During a Case Based Peer Perspectives event Brian T. Hill, MD, PhD, director, Lymphoid Malignancy Program, Cleveland Clinic discussed the case of a 53-year-old patients with chronic lymphocytic leukemia (CLL).

™: What regimen are you most likely to recommend for this patient with relapsed CLL and a 

For this patient, we can consider ibrutinib [Imbruvica] or acalabrutinib [Calquence], maybe venetoclax [Venclexta] and rituximab [Rituxan]. The NCCN [National Comprehensive Cancer Network] guidelines suggest the preferred regimens are acalabrutinib, with or without obinutuzumab [Gazyva], ibrutinib, and venetoclax with obinutuzumab.

How do the toxicities between ibrutinib and acalabrutinib compare?

Both agents are active, but there are unique toxicities associated with acalabrutinib, like headaches. Although it sounds like a minor toxicity, it can be significant for 

some patients, [especially] if they experience a headache every day.

Prior to the approval of ibrutinib, what was the standard of care?

The results from RESONATE [NCT01578707]—which compared ofatumumab [Arzerra], the standard of care, with ibrutinib in patients with previously treated CLL—demonstrated a progression-free survival [PFS] advantage of ibrutinib over ofatumumab after a 6-year follow-up [

 The overall survival [OS] for the 2 arms favored ibrutinib as well; HR, 0.591, 95% CI, 0.378-0.926]. These results demonstrate the importance of giving the best treatment in the relapsed setting. You want to go with the best treatment that you have. 

Reviewing the adverse effects greater than or equal to grade 3 demonstrates that over time, infections tend to dissipate rather than increase in number.

In the relapsed setting, please compare acalabrutinib to idelalisib (Zydelig) or bendamustine.

The phase 3 randomized trial in the relapsed setting ASCEND [NCT02970318] evaluated the 1:1 randomization of patients treated with the BTK [Bruton tyrosine kinase] inhibitor acalabrutinib versus investigator’s discretion therapy. Patients either received acalabrutinib or the PI3K inhibitor idelalisib and rituximab or bendamustine and rituximab.

In this setting, the median PFS for acalabrutinib has not been reached yet, and the median PFS for idelalisib and bendamustine was 16.5 months. One-year PFS rate was reported at 88% for acalabrutinib compared with 68% in patients who received idelalisib and bendamustine (HR, 0.31; 95% CI, 0.20-0.49; 

Reviewing the subgroup analysis toxicity data, they still favor the BTK inhibitor in all subgroups. [Regarding] adverse events and safety, we haven’t discussed the toxicities for idelalisib and rituximab, but there can be a fair amount of diarrhea. In the ASCEND trial, the investigators reported that 47% of patients experienced diarrhea with idelalisib, [whereas] diarrhea was much lower with the other agents. Regarding headache, 23% of 

patients experienced headache in the acalabrutinib arm. It was reported as grade 3 or greater.

When choosing a BTK inhibitor, what findings from the trial for the treatment are most influential?

I think most clinicians are concerned about duration of response, with length of follow-up being less important.

In the relapsed setting of CLL, the MURANO study [NCT02005471] evaluated patients who received venetoclax with rituximab or bendamustine with rituximab. Most of these patients had received prior chemoimmunotherapy, but none had received a prior BTK inhibitor.

In the study, the 4-year PFS rate for venetoclax was remarkably better for bendamustine [75.5% vs 68.0%; HR, 0.19; 

<.0001]. This demonstrates that bendamustine and rituximab in the relapsed setting should be avoided, in my opinion, because you get such a dramatically improved PFS by using venetoclax over chemotherapy. [Further], there is a remarkable improvement in the [OS for venetoclax] compared with chemoimmunotherapy. The MURANO trial is important because in contrast to some of the other studies, where the comparator was ofatumumab or drugs we don’t use, bendamustine and rituximab is a standard regimen.

The preplanned interim analysis of subgroups showed that patients with or without a 17p deletion had equal benefit. Across all subgroups, there was a PFS advantage to venetoclax. Objective response rates also favored venetoclax, 92% versus 72%. The complete remission rate was higher for the group receiving venetoclax compared with the group receiving bendamustine. Negative MRD [minimal residual disease] rates were significantly higher in the venetoclax arm, at 83%. That’s according to peripheral blood, which is why the numbers are so high.

Reviewing the grade 3/4 treatment-related adverse effects indicates that patients who received venetoclax had a higher incidence of neutropenia compared with bendamustine [58.8% vs 39.9%, respectively]. Interestingly, if you look at the incidence of febrile neutropenia, patients in the venetoclax [arm] experienced it less frequently than [those who received] bendamustine [3.6% vs 9.6%, respectively]. I think that there is some unique toxicity associated with venetoclax that causes neutropenia, but it doesn’t necessarily lead to neutropenic fever.

