CE lesson worth 1 contact hour that is intended to advanced practice nurses, registered nurses, and other healthcare professionals who care for patients with cancer.
Release Date: April 22, 2021½ Expiration Date: April 22, 2022½ This activity is provided free of charge.
STATEMENT OF NEED
This CE article is designed to serve as an update on cancer detection and prevention and to facilitate clinical awareness of current and new research regarding state-of-the-art care for those with or at risk for cancer.
Advanced practice nurses, registered nurses, and other healthcare professionals who care for cancer patients may participate in this CE activity.
Upon completion, participants should be able to:
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Mutations, irAEs May Help PredictImmunotherapy Response in NSCLC
Patients with non–small cell lung cancer (NSCLC) who experience immune-related adverse events (irAEs) may have better survival outcomes than those without irAEs, according to research presented at the IASLC 2020 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer, held January 28 to 31, 2021.
Overall, 30 Hispanic and 97 non-Hispanic patients were involved. Neither STK11 mutations nor irAEs were found to occur at significantly different rates between these 2 patient groups.
Additionally, patients with an STK11 gene mutation had shorter median overall survival (OS) than those with wild-type STK11. The presence of a STK11-KRAS double mutation was also correlated with a lower 12-month OS rate compared with doubly wild-type tumors.
The investigators retrospectively analyzed the outcomes of patients with stage IIIB/IV NSCLC who were tested for mutations in the STK11 and KRAS genes and who were treated with immune checkpoint inhibitors between July 2014 and November 2019. In addition to examining the role of STK11 mutations and irAEs in predicting immunotherapy response, the research team sought to compare the incidence of STK11 mutations and irAEs between Hispanic and non-Hispanic patients.
The study population included 96 patients with STK11 wild-type tumors and 31 with an STK11 mutation. Both groups had a median age at diagnosis of 65 years. Forty-eight patients experienced an irAE (median 70 years old at diagnosis), and 77 patients were irAE negative (median 66 years old at diagnosis). Overall, 30 Hispanic patients were involved: 8 harbored an STK11 mutation, and 14 experienced an irAE.
Effects of STK11 Mutation Status on Survival Outcomes
Median OS was significantly longer in patients who were STK11 wild type compared with the STK11-mutant group (12.1 vs 8.6 months, respectively; HR, 1.7; 95% CI, 1.0-3.6; P = .03). The wild-type group also had a higher 12-month OS rate (73% vs 55%; P = .03). Patientswith STK11 wild-type cancer had slightly better median progression-free survival (PFS) (6.3 vs 5.6 months; HR, 1.35; 95% CI, 0.76-2.1; P = .35) and 12-month PFS (45% vs 43%; P = .85) than the STK11-mutant group, though the differences were not statistically significant.
Patients who were wild type for both STK11 and KRAS had a significantly higher 12-month OS rate compared with patients harboring both mutations (70% vs 40%, respectively; P = .03).
However, median OS did not differ significantly between the 2 groups (11.4 vs 5.3 months; HR, 1.8; 95% CI, 0.69-4.62; P = .13), nor did median PFS, at 5.1 months in the fully wild-type group and 3.0 months in the double-mutant group (HR, 1.2; 95% CI, 0.58-2.54; P = .56).
The rate of STK11 mutations did not differ significantly between Hispanic and non-Hispanic patients (26.7% vs 23.7%, respectively; OR, 1.2; 95% CI, 0.46-3.0; P = .8).
Effects of irAE Status on Survival Outcomes
Patients who experienced an irAE had significantly better PFS and OS outcomes.
Median PFS was 9.5 months in patients who had an irAE compared with 4.4 months in those who did not (HR, 0.54; 95% CI, 0.35-0.82; P = .005). Twelve-month PFS was also significantly better in irAE-positive patients than in irAE-negative ones (60% vs 33%, respectively; P = .0001).
Median OS was 14.2 vs 7.3 months in the irAE-positive and -negative groups, respectively (HR, 0.35; 95% CI, 0.20-0.61; P < .001). Twelve-month OS was also significantly higher in patients who had an irAE compared with those who did not (85% vs 60%; P = .00008).
