) (ID 3272)
15:45 - 17:15 | Presenting Author(s): Hideo Kunitoh
- Abstract
- Presentation
Abstract
A series of randomized trials (1-3), 2 of them specifically conducted for non-small cell lung cancer (NSCLC) patients (2,3), have shown that those with OMD could get clinical benefit from the addition of local ablative therapy to the standard systemic treatment. All 3 trials demonstrated improvement of progression-free survival (PFS), and 2 of them suggested overall survival (OS) benefit (1,2). OS was the primary endpoint of the 2 studies.
In each of the trials, however, the “standard systemic treatment” was not specified; in fact, it was merely described that the systemic therapy was determined by the treating oncologists from a set of “standard-of-care options” (3). It would be easy to imagine that the “standard-of-care options” for OMD in these trials would be no different from those for other stage IV diseases.
For NSCLC, they are cytotoxic chemotherapies according to histologic subtypes, appropriate target-based therapies when the tumors have druggable targets, and, more recently, immune-oncology (IO) drugs when the tumors have potentially predictive markers, such as PD-L1 (4) or tumor mutation burdens (5). The question is, is the optimal systemic therapy of OMD really exactly same with the “standards” of other, more advanced, poly-metastatic stage IV NSCLC?
First of all, let me suppose that the disease is truly oligo-metastatic, meaning there are no other metastatic foci than those which are detected by the image scans. In this scenario, you do not require systemic therapy at all; the disease is “cured” by a series of local ablative therapies, since no other diseases exist.
However, in the vast majority of the patients, this would not be the case. Instead, there should be some other “microscopic” metastases which are undetected by the scans, evade the local therapies, and get relapsed without systemic treatment. By focusing on the “microscopic metastases” status, you could make analogy to post-operative adjuvant therapy.
After the apparently curative surgery, without no “macroscopic” metastases in sight, we usually use conventional chemotherapies for prevention of recurrence. It is hoped that these “cytotoxic” drugs would eradicate the residual cancer cells, leading to true “cures”. The long-tails of the survival curves, with increased number of long-term survivors with the adjuvant chemotherapy (6), show that this theory actually works.
On the other hand, use of target-based drugs as post-operative adjuvant therapy has so far had only limited success (7,8). The PFS is elongated, without OS benefit (7). It appears that the patients do as good with the use of “targeted” drugs after relapse, and those drugs suppress tumors only as long as they are taken (9). In other words, they appear “cytostatic” and unable to “cure” the disease. Results of IO adjuvant trials are not yet available, but the “long-tails” of the survival curves of IO treatment make us hope for strong cytotoxic, “cure-oriented” effect.
Therefore, when you aim at “cure” of the OMD, you should choose cytotoxic chemotherapies and/or IO drugs. However, if you are to “control” the disease and get some OS improvement, target-drugs are strong candidates.
Let me see the topic from another viewpoint. The “local ablative” therapies employed in OMD are surgery and (stereotactic) radiotherapy. Which systemic therapy would make a better partner to which local therapy?
Almost all target drugs are eventually turned ineffective, due to acquired resistance. However, in some cases, you could elucidate the resistance mechanism and conquer it (10), with modification of the target-based “precision” medicine.
At present, investigation of the tumor itself is the most certain method, as expressed in the “tissue is the issue” slogan. Very often, however, tiny pathological specimens obtained from transbronchial or CT-guided biopsies are insufficient for the full molecular analysis. Surgical resection of the tumor has advantages both in terms of curative therapy and supply of ample specimens. It also minimizes the late effect on pneumonitis, which is a rare but dreadful toxicity of target-based tyrosine kinase inhibitors. Taken together, use of surgery would be (more) appropriate when you use target-based drugs in OMD.
On the other hand, there are some clinical data that prior use of radiotherapy is associated with better outcome of IO therapy, implying the so-called “abscopal” effect (11). Investigations are on-going, which are aimed at showing synergistic effect of stereotactic radiotherapy and IO treatment (12,13). This could be applied in the management of OMD.