What are the treatment options for patients with relapsed CLL who are not candidates for chemotherapy?

The phase 3 IDELA study [NCT02136511] evaluated idelalisib and rituximab compared with rituximab and placebo.5 These drugs are active. The PFS of idelalisib and rituximab was remarkably better than rituximab alone [19.4 months (95% CI, 12.3–not reached) vs 6.5 months (95% CI, 4.0-7.3)]. In addition, OS also favored idelalisib and rituximab over rituximab alone [40.6 months (95% CI, 28.5-57.3) vs 34.6 months (95% CI, 16.0–not reached)].

Another option is duvelisib [Copiktra]. The phase 3 DUO study [NCT02004522] compared duvelisib with the comparator ofatumumab.6 The median PFS rate favored duvelisib over ofatumumab, although it doesn’t look quite as striking as idelalisib data [13.3 months (95% CI, 12.1-16.8) compared with 9.9 months (95% CI, 9.2-11.3); 

1. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/ small lymphocytic lymphoma, version 4.2020. Accessed May 19, 2020. nccn.org/ professionals/physician_gls/pdf/cll.pdf

2. Byrd JC, Hillmen P, O’Brien S, et al. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. 

. 2019;133(19):2031-2042. doi:10.1182/ blood-2018-08-870238

3. Ghia P, Pluta A, Wach M, et al. Acalabrutinib vs rituximab plus idelalisib (idr) or bendamustine (br) by investigator choice in relapsed/refractory (rr) chronic lymphocytic leukemia: phase 3 ASCEND study. 

. 2019;37(S2):86-87. doi:10.1002/ hon.54_2629

4. Seymore JF, Kipps TJ, Eichors BF, et al. Venetoclax plus rituximab is superior to bendamustine plus rituximab in patients with relapsed/ refractory chronic lymphocytic leukemia - results from pre-planned interim analysis of the randomized phase 3 MURANO study. 

. 2017;130(suppl 1):LBA-2. doi:10.1182/blood.V130.Suppl_1. LBA-2.LBA-2

5. Sharman JP, Coutre SE, Furman RR, et al. Final results of a randomized, phase III study of rituximab with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia. 

. 2019;37(16):1391-1402. doi:10.1200/JCO.18.01460

6. Flinn IW, Hillmen P, Montillo M, et al. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. 

. 2018;132(23):2446-2455. doi:10.1182/ blood-2018-05-850461

Articles

Clinical Articles

During a Case Based Peer Perspectives event Brian T. Hill, MD, PhD, discussed the case of a 53-year-old patients with chronic lymphocytic leukemia.

Hill Compares Toxicity Profiles of Current Treatment Regimens in Relapsed CLL

During a Case Based Peer Perspective event, Alicia K. Morgans, MD, MPH, associate professor of Medicine, Hematology and Oncology, at the Feinberg School of Medicine, Northwestern University in Chicago, IL, discussed the case of a 75-year-old male with metastatic castration-resistant prostate cancer (mCRPC).

™: What are potential treatment options for the second-line setting in patients with metastatic castration-resistant prostate cancer (mCRPC)?

This patient was started on enzalutamide [Xtandi] and had progression after 8 months; he was started on docetaxel at that time. He received 4 cycles but had neuropathy that resulted in the patient and provider stopping the treatment.

The patient had a rising PSA level and required treatment. We know that we have multiple treatment options in this second-line setting for mCRPC.

We have to consider what these patients were treated with prior to seeing us. This includes assessing the fitness of the patient and the patient’s goals and preferences. We now know 

that this patient was treated with enzalutamide. We also know that the options are abiraterone acetate [Zytiga], cabazitaxel [Jevtana], and docetaxel.

After 4 cycles, the patient experienced neuropathy and a rising PSA level after less than 12 months on treatment.

Would you give cabazitaxel to a patient after experiencing neuropathy from docetaxel?

We have data from a study in patients with mCRPC called FIRSTANA [NCT01308567].

 Patients were randomized in the first-line setting in mCRPC to receive either cabazitaxel 25 mg/m

 dose in the NCCN [National Comprehensive Cancer Network] guidelines in the United States.

Although none of these agents demonstrated superiority in terms of disease control or efficacy, there was a slightly higher response observed in the cabazitaxel 25-mg/m

 dose. Fewer adverse events [AEs] such as neuropathy, neutropenia, and neutropenic fever were observed in patients who received 20 mg/m

 versus docetaxel, which was a little surprising to me.

The study came out just a few years after cabazitaxel was approved.