The rate of irAE positivity did not differ significantly between Hispanic and non-Hispanic patients (46.7% vs 35.8%, respectively; OR, 1.6; 95% CI, 0.68-3.5; P = .29). Similarly, the irAE-positive patients in the 2 groups did not have significantly different rates of the most common irAEs: hypothyroidism (35.7% vs 14.7%; P = .13), rash (21.4% vs 29.4%; P = .73), and pneumonitis (7.1% vs 5.9%; P > .99).
This study’s findings provide additional support for the use of irAE and STK11 mutation status to better identify patients who may respond to immune checkpoint inhibitors. The investigators also suggested further evaluation of their findings in larger studies in the future.
Raez LE, Uba R, North A, et al. STK11/LKB1, KRAS mutations and immune-related adverse events as predictors of response to immunotherapy in lung cancer. Presented at: IASLC 2020World Conference on Lung Cancer; January 28-31, 2021; Virtual. Poster P33.14. Accessed January 31, 2021.
Virtual Prehabilitation Is Efficacious Before Lung Cancer Surgery
By Brielle Benyon
Virtual prehabilitation may improve patients’ physical activity level and exercise capacity before they undergo lung cancer surgery, according to recent research presented at the IASLC 2020 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer, held January 28 to 31, 2021.
“Prehabilitation is the practice of enhancing a patient’s functional capacity before surgery, with the aim of improving postoperative outcomes,” explained lead study author Stephanie Wynne, BSc, psychical therapist at Guy’s and St. Thomas’ NJH Foundation Trust in London, England while presenting the data. “In lung cancer surgery, [prehabilitation] is associated with improved functional capacity and quality of life and reduced hospital length of stay, postoperative complications, and readmission.”
Wynne explained that lung resection is the most common radical treatment for lung cancer, yet only 10% to 30% of individuals referred are actual candidates for the procedure “due to their disease stage and a number of surgical risk factors, including advanced age, performance status, high comorbidities, and reduced cardiopulmonary reserve.” Prehabilitation may help increase patients’ presurgical physical fitness.
Although prehabilitation typically occurs in a face-to-face setting, an at-home option is particularly attractive during the COVID-19 pandemic.
A study was conducted during the summer of 2020 that included 20 patients who were about to undergo lung surgery at a National Health Service Trust in London, England. They were all given a personalized home-based exercise program and a diary to monitor compliance. Patients also received written advice and counseling for symptom management and participated in virtual follow-ups every 1 or 2 weeks via telephone or video.
The majority (65%) of participants were female, and the average age was 68 years. The preintervention assessment revealed that 45% of patients had 5 or more comorbidities, 70% had a history of smoking, and 15% were classified as “vulnerable-mildly frail” per the Rockwood Clinical Frailty Score.
Participants were assessed before and after the intervention on the following outcomes:
Among the 14 patients who completed both the pre- and postintervention assessments, significant changes from baseline were observed in 2 of the outcomes: physical activity and exercise capacity. The GLTEQ score improved by 50 points on average (95% CI, 36-65; P < .001), with the percentage of patients who met the recommended levels of physical activity increasing from 40% before to 100% after the intervention. Additionally, the average STS score improved by 6 points (95% CI, 3-8; P < .001), which exceeded the minimum clinically significant difference of +3 points. There were no significant changes in average MRC Dyspnoea, HADS, or FACIT-Fatigue scores.
“To conclude, our findings demonstrate that remote, home-based prehab is feasible, [and it] may improve patients’ presurgical physical activity and exercise capacity,” Wynne said. “This is pertinent given the ongoing uncertainty surrounding COVID-19 and its impact on face-to-face health care delivery.”
Although this study highlights the promise of at-home prehabilitation, the authors noted that modifications are being considered, especially for elderly or vulnerable patients, who may have limited access to technology.
“We’re now designing a triage tool to best support patients based on their therapeutic needs and access to technology,” Wynne said.
Wynne S, Dickinson F, Fraser SF, et al. Providing thoracic prehabilitation during COVID-19: review of a virtual model. Presented at: IASLC 2020 World Conference on Lung Cancer; January 28-31, 2021; Virtual. Abstract OA08.04. Accessed January 28, 2021.
Durvalumab Delivers Durable Benefit in NSCLC Regardless of PD-L1 Expression
Durvalumab (Imfinzi) continues to display a significant overall survival (OS) and progression-free survival (PFS) advantage for patients with unresectable stage III non–small cell lung cancer. This benefit is irrespective of PD-L1 expression, which should not be used to determine a patient’s eligibility for the agent, according to Mark A. Socinski, MD.