So, in conclusion, what is the optimal systemic treatment of OMD? It depends on the aim of the therapy, cure vs elongation of PFS/OS, as well as on the choice of main local therapy, surgery vs radiotherapy. Future studies should specify the aim of the clinical investigation, not only to maximize the efficacy of local therapies and benefit to the patients, but to increase the statistical power of the clinical trials.
References
1. Palma DA, et al. Lancet 2019
2. Gomez DR, et al. J Clin Oncol 2019
3. Iyenger P, et al. JAMA Oncol 2018
4. Sacher AG, Gandhi L. JAMA Oncol 2016
5. Goto Y. J Clin Oncol 2018
6. Pignon J-P, et al. J Clin Oncol 2008
7. Kelly K, et al. J Clin Oncol 2015
8. Zhong WZ, et al. Lancet Oncol 2018
9. Pennell NA, et al. J Clin Oncol 2019
10. Jänne PA, et al. New Engl J Med 2015
11. Shaverdian N, et al. Lancet Oncol 2017
12. Luke JJ, et al. J Clin Oncol 2018
13. Miyamoto S, et al. Jpn J Clin Oncol 2019
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MA06 - Challenges in the Treatment of Early Stage NSCLC (ID 124)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Now Available
- Moderators:Florentino Hernando-Trancho, Ayten Kayi Cangir
- Coordinates: 9/08/2019, 13:30 - 15:00, Colorado Springs (1994)
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MA06.06 - A Phase III Study of Adjuvant Chemotherapy in Patients with Completely Resected, Node-Negative Non-Small Cell Lung Cancer (Now Available) (ID 285)
13:30 - 15:00 | Presenting Author(s): Hideo Kunitoh
- Abstract
- Presentation
Background
Post-operative UFT (tegafur/uracil) has been shown to prolong survival of Japanese patients with completely resected, p-stage I (T1> 2 cm) non-small cell lung cancer (NSCLC). This trial, the Japan Clinical Oncology Group (JCOG) 0707, aimed at estimating the efficacy of S-1 (tegafur/gimeracil/oteracil) compared to UFT as adjuvant therapy in this population.
Method
Eligible patients had received complete resection with lymph node dissection for p-stage I (T1-2N0M0, T1> 2 cm, by 5thEdition UICC TNM) NSCLC, within 56 days of enrollment. Patients were randomized to receive: oral UFT 250mg/m2/day for 2 years (Arm A), or oral S-1 80mg/m2/day for 2 weeks and 1 week rest, for 1 year (Arm B). The initial primary endpoint was overall survival (OS). Based upon the monitoring in Jun. 2013, which showed the combined OS of the 2 arms better than expected (4-year OS of 91.6% vs. presumed 5-year OS of 70-76.5%), it was judged to be underpowered. The study protocol was amended so that the primary endpoint is relapse-free survival (RFS). With the calculated sample size of 960, this study would detect the superiority of Arm B over Arm A with power 80% and one-sided type I error of 0.05, assuming the 5-year RFS of 75% in Arm A and the hazard ratio of 0.75.