. We can give this in patients who have had complications with docetaxel. It’s on a cycle-by-cycle basis, but it seems reasonable based on these data and on personal experience. I thought this was an interesting postapproval study that was required of the organization to enlighten us about different doses.

There is also the phase 4 CARD study [NCT02485691], which was shared at the ESMO [European Society of Medical Oncology] Congress last year.

 These patients had already progressed on their AR [androgen receptor]–targeted agent and docetaxel. This is a European study, so patients had received an AR-targeted agent in the metastatic castration-resistant setting as well as chemotherapy in the metastatic castration-resistant setting. They were not patients who received AR-targeted agents in the hormone-sensitive setting.

Patients were randomized for their next treatment to cabazitaxel at the full 25-mg/m

 dose with Neulasta [pegfilgrastim versus either abiraterone or enzalutamide, depending on which agent that they had not previously received and progressed on in an earlier phase of the disease. Radiographic progression-free survival [rPFS] was the primary end point, overall survival was a secondary end point, as well as quality-of-life concerns including pain and PSA responses.

The baseline characteristics suggested that there were more patients who were older in the cabazitaxel arm. The investigators reported that patients in the AR-targeted arm experienced pain more frequently, but overall, both arms were fairly well matched. This was a small study to begin with, but they matched well overall

Please explain the efficacy of the CARD trial.

We saw that the rPFS was significantly better for patients who received cabazitaxel versus those treated with either abiraterone or enzalutamide. The median rPFS for the cabazitaxel arm was 8.0 months versus the abiraterone or enzalutamide arm at 3.7 months [HR, 0.54; 95% CI, 0.40-0.73; 

<.0001]. Subgroup analysis revealed that most subgroups benefited from an rPFS standpoint.

The overall survival data were also presented at ESMO, and this is why I think it was considered one of the presidential symposia. Patients treated with cabazitaxel had a significant improvement in mortality as compared with patients who received either abiraterone or enzalutamide.

There was a 46% reduction in mortality when patients were treated with cabazitaxel compared with the other 2 regimens. Although this is a higher dose than what I normally prescribe, these patients were still able to tolerate it and had an improved survival.

Interestingly, there were significantly more PSA responses reported with treatment with cabazitaxel versus an AR-targeted agent, and significantly more tumor responses [reported] by [the] RECIST [trial]. When investigators measured the tumor size, it seemed to have decreased in size, and a much better pain response was observed. This was determined by using the percentage of the patients who had an improvement in their pain score that was maintained and clinically meaningful over time. Better pain control with cabazitaxel was reported as well. Investigators also observed a longer time to symptomatic skeletal events in the cabazitaxel arm versus the AR-targeted agent.

What’s important to note is when looking at chemotherapy versus AR-targeted agents, there were more AEs that led to treatment discontinuation, with slightly more discontinuations in the cabazitaxel arm. What surprised me and a fair number of people was that there were more AEs leading to death in those patients treated with the AR-targeted agents than with the chemotherapy. This suggests more mortality-related AEs associated with the AR-targeted agents.

Health-related quality of life seemed to be maintained, probably because the disease was better controlled. This was just 

presented at the 2020 Genitourinary Cancers Symposium. Patients had better pain control and certainly better prostate-specific concerns with cabazitaxel than with the AR-targeted agents, at least through cycle 5 or so.⁵

What other presentations at the 2019 ESMO Congress were noteworthy?

The other study that I think was groundbreaking at ESMO was a phase 3 trial that targeted DNA repair defects.

 PROfound [NCT02987543] evaluated patients with mCRPC who had also progressed on the AR-targeted agents as well as chemotherapy. They were randomized to receive olaparib [Lynparza] or the second AR-targeted agent. All patients had to have DNA repair defects in their tissue to get into this trial. This was an ambitious study to carry out in a population with prostate cancer. The investigators were able to complete it and do a nice phase 3 trial and present it.

When the 2 arms were compared, the rate of AEs was higher in the olaparib arm; those included cytopenias, some nausea, and other complications. Those are some of the common AEs. Importantly, the treatment duration was significantly longer for patients treated with olaparib than AR-targeted agents.

Reviewing the disease response, rPFS as determined by a blinded independent reviewer was significantly longer for patients treated with olaparib compared with patients who received that second AR-targeted agent. Importantly, patients who received that second AR-targeted agent did not have any restrictions on how long they had to have been on that agent in the first place.

This differs from the CARD study, in which patients had to be on treatment for 12 months or less with a response to an AR-targeted agent. These patients, in contrast, could have been on for however long they were responding; they just had to have received treatment in the past. We see at 3.5 months, 50% of patients treated with that second AR-targeted agent are falling off for radiographic progression, which demonstrates that it’s not an effective treatment. In any event, olapaolaparib seemed to be significantly more effective in terms of rPFS.