Updated findings from the PACIFIC trial (NCT02125461) confirmed trends seen in earlier analyses. Patients who did not have progressive disease after concurrent chemoradiation had a 4-year OS rate of 49.6% with durvalumab vs 36.3% with placebo. The 4-year PFS rates were 35.3% and 19.5%, respectively.1
“When you look at the approval of durvalumab after chemoradiation, the benefit is there in the [PD-L1–]high and [PD-L1–]low [populations]. The FDA [approval] in the United States is agnostic to PD-L1 status,” said Socinski.
Although durvalumab is also approved in Europe, the label restricts use to patients with PD-L1 expression on at least 1% of tumor cells, based on a small post hoc analysis of PACIFIC data that failed to show an OS benefit in patients with less than 1% PD-L1 expression (HR, 1.14; 95% CI, 0.71-1.84).2
“Many of us think that that’s not the right thing to do, because you could not scientifically conclude that from a retrospective unplanned analysis where there were a lot of missing data,” said Socinski.
As such, ongoing research evaluating whether the addition of the PD-L1 inhibitor to chemoradiation (PACIFIC-2; NCT03519971) or stereotactic body radiation therapy (PACIFIC-4; NCT03833154) can further improve outcomes for patients with stage III and I/II disease, respectively, will not use PD-L1 expression as an inclusion criterion.
In an interview with Oncology Nursing News®’ sister publication, OncLive®, during the 18th Annual Winter Lung Cancer Conference®, a program hosted by Physicians’ Education Resource®, LLC, February 5 to 7, 2021, Socinski, executive medical director of the AdventHealth Cancer Institute in Orlando, Florida, discussed the nuances of the PACIFIC trial and ongoing research with durvalumab that could extend the applications of immunotherapy in early-stage cancer.
OncLive®: Is there a role for immunotherapy in patients with PD-L1–negative disease in the advanced setting?
Socinski: PD-L1 is a pretty good biomarker to use. It’s not a perfect biomarker. If you look at large tumor biopsies or excisions, there will be parts of the tumor that are very PD-L1 positive, and then there’ll parts of the tumor that are PD-L1 negative. When you biopsy a tumor, just by sampling chance, you may biopsy the part of [the tumor] that doesn’t have any PD-L1, which we would call that PD-L1 negative even though that may not be truly reflective of the entire cancer.
It’s pretty clear from the phase 3 trials that have been done that PD-L1–negative patients still get very similar benefit [as PD-L1–positive patients] when you give immunotherapy with chemotherapy, though not so much when you give [immunotherapy] by itself.
In an analysis from the PACIFIC trial broken down by PD-L1 expression, patients who are PD-L1 negative derive benefit with durvalumab, but in the metastatic setting, we’re not seeing that same benefit with single-agent immunotherapy in those with PD-L1–negative disease. What might explain that difference?
In stage IV disease, in the PD-L1–negative population, you would never use immunotherapy alone. You could always use [immunotherapy] with chemotherapy, and when you use [immunotherapy] with chemotherapy, the benefit in the PD-L1–negative population seems to be roughly similar to the benefit in the PD-L1–positive population.
One of the issues with interpreting the PD-L1 story from the PACIFIC trial is that at least one-third or so of the patients didn’t have [biopsied tumor] tissue to measure PD-L1, so there are a lot of missing data there. Less than 60% of patients had PD-L1 [testing], so you don’t know the whole story.
PD-L1 [testing] was not a requirement for the study. That’s why many patients didn’t have it available from their tissue. In the trial, the investigators did look at PD-L1[–high tumors], which AstraZeneca defined as greater than 25% vs the [PD-L1–low tumors, defined as] less than 25%. Like we’ve seen with most [single-agent] immunotherapies, the higher you stain for PD-L1, the greater the benefit you get from immunotherapy.