Result
From Nov. 2008 to Dec. 2013, 963 patients were enrolled (Arm A : 482, Arm B : 481): median age 66 (range: 33 to 80), male 58%, adenocarcinoma 80%, p-T1/T2 46%/54%. Only 2 received pneumonectomy. >Grade 3 toxicities (hematologic/nonhematologic) were observed in 15.9 (1.5/14.7) % in Arm A, and in 14.9 (3.6/12.1) % in Arm B, respectively. 60.0% of the patients in Arm A and 54.7% of them in Arm B completed the protocol treatment (p=0.10). There were 4 cases of deaths during protocol treatment, probably of cardio-vascular origin, with 1 in Arm A and 3 in Arm B. At the data cut-off of Dec. 2018, the hazard ratio (HR, Arm B vs. Arm A) of RFS was 1.06 (95% confidence interval (C.I.): 0.82-1.36), showing no superiority of S-1 over UFT. The HR of OS was 1.10 (95% C.I.: 0.81-1.50). The 5-year RFS/OS rates were 79.4%/88.8% in Arm A and 79.5%/89.7% in Arm B, respectively. Pre-specified subset analyses for gender, age, smoking, stage, tumor side, lymph node dissection area, pleural invasion and histology revealed no remarkable results; S-1 arm was not superior to UFT arm in each analysis. Of the 77 and 85 OS events for Arm A/Arm B, 45 each (58%/53%, respectively) were due to the NSCLC. During the follow-up period, secondary malignancy was observed in 85 (17.8%) and 84 (17.8%) in Arm A and Arm B, respectively.
Conclusion
Post-operative adjuvant therapy with oral S-1 was not superior to that with UFT in stage I (T>2 cm) NSCLC after complete resection. UFT remains standard in this population. Future investigation should incorporate identification of high-risk population for recurrence, since survival of each arm was so good with substantial number of OS events due to other causes of deaths in this trial.
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MA21 - Non EGFR/MET Targeted Therapies (ID 153)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:Benjamin Besse, Michael Thomas
- Coordinates: 9/10/2019, 14:30 - 16:00, Vienna (2016)
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MA21.11 - A Multicenter Phase II Study of Low-Dose Erlotinib in Frail Patients with EGFR Mutation-Positive, Non-Small Cell Lung Cancer: TORG1425 (Now Available) (ID 633)
14:30 - 16:00 | Author(s): Hideo Kunitoh
- Abstract
- Presentation
Background
We conducted a multicenter phase II trial evaluating the efficacy of low-dose erlotinib (ERL) in frail patients with EGFR-mt non-small cell lung cancer (NSCLC). The primary endpoint was met, with the objective response rate (ORR) of 60%. Here we present the final overall survival (OS) results. Furthermore, we investigated the effect of ABCB1 genetic polymorphisms on the ERL plasma concentration pharmacokinetics (PK) and pharmacodynamics (PD).
Method
Chemotherapy-naïve NSCLC patients with EGFR mt who had frailty were enrolled and received ERL 50 mg/d. Patient’s frailty was defined as follows: (Group 1) 20 to 74 years of age with Eastern Cooperative Oncology Group performance status (PS) ≥2 or Charlson Comorbidity Index (CCI) ≥6 points; (Group 2) 75 to 80 years of age with PS ≥1 or CCI ≥6 points; (Group 3) ≥81 years of age with any PS and CCI. ABCB1 gene polymorphism analysis were using the i-densyTM genetic testing platform, and blood samples for the ABCB1 genetic testing were collected prior to treatment. Steady-state trough plasma ERL concentration was measured with a high-performance liquid chromatograph-tandem mass spectrometry at 15 days (±7 days) after initiating ERL administration.
Result
From December 2014 and April 2017, 80 patients were enrolled: males/females 26/54; median age 80 (range 49-90); Group 1/2/3 15/28/37; Ad/Sq/Others 76/1/3. EGFR mt types were: exon 19/21 42/38. All 80 patients were included in efficacy and safety analysis. Median progression-free survival and OS were 9.3 (95%CI: 7.2-11.4), 26.1 (95%CI: 21.9-30.4) months respectively. The trough of ERL could be measured in 48 patients, and 45 of these patients were analyzed for ABCB1 genetic polymorphism. The ORR for the 48 patients was 62.5%, and their median trough of ERL was 685 ng/ml (range 153-1950) , which surpassed the reported “effective” level (500ng/ml). Nine (60%) of 15 the patients who failed to achieve the level responded. Genetic polymorphisms were not correlated with ERL PK, nor were they associated with efficacy and adverse events.