Looking at the confirmed overall response rate in cohort A, which included patients with 

mutations, there was a significant improvement in objective response rate, 33% versus 2.3% [odds ratio, 20.86; 95% CI, 4.18-379.18; 

Reviewing the data for cohort B, which included patients with DNA repair-defect mutations and not just 

mutations, the investigators reported an improvement in rPFS for this selected patient population.

In this particular case, the patient received cabazitaxel. In a pandemic, I think it’s especially important to try to prevent our patients from being hospitalized for neutropenic fever.

1. Oudard S, Fizazi K, Sengeløv L, et al. Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: a randomized phase III trial-FIRSTANA. 

. 2017;35(28):31893197. doi:10.1200/ JCO.2016.72.1068

2. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 1.2020. Accessed May 12, 2020. https://www.nccn.org/professionals/physician_gls/pdf/ prostate.pdf

3. FDA approves lower dose of cabazitaxel for prostate cancer. Updated September 14, 2017. Accessed May 12, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lower-dose-cabazitaxel-prostate-cancer

4. deWit R, Kramer G, Eymard J, et al. CARD: randomized, open-label study of cabazitaxel (cbz) vs abiraterone (abi) or enzalutamide (enz) in metastatic castration-resistant prostate cancer (mcrpc). 

. 2019;30(suppl 5):v851-v934. doi:10.1093/annonc/mdz394

5. Fizazi K, Kramer G, Eymard J-C, et al. Pain response and health-related quality of life (HRQL) analysis in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving cabazitaxel (CBZ) versus abiraterone or enzalutamide in the CARD study. 

. 2020;38(suppl 6):16. doi:10.1200/JCO.2020.38.6_suppl.16

6. Hussain M. PROFOUND: phase 3 study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mcrpc) with homologous recombination repair (hrr) gene alterations. 

. 2019;30(suppl 5):v851- v934. doi:10.1093/annonc/mdz394

Alicia K. Morgans, MD, MPH, discussed the case of a 75-year-old male with metastatic castration-resistant prostate cancer.

Morgans Addresses Neuropathic Toxicity in Second-Line Metastatic CRPC

Edward Kim, MD, chair, Department of Solid Tumor Oncology, Levine Cancer Institute in Charlotte, NC, discussed the use of atezolizumab (Tecentriq) and durvalumab (Imfinzi) as treatment of a 73-year-old female patient with extensive-stage small cell lung cancer (ES-SCLC) during a virtual Case Based Peer Perspective event.

What are the treatment choices for patients with ES-SCLC?

The current NCCN [National Comprehensive Cancer Network] guidelines for ES therapy [say] that the preferred regimens are combinations; so, a 2-drug combination with the addition of immunotherapy.

 Atezolizumab and durvalumab have been added to the guidelines [as preferred regimens]. They are [administered] with either cisplatin or carboplatin. Then other regimens, if you can’t give that, are listed. There are at least options here with different immunotherapies.

How do the data in this setting support the patient’s treatment?

The phase 3 IMpower133 [NCT02763579] study, published in the 

by lead author Leora Horn, MD, investigated 4 cycles of the triplet versus the doublet [regimens] and placebo.

There was maintenance immunotherapy afterward, with the single agent or placebo. Overall survival [OS] and progression-free survival [PFS] were the primary end points. All these patients had PS [performance status] 0 or 1 with ES disease, and they could have treated asymptomatic brain metastases.

The median OS was 12.3 months with atezolizumab versus 10.3 months with placebo [HR, 0.70; 95% CI, 0.54-0.91; 

= .007]. Then the PFS was 5.2 months versus 4.3 months, respectively [HR, 0.77; 95% CI, 0.62-0.96; 

For the 2-year OS follow-up, the Kaplan-Meier curves stay tight together for the first 8 to 10 months, then there’s some separation, so maybe there is an effect with the maintenance [therapy].

 The curves start [to approach] each other as the data get past the 18-month period.

The 2-year OS rates by subsets had some positive [benefit], but many of the intervals cross the 1.00 range. So, not too [many] subgroups were statistically significant, but there is a trend toward a benefit observed with the atezolizumab-treatment arm.

The response rate with atezolizumab versus placebo was not what we’ve seen as far as an overall increase. In fact, objectively, it was less with the objective confirmed response rates [60.2% with atezolizumab vs 64.4% with placebo]. Partial responses were less [57.7% vs 63.4%, respectively]. There was good disease control overall, and there were high response rates, but it was still odd to not see that enhanced response rate with the addition of the immunotherapy.

The grade 3/4 adverse events [AEs] on both sides did not have a ton of difference.2 So, whether you start the triplet or the 

doublet, you’re not imparting many more AEs on patients. That’s something to think about. You’re not adding too much more toxicity, if any, in many areas.