The [United States] indication doesn’t say anything about [PD-L1]. However, the Europeans wanted data from the PACIFIC trial to a greater degree of granularity, and they specifically wanted to look at these [patients with] less than 25% [PD-L1 expression]. The issue that many of us have with that—and this actually came up in an advisory board that I was on earlier today—is that this was not a planned analysis. Up to 40% of the patients didn’t have PD-L1 tested. When they looked at this in a very small subset of patients who were PD-L1 negative, the benefit did not seem to be there for [durvalumab]. Therefore, the European Medicines Agency [EMA] labeled durvalumab only for PD-L1–positive patients.
Now, it certainly creates a hypothesis that maybe PD-L1–negative patients with stage III disease [don’t derive benefit from] single-agent immunotherapy, but I don’t think you can conclude that based upon that specific analysis. In Europe, you have to be PD-L1 positive to get consolidation durvalumab after chemoradiation, whereas in the United States, everyone gets it.
Now that we’re 2 years out from the FDA approval of durvalumab in the stage III setting, what impact has it had on patients who would have otherwise only received chemoradiation?
We recently had the 4-year update of the PACIFIC trial, and there continues to be separation and plateauing of the curves in favor of consolidation durvalumab. It really has been an important development in increasing cure rates. With standard chemoradiotherapy, the average person would typically live 2 to 2.5 years. Now, with the addition of immunotherapy, the average patient lives more than 4 years.
Therefore, there is this significant benefit that seems to last at least 3 to 4 years. It has been interesting over the past couple of years to see the updates of the PACIFIC trial at various major oncology meetings. One of the concerns early on was [whether] this early benefit [would] eventually go away. According to the latest update, which is out to 4 years, [the benefit is] not going away.
1. Faivre-Finn C, Vicente D, Kurata T, et al. Durvalumab after chemoradiotherapy in stage III NSCLC: 4-year survival update from the phase III PACIFIC trial. Ann Oncol. 2020;31(suppl 4):S1178-S1179. doi:10.1016/j.annonc.2020.08.2281
2. Paz-Ares L, Spira A, Raben D, et al. Outcomes with durvalumab by tumour PD-L1 expression in unresectable, stage III non-small-cell lung cancer in the PACIFIC trial. Ann Oncol. 2020;31(6):P798-806. doi:10.1016/j.annonc.2020.03.287
HRQOL Maintained With Adjuvant Osimertinib in EGFR-Mutated NSCLC
Health-related quality of life (HRQOL) was maintained for patients with completely resected EGFR-mutated non–small cell lung cancer who received adjuvant treatment with the EGFR inhibitor osimertinib (Tagrisso), with no clinically meaningful differences from the placebo arm, according to an analysis of patient-reported outcomes (PROs) from the phase 3 ADAURA trial (NCT02511106) presented at the IASLC 2020 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer, held January 28 to 31, 2021.1,2
In December 2020, osimertinib received FDA approval in this setting3 following a report of remarkably high interim efficacy by ADAURA investigators. Among 682 patients with stage IB to IIIA disease, there was an 80% reduction in the risk of disease recurrence or death. A key secondary end point of the trial was HRQOL; these results were presented by lead study author Margarita Majem, MD, PhD, a faculty member in the Department of Medical Oncology at the Hospital de la Santa Creu i Sant Pau in Barcelona, Spain.
In the adjuvant setting, HRQOL is an important clinical consideration for patients who have undergone surgery with curative intent, are free of disease, and are need long-term treatment to reduce the risk of recurrence. The goal of adjuvant treatment is to improve efficacy outcomes while maintaining HRQOL.
In ADAURA, HRQOL was assessed using the 36-Item Short Form Health Survey (SF-36). SF-36 consists of 8 individual health domains (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health) and 2 aggregated summary scores: the physical component summary (PCS) and mental component summary (MCS).
Although SF-36 is not cancer specific, this questionnaire “has been used in previous adjuvant therapy trials to assess HRQOL in patients who, similar to those in this analysis, were cancer free following surgery..
Patients were asked to complete the SF-36 questionnaire at baseline, 12 weeks, and 24 weeks, followed by every 24 weeks thereafter until treatment completion, treatment discontinuation, or disease recurrence. The survey was scored through norm-based scoring relative to the 2009 US general population, which yielded T-scores. Higher T-scores were indicative of better health, with the general population having a mean score of 50 (SD, 10).
Results indicated a high rate of compliance with completing the SF-36, which was 85% or higher across all visits in both the osimertinib arm and the placebo arm. Baseline PCS and MCS T-scores were also comparable between the arms (range, 46-47) and were only slightly (0.3-0.4 SD) below the normative mean of 50 in the general population.