Conclusion
This is the first prospective study evaluating low-dose ERL for frail patients with EGFR mt NSCLC. This treatment was safe and effective, and the ABCB1 genetic polymorphisms did not affect ERL PK/PD. Clinical trial information: UMIN 000015949.
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P1.17 - Treatment of Early Stage/Localized Disease (ID 188)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.17-04 - Multicenter Observational Study of Node-Negative Non-Small Cell Lung Cancer Patients Who Are Excluded from a Clinical Trial (ID 678)
09:45 - 18:00 | Author(s): Hideo Kunitoh
- Abstract
Background
The Japan Clinical Oncology Group (JCOG) conducted a randomized phase III trial (JCOG0707), which compared the survival benefit of tegafur/uracil (UFT) and tegafur/gimeracil/oteracil (S-1) for completely resected pathological stage I (T1>2 cm and T2 in the 6th TNM classification) non-small cell lung cancer (NSCLC). A total of 963 patients were enrolled. Recently, there is a growing concern that those who participated in clinical trials are highly selected and do not represent the “real-world” population. Hereby, we conducted a multicenter observational study of patients excluded from JCOG0707 trial during the study period.
Method
Patients with completely resected pathological stage I NSCLC, eligible for, but excluded from the JCOG0707 trial during the enrollment period (Nov. 2008– Dec. 2013) were eligible for this study. Physicians from institutions that participated in the JCOG0707 retrospectively assessed the medical records of each patient. The final survival data were collected as of Dec. 2018.
Result
Of the 48 institutions participating in JCOG0707, 34 participated in this observational study. They had enrolled 917 (“JCOG” cohort) to JCOG0707. To this study, 5004 patients (“All” cohort), or 85% of those initially considered for JCOG0707 at the 34 institutions, were enrolled. Among them, 2388 (47.7%) were ineligible for the trial and 2616 (52.3%) had not been enrolled to JCOG0707 despite being eligible (“Eligible” cohort). Of the 5004 patients, 1659 (33.2%) received adjuvant chemotherapy, mainly UFT (1550 of 1659, or 93.4% of those received any adjuvant chemotherapy).
The 5-year survival rates (5yOS) for All and Eligible cohorts were 83.9% and 89.1%, respectively, versus 89.2% in the JCOG cohort. The 5yOS with UFT adjuvant were 89.4% in Eligible and 88.9% in JCOG cohorts, respectively.
UFT administration was a significant prognostic factor in All (adjusted HR=0.66, p<0.0001), but not in Eligible cohort (adjusted HR=0.88, p=0.28). The patients were classified into 3 subgroups, those with tumors without GGA (ground-glass area, non-invasive component; GGA-), with GGA (GGA+) and tumor size < 3 cm, and GGA+ with tumor size > 3cm. 5yOS of 744 patients in the Eligible cohort with GGA+ and tumor size < 3cm were excellent, 96.9%/96.4% with/without UFT. For 416 patients with GGA+ tumor sized > 3cm in Eligible cohort, invasive tumor size in the pathological specimen was prognostic but not predictive for UFT effect. When the invasive tumor size was >3 cm, 5yOS with/without UFT were 90.0/87.8%, whereas when it was <3 cm, 5yOS with/without UFT were 96.2/96.2%. UFT tended to be associated with better prognosis in 1389 patients with GGA- tumor when the tumor size was >3 cm, (5yOS 83.8% vs 77.4%, adjusted HR=0.82, p=0.27), but not when it was <3 cm (5yOS 88.1% vs 88.1%, adjusted HR=0.97, p=0.87).
Conclusion
Our “real-world” data reproduced the survival outcome of JCOG0707, especially in Eligible cohort. Invasive tumor size was a prognostic factor in GGA+ tumors, suggesting validity of the 8th IASLC TNM classification. GGA+ tumor with invasive tumor size of <3 cm would not require any adjuvant therapy. UFT effect appears to be limited to large GGA- tumor.