Have you used durvalumab with platinum chemotherapy and etoposide to treat your patients? What are the data with this agent in this setting?

It has only been approved for a short period of time, and [many physicians] have already incorporated it.4 If they were happy with the current triplet, I think you’d see slower adoption, but the fact that people are jumping onto it means that there’s something else [going on].

The phase 3 CASPIAN study [NCT03043872] that led to the approval of durvalumab was published in 

.5 This was a large study, with over 800 patients receiving the triplet with durvalumab followed by the every-4-weeks regimen at 1500 mg versus the doublet. There was also a third arm that was durvalumab and tremelimumab with chemotherapy, followed by durvalumab. But this analysis was of the first 2 [cohorts].

The median OS was 13.0 months in the durvalumab arm versus 10.3 months in the placebo arm [HR, 0.73; 95% CI, 0.59- 0.91; 

= .0047]. The PFS, though, was odd; as you look at the overall Kaplan-Meier curves, you can see that there’s a benefit, but they were overlapping early on. So, that median [PFS; 5.1 months vs 5.4 months, respectively] was a little deceptive on how the curve was shaped.

For OS by subgroup, everything favored the durvalumab arm. There were some small subgroups that had wide ranges, but [they still] favored durvalumab in these subgroups. None of the medians fall above 1.00.

The unconfirmed objective response rate here was 79% with durvalumab versus 70% without. The confirmed was 68% versus 58%, respectively. IMpower133 was about 60% to 65%, so it was in the same ballpark but a different magnitude.3 [These responses] all fell within a similar range; not anything huge, like 20% [difference], but definitely something incremental as far as improvement.

The AEs that occurred [included] neutropenia and anemia.5 Chemotherapy alone had more of an impact on AEs versus durvalumab with chemotherapy, which we’re not necessarily used to seeing. I don’t think we should read anything into it, other than that it seems like this drug was well tolerated. It didn’t show a huge worsening of AE events, similar to what we see with atezolizumab. It didn’t add too much from an AE standpoint.

How did the IMpower133 and CASPIAN trials differ?

There were 4 cycles in the IMpower133 study; there were 6 cycles in the CASPIAN. The PFS in the control arm was much higher in the CASPIAN study, but the overall hazard ratio was similar in both [IMpower133 PFS HR was 0.76; CASPIAN, 0.78]. The immune-related AEs were lower with durvalumab. So, there are a couple of choices out there. [There’s been an] indication of a desire to switch [in this setting], as far as atezolizumab versus anything else, so I think that’s reflective of what the data are speaking to.

What do you think of the patient’s smoking status?

It’s never too late to talk about smoking cessation, but it wouldn’t necessarily be on the top 3 [things to talk about]. You never know; maybe the smoking is helping to get the immunotherapy jacked up more, so [she has] constant antigen load stimulation.

Is there a difference with atezolizumab or durvalumab in patients with brain metastasis?

It wasn’t reported [in the CASPIAN or IMpower133 trials]. I’m sure they probably have some data behind it, but I have not seen that same data that were shown in the PACIFIC study [NCT02125461], where they showed the sites of disease; they allowed asymptomatic brain metastasis, so it might be clouded from that regard.

NCCN. Clinical Practice Guidelines in Oncology. Small cell lung cancer, version 3.2020. Accessed June 30, 2020. https://www.nccn.org/professionals/physician_ gls/pdf/sclc.pdf

Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. 

. 2018;379(23):2220-2229. doi:10.1056/NEJMoa1809064

Reck M, Liu SV, Mansfield AS, et al. IMPOWER133: updated overall survival (OS) analysis of first-line (1L) atezolizumab (ATEZO) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC). 

2019;30(suppl 5):v710-v717. doi:10.1093/ annonc/mdz264

FDA approves durvalumab for extensive-stage small cell lung cancer. FDA. Updated March 30, 2020. Accessed June 30, 2020. https://www.fda.gov/drugs/ resources-information-approved-drugs/fda-approves-durvalumab-extensive-stage-small-cell-lung-cancer#:~:text=FDA%20approves%20durvalumab%20for%20 extensive%2Dstage%20small%20cell%20lung%20cancer,-Share&text=On%20 March%2027%2C%202020%2C%20the,cancer%20(ES%2DSCLC)

Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. 

. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6

Edward Kim, MD, chair, Department of Solid Tumor Oncology, Levine Cancer Institute in Charlotte, NC, discussed the use of atezolizumab  and durvalumab as treatment of a 73-year-old female patient with extensive-stage small cell lung cancer during a virtual Case Based Peer Perspective event.