At baseline, T-scores on the 8 health domains were comparable between patients who received osimertinib and those who received placebo. Scores on most domains were also comparable with the general population (within ±0.3 SD of the normative mean). However, investigators noted that both the osimertinib and placebo arms had lower T-scores than the general population (0.4-0.9 SD below the normative mean) on the role-physical, social functioning, and role-emotional domains.
Investigators used a mixed model of repeated measures (MMRM) to analyze changes in SF-36 scores from baseline through week 96. Time to deterioration (TTD), defined as the time from randomization to the first confirmed clinically important worsening (which was confirmed at a subsequent assessment) or death, was assessed for some measures.
More than 80% of patients did not experience a clinically meaningful deterioration in PCS or MCS. For patients who did experience deterioration, no differences in the TTD of PCS (HR, 1.17; 95% CI, 0.82-1.67) or MCS (HR, 0.98; 95% CI, 0.70-1.39) were observed between the study arms. Patients in both the osimertinib arm and the placebo arm experienced a slight increase in the PCS score, with changes from baseline to week 96 of 1.13 (95% CI, 0.54-1.72) and 2.31 points (95% CI, 1.70-2.91), respectively; this was also true with regard to MCS, with changes of 1.34 (95% CI, 0.60-2.08) and 2.68 points (95% CI, 1.92-3.44). No clinically meaningful differences, defined as ±2 points for PCS and ±3 points for MCS, were noted between the osimertinib and placebo arms (PCS, −1.18; 95% CI, −2.02 to −0.34; MCS, −1.34; 95% CI, −2.40 to −0.28).
“At baseline, we saw that patients had almost the same mean value QOL as the normal population,” Majem said in an interview with Oncology Nursing News®’ sister publication, OncLive®. “During treatment, what we saw was that this QOL was practically maintained in all of the domains [analyzed]. This treatment, compared with placebo, did not impact patient QOL.”
The MMRM-adjusted mean changes in T-scores from baseline to 96 weeks revealed no clinically meaningful difference between the study arms for any of the health domains of the SF-36. For the physical functioning domain, the change in the osimertinib arm was 0.53; that of the placebo arm was 1.38. The difference (osimertinib change minus placebo change) of −0.86 did not meet the definition of a clinically meaningful change (±3 points). The equivalent numbers for role-physical were 2.67, 4.47, and −1.8 (±3); for bodily pain, 1.66, 2.22, and −0.57 (±3); for general health, −0.41, 1.09, and −1.5 (±2); for vitality, 0.98, 2.91, and −1.93 (±2); for social functioning, 2.77, 3.88, and −1.11 (±3); for role-emotional, 1.05, 2.51, and −1.46 (±4); and for mental health, 1.17, 2.05, and −0.88 (±3), respectively.
By demonstrating that HRQOL was maintained during prolonged adjuvant osimertinib treatment, data from the PRO analysis further support this novel treatment strategy in patients with EGFR-mutated NSCLC, concluded Majem.
References are available at OncNursingNews.com.
Choosing an Immunotherapy Approach in Lung Cancer: An Expert Weighs In
With the emergence of multiple immunotherapy approaches in recent years, the decision whether to use a single agent, to pair it with chemotherapy, or to pair it with another immunotherapy agent has come to the forefront of treatment, according to Hossein Borghaei, DO, MS.
“[The emergence of so many options is] progress; I consider that a [win] for our patients and for what we can offer them,” said Borghaei. “At the end of the day, you consider the patient’s best interest and what you, as a physician, think they can or cannot tolerate. With appropriate discussion and patient engagement, you come up with the best treatment option for each patient.”
In an interview during the 18th Annual Winter Lung Cancer Conference®, a program hosted by Physicians’ Education Resource®, LLC, February 5 to 7, 2021, Borghaei, chief of the Division of Thoracic Medical Oncology and professor in the Department of Hematology/Oncology at Fox Chase Cancer Center in Philadelphia, Pennsylvania, discussed different immunotherapy strategies in the treatment arsenal, potential biomarkers of response to this approach, and ways to make the right decision for each patient with lung cancer.