Kim Evaluates Atezolizumab and Durvalumab for ES-SCLC

Nathan A. Pennell, MD, PhD, associate professor, director, Lung Medical Oncology Program, Taussig Cancer Institute, Cleveland Clinic, in Cleveland, Ohio, discussed the case of 66-year-old patient with 

-mutant non–small cell lung cancer (NSCLC), during a virtual Case Based Peer Perspectives event.

™: Would you initiate immunotherapy at this point or wait for molecular panel test results?

Regarding recommendations about up-front molecular panel testing, we know that patients with nonsquamous, non– small cell lung cancer need to be routinely tested for genomic alterations because we have effective treatments for those. The College of American Pathology [CAP], International Association for the Study of Lung Cancer, and Association for Molecular Pathologists have come together with guidelines recommending that every patient be tested up front for 

was not included in the most recent guidelines because the panel closed their deliberations before the approval of dabrafenib [Tafinlar] and trametinib [Mekinist] in lung cancer, but the American Society of Clinical Oncology’s guidelines then added those agents as a standard recommendation. The National Comprehensive Cancer Network [NCCN] endorses that as well.

is not included in the major guidelines, but it is a recommendation, especially through NCCN, mostly because there is highly effective treatment if you find it. A major downside of 

is that it is so rare, probably something in the range of 0.1% 

to 0.3%, or 1 of every 300 to 1000 patients with lung cancer. I personally have not yet seen a patient with 

I think we’ll have agents approved in the 

exon 20 insertion mutations, all in the next year or so. It’s becoming clear that you need to do multiplex testing, and you can’t just do a single polymerase chain reaction test or an immunohistochemistry test or a fluorescence in situ hybridization [FISH] test. You’re going to exhaust your tissue, and it’s going to end up costing way too much and taking way too long. You need to do a single multiplex test such as next-generation sequencing [NGS] routinely for these patients, and that is the recommendation from NCCN and the CAP guidelines.

The truth is that Cleveland Clinic still uses hotspot testing— using a limited NGS panel with companion FISH, although we’re hoping to move to a more comprehensive NGS panel sometime soon. I think as we identify more mutations that require checking, that [change] becomes more pressing. Also, PD-L1 is to help guide patients eligible for frontline single-agent PD-1 therapy versus chemotherapy plus PD-1.

Do you perform molecular testing on patients with squamous cell lung cancer?

The guidelines still haven’t come around to that. I am aware of studies showing that [genomic aberrations] can be found in squamous cells. I’ve done [some] digging, and some [evidence] suggests that [those aberrations] aren’t as common in squamous cell as some studies have said, and that it may be quite rare. So, as of right now, we’re not routinely testing patients with squamous cell lung cancer, although for any refractory patient after standard treatment, it’s not unreasonable to do prompt genomic testing. A 

subset of patients with squamous cell will have mixed adenosquamous [lung cancer], and those patients can have drivers.

What are some reasons for obtaining liquid biopsies for these patients?

In my use of liquid biopsies, it’s less about not having enough tissue and more about timing. In the case of tissue biopsy, sometimes the hospital where the patient had the biopsy done is the challenge because we don’t know where the tissue has been sent, or it’s been sent somewhere and we don’t know how to obtain the tissue. [We may not know] who ordered it and when it’s coming back, or the patient needs treatment but weeks are going by and we don’t have those results. Liquid biopsy has been useful in at least getting some up-front results, though. In some hospitals, you can order liquid biopsies at the same time as tissue biopsies, and that can improve the whole process.

Are there drawbacks of relying on liquid biopsies for diagnostic purposes?

I think the primary concern with liquid biopsies is that as stand-alone tests, they may not be as sensitive as tissue tests. Of course, tissue tests themselves are not perfect; they’re subject to sampling and preparation and fixation and the quality of the DNA and RNA that comes out of them.

Most of the time, when you see discordance between liquid and solid [biopsies], it’s something technical that caused that test to fail. But, more likely, you’ll see a positive result in tissue that failed in liquid. It seems to be related to tumor burden. Patients who have bone metastases or liver metastases are positive on a liquid biopsy, whereas people who have lung-only disease are relatively limited—with malignant infusions, etcetera—which may result in negative liquid biopsies, at least in my experience.

The general recommendation is that although liquid biopsies can be useful, they shouldn’t replace tissue biopsies. If you get a negative result on a liquid biopsy, you should follow it up with a tissue test.

I prefer to order a liquid biopsy because it’s so fast. Lack of insurance coverage is probably the main barrier to not having the liquid biopsy for everyone. The evidence suggests that you get more positive test results by doing both tests.

Regarding a lack of tissue harvesting: I think that having reliable communication and understanding from your interventionalists—the [doctors] who are getting your biopsies, whether it’s [via] interventional radiology [IR] or bronchoscopy—is invaluable, because when they’re in there getting that fine needle aspiration [FNA], they don’t have to just do a single pass. Even if they can get only an FNA, they can usually get multiple passes. If the interventional radiologist is working closely with the pathologist, you can often get enough tissue provided from 1 lesion. But it depends a lot on how it’s done and whether the IR [person] is aware ahead of time that they need [to get enough] tissue.

What are the treatment options for this patient considering his molecular testing results?

The patient does not have a lot of symptoms but does have a brain metastasis. The patient also has an 

exon 19 deletion and high PD-L1. I’m leaning toward an EGFR tyrosine kinase inhibitor [TKI] as frontline treatment.

The brain metastasis might be a decision factor. Some agents that we use now, such as osimertinib [Tagrisso], have some pretty good activity in the central nervous system [CNS]. We could consider referring this patient for stereotactic radiation and/or surgery versus no surgery, given that I think there’s a lesion in the vision center. It’s a decision on stereotactic radiation versus treating with primary systemic therapy. This might be a case in which we don’t know the right answer. At Cleveland Clinic, an osimertinib plus gamma knife trial is going on [NCT03535363], although it’s not a randomized trial.

We do know that the CNS response rate is similar to the systemic response rate with osimertinib. But at the same time— as has been pointed out to me by my colleagues in radiation oncology—during the period between scans, if patients’ lesions were to grow significantly, their risk of complications from gamma knife grows significantly. It’s much less morbid to treat them when they’re small.

So in the case of a patient whose testing results [didn’t com back for] a week or 2, especially when you don’t know at that time that they had an 

mutation like this patient, he probably would be referred for gamma knife radiation while waiting for test results.

Are there options besides osimertinib available for these patients?

Options other than osimertinib would include a first-generation or second-generation TKI: erlotinib [Tarceva], afatinib [Gilotrif], or dacomitinib [Vizimpro].

If the patient is progressing and we see [they are] T790M positive, you could switch to osimertinib, which might, potentially, lengthen the patient’s disease control. Perhaps [you could] use chemoimmunotherapy, based on the IMpower150 [NCT02366143] trial results. However, patients in IMpower150 had already progressed from an EGFR TKI treatment prior to the trial, so it didn’t include first-line patients. Now we also have some positive trials with erlotinib with ramucirumab [Cyramza] that yielded an impressive progression-free survival [PFS] of about 19 months [NCT02411448].

What do the NCCN guidelines say for this setting?

Generally, they suggest that the use of PD-1 or PD-L1 inhibitors is contraindicated in the presence of an oncogene, which would predict lack of benefit

What data do we have that demonstrate the benefit of avoiding the use of an immune checkpoint inhibitor (ICI) in a patient with an 

The trial conducted by Aaron Lisberg, MD, and colleagues is among the most meaningful, although it’s small, in [showing] why you should not give an ICI to a patient with 

This was a phase 2 trial, and all patients were 

mutation positive, PD-L1 positive, and previously untreated. A total of 75% of the enrolled patients had high PD-L1 expression, and they were treated with a TKI with pembrolizumab in the first-line setting.

The investigators intended to enroll 25 patients, but they had to halt accrual after 11 patients because they did not see a single response in any of the patients with a confirmed 

mutation. There was 1 response, but that patient was later confirmed to not have an 

mutation. So 10 of 10 patients did not respond, even though three-quarters of them were PD-L1 positive. And, importantly, most of these patients switched over to a TKI. Most patients received a TKI even after going off pembrolizumab, but a couple of them died and one of them had a grade 5 pneumonitis risk event after being treated with osimertinib.

The take-home message is that patients with an 

mutation tend to not respond even in the presence of a high PD-L1. If you think about it, PD-L1 positivity is a secondary reaction. There is an immune response that is essentially inducing local cytokines. PD-L1 is reacting to an inflammatory response in a patient who is likely to benefit from ICIs.

mutation and other driver oncogenes have constitutive high expression of PD-L1, because everything is essentially turned on in patients who have driver oncogenes. It is not a reaction to an immune response, and therefore you simply can’t trust PD-L1 expression as a meaningful biomarker in driver oncogene patients.

Additionally, if you give someone pembrolizumab, which has a half-life of weeks to months, that patient is going to have it in their system for a long time when you might want to be giving them a TKI.

What are the safety considerations associated with ICIs and EGFR-TKI sequencing?

A number of toxicity concerns exist. There have been a number of phase 1 trials as well as retrospective experiences of patients with 

mutations who received PD-L1 or PD-1 inhibitors and then went on to osimertinib. Adam J. Schoenfeld, MD, and colleagues demonstrated a 15% risk of severe immune related adverse effects [irAEs].