OncLive®: Broadly speaking, single-agent immunotherapy, combination chemoimmunotherapy, and dual immunotherapy strategies are all available for use. What factors do you consider when choosing one approach over another?
Borghaei: [When making this decision,] we want to tailor the treatment to what each patient needs, and we also need to take into consideration their preferences. In general, for more simplified treatment, if I can get adequate control of the disease with 1 drug, that will be my preference—especially if that approach is supported by clinical data. On the other hand, we do know that the chemotherapy combinations, even the dual immunotherapy combinations, that have been approved are fairly well tolerated, and they have a toxicity profile that’s manageable.
As such, for an appropriate patient, I don’t hesitate to use combinations. I believe this is an area where additional biomarkers can be helpful. However, at this point, PD-L1 [positivity] levels are quite helpful in deciding who might be a good candidate for single-agent treatment versus someone who might benefit more from a combination approach.
You mentioned patient preference. Given the pandemic, patients may be concerned about spending extended periods of time in the clinic and potentially contracting COVID-19. Are any regimens preferred for these patients?
Clearly, combination treatments require more time [to administer]. Chemotherapy with immunotherapy needs a little bit more time, and 2 immunotherapy drugs given together obviously requires more time. Some single-agent immunotherapy drugs, or checkpoint inhibitors, can be given on an alternate schedule, where the patient doesn’t need to come in quite as often. From those perspectives, you can modify treatment for patients who are being treated with a single drug.
Many of the chemotherapy protocols have been developed around this once-every-3-weeks type of dosing and schedule; if your patient is getting a combination of chemotherapy and immunotherapy, it’s kind of hard to separate the 2. The patient still has to come in every 3 weeks for chemotherapy.
[That being said,] I don’t find that to be a major barrier, with all the screening and other processes that most cancer centers and offices have put in place. I don’t believe this is a major issue to the extent that I would choose a treatment strictly because patients [may be able to] come [into the clinic] less frequently.
We saw a benefit with atezolizumab and chemotherapy in patients with pretreated EGFR-mutant disease in the IMpower150 trial (NCT02366143), with the caveat that this was a small subgroup analysis. Is there a rationale to suggest that maybe those patients who receive osimertinib in the adjuvant setting and then progress could potentially receive immunotherapy in the metastatic setting?
IMpower150 tells us that there is a potential path forward for patients who have an EGFR-positive tumor post osimertinib, for instance. [It also shows us that,] at least hypothetically and theoretically, the combination of a checkpoint inhibitor plus VEGF inhibition can be more effective in treating these tumors. I still believe that immunotherapy alone does not have a role in the treatment of patients with these molecularly driven tumors. Whether the combination of chemotherapy and a VEGF inhibitor is definitely better than chemotherapy alone is [a question that requires] additional data. An ongoing randomized study [is evaluating this further].
If access to a clinical trial [is not an option], am I OK with a combination of chemotherapy plus immunotherapy? Yes, I’m fine with it, but I would also tell the patient that I don’t believe there are a lot of data right now to tell us whether that combination is necessarily going to be a lot better than chemotherapy alone; however, it’s a reasonable option to consider.
I definitely do not believe that patients who have these molecularly driven tumors, especially [those driven by changes in] EGFR or ALK, should receive single-agent immunotherapy. IMpower150 really provided at least a hypothesis that can be tested in subsequent studies, and hopefully we’ll have answers [to these questions] sooner rather than later.
Is there anything else you would like to relay to your colleagues who are currently deciding among all these potential regimens in the clinic?
I know it appears to be a little bit confusing [deciding among] single-agent immunotherapy, chemoimmunotherapy, and dual immunotherapy. However, we now have a lot of choices for our patients, and that’s a good thing. If we have a patient who wants to avoid chemotherapy, a dual immunotherapy combination might be reasonable, or a short course of chemotherapy with immunotherapy like in CheckMate 9LA [NCT03215706] might be appropriate for some patients who are truly unhappy about receiving chemotherapy for whatever reason. If a patient comes in with really high PD-L1 expression, it is very reasonable to consider single-agent immunotherapy, but it’s also very reasonable to consider chemotherapy plus immunotherapy.
It just gives us these additional options that we didn’t have. In the world of lung cancer, we have to get used to the fact that we now have all these options, whereas 10 to 15 years ago, our options were very, very limited.