 This was observed in all-comers. Patients who received treatment within 3 months of a checkpoint inhibitor had a much higher rate [of irAEs]. That is my general rule of thumb: to wait at least 3 months after giving an ICI before using osimertinib if possible.

This safety profile is not unique to EGFR inhibitors. It has been observed in patients who are 

positive, as well. Usually, we see more hepatotoxicity in combinations with drugs like alectinib [Alecensa], ceritinib [Zykadia], and pegaptanib [Macugen]. It’s probably risky to combine a checkpoint inhibitor with a TKI. This is one of the biggest reasons it’s critically important to get that molecular testing done before you start the patient on immune therapy.

Chee Khoon Lee, PhD, and colleagues conducted a meta-analysis of multiple phase 3, second-line trials with atezolizumab [Tecentriq], nivolumab [Opdivo], and pembrolizumab [Keytruda].5 These studies, in general, showed that patients with the 

mutation received no hint of a survival benefit. In fact, there may have been a hint of harm in patients treated with ICIs compared with chemotherapy.

Lee further demonstrated that there was no significant difference [between the chemotherapy and ICI arms], but there was a trend to favor the chemotherapy arm in patients with 

That’s not to say this combination can never work; some evidence shows that patients who were previously treated with TKIs and who are treated with chemotherapy plus a checkpoint inhibitor may benefit. That comes from the IMpower150 study, which was platinum and either paclitaxel or nab-paclitaxel [Abraxane], bevacizumab [Avastin], and atezolizumab.6 About 20% of the patients on the trial had an 

gene fusion, although most of them were patients who were 

positive. There seemed to be a similar magnitude of PFS and overall survival [OS] benefit seen in the [population with mutations] compared with the overall population. It wasn’t statistically significant, and it was a small subset, but the hazard ratio is essentially the same. And just recently I saw that, with updated [results], it is still holding true that the patients with mutations seemed to be doing better on that trial.

If you’re going to use an ICI in a patient with an 

mutation, after TKIs have been exhausted, if you’re going to switch them to chemotherapy, that would be a time to consider [doing so].

What evidence do we have about using osimertinib in the first-line setting?

The FLAURA study [NCT02296125] evaluated patients with 

mutations.7 It evaluated osimertinib versus either erlotinib [Tarceva] or gefitinib [Iressa], and the primary end point was PFS.

The investigators allowed patients with untreated CNS metastases to participate. The PFS of the osimertinib arm was 19 months compared with 10 months, which is exactly what you would expect with a first-generation inhibitor.

The important end point in this study was OS, and the OS was statistically significantly improved compared with first-generation inhibitors, with about a 7-month difference between median OS. One of the most remarkable things about this is that the median survival of these patients is 38.6 months. That’s in excess of 3 years, median, for our patients with newly diagnosed metastatic lung cancer, which is absolutely extraordinary if I think back to what it was like at the beginning of my career when the stage IV patients’ median OS was [about] 10 months.

Some oncologists have considered waiting and treating with a first-generation inhibitor. Would patients do just as well? Importantly, although I don’t think this gets emphasized enough, the FLAURA trial did that. The investigators followed patients who progressed and crossed over to osimertinib from the control arm. In fact, 47% of people in the standard-of-care, first-generation TKI arm crossed over to osimertinib. This is exactly what you would anticipate the T790M population being, which is about half of people. Despite the number of patients crossing over, there was still an OS benefit in support of osimertinib.

I think [FLAURA] was a sequencing trial, and it failed to be better with sequencing and osimertinib. I think this just confirms that this should be the best available treatment until, of course, there’s one that is better.

Would you consider ordering a new biopsy in a patient on osimertinib at the time of progression? Would it be tissue or liquid?

Nathan A. Pennell, MD, PhD, discussed the case of 66-year-old patient with EGFR-mutant non–small cell lung cancer, during a virtual Case Based Peer Perspectives event.







July 2 2020 CBPP Spotlight

Hill Compares Toxicity Profiles of Current Treatment Regimens in Relapsed CLL

Morgans Addresses Neuropathic Toxicity in Second-Line Metastatic CRPC

Kim Evaluates Atezolizumab and Durvalumab for ES-SCLC

Pennell Examines Targeted Therapies in EGFR-Mutated NSCLC

Mesa Discusses Treating Myelofibrosis and Other MPNs

Kundranda Evaluates Therapies for Metastatic Gastric Cancer

Danilov Discusses Therapies for Relapsed/Refractory CLL

Cohen Expands on Treatment Options in Patients With Genomic Aberrations in CLL

Hoffman Explores Frontline Treatments in CLL

Randall Discusses Therapies in HRD and BRCA-Mutated Ovarian Cancer

Singal and Kim Talk Trials and Treatments for HCC