 case-based peer perspectives live discussion, David H. Ilson, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, New York, NY, discusses the treatment options for patients with hepatocellular carcinoma (HCC).

Would you consider a liver transplant for this patient? What are the frontline options in this setting?

Liver transplant is reserved for patients with HCC who have liver dysfunction. In a patient with a healthy liver, hepatic resection is the up-front treatment for this disease, and he under-went hepatic resection.

Then, 6 months later, he had metastatic disease and was started on standard sorafenib 400 mg twice daily and toler-ated it well. Alternatives to sorafenib in the first line [are] lenvatinib [Lenvima], which is also a multitargeted tyrosine kinase inhibitor.

Please describe the data for these 2 therapies.

This was the subject of the REFLECT trial [NCT01761226], a large, randomized trial in nearly 1000 patients with untreated HCC. Stratifi cation included the region they were treated, and they were randomized 1:1 to lenvatinib versus sorafenib with a primary end point of overall survival [OS]. The investigators were trying to demonstrate that lenvatinib was noninferior to sorafenib. Secondary end points were progression-free survival [PFS], time to progression, and response rate.

Lenvatinib was noninferior to sorafenib in OS, but there were trends suggesting better PFS for lenvatinib, better time to progression, and a higher response rate for lenvatinib over sorafenib. But in terms of the primary end point, lenvatinib was noninferior; it was not superior with suggestion of a better PFS and response rate.Based on these data, lenvatinib has been approved.

 Adverse effects [AEs] with lenvatinib were more hypertension, diarrhea, and anorexia; there was incidence of more hand-foot syndrome and cutaneous toxicity with sorafenib. There was a suggestion of a longer treatment duration for lenvatinib over sorafenib and a slightly higher rate of discontinuation for AEs.

What other drugs are being evaluated for this patient population?

The IMbrave150 trial [NCT03434379] recently reported results. This was first-line treatment with atezolizumab [Tecentriq] plus bevacizumab [Avastin], so a PD-L1 inhibitor plus bevacizumab versus sorafenib in first-line treatment.

IMbrave150 may potentially be a practice-changing trial globally. Until the presentation of this trial, sorafenib was the standard first-line treatment for HCC. This was a randomized first-line trial in 500 patients with HCC without previous systemic therapy. The stratification was by region, performance status, and AFP. The standard arm was sorafenib 400 mg twice daily, and the investigational arm was the anti–PD-L1 drug atezolizumab every 3 weeks with bevacizumab every 3 weeks. There were 2 co-primary end points: OS and PFS.

How did atezolizumab and bevacizumab compare with sorafenib in the IMbrave150 trial?

There was a striking survival benefit for atezolizumab plus beva-cizumab versus sorafenib. The 6-month OS rate was 85% for atezolizumab and bevacizumab versus 72% for sorafenib. The median survival had not yet been reached on the experimental arm compared with 13.2 months for sorafenib. The hazard ratio was 0.58 [95% CI, 0.42-0.79; P = .0006], so that translates into over a 40% reduction in the risk of death. This was highly statistically significant. These data were presented at the European Society for Medical Oncology Asia 2019 meeting.

PFS was also improved with a median difference of about 2.5 months [6.8 months with atezolizumab and bevacizumab, 4.3 months with sorafenib]. There was a hazard ratio of 0.60 [95% CI, 0.47-0.76; P <.0001]...and a 40% reduction in progression, which is statistically significant. There was a significant portion of patients who were still progression free into the second year of treatment.

I suspect that regulatory approval for atezolizumab and beva-cizumab will be forthcoming. This is the first randomized trial [whose results] show a survival benefit above sorafenib. The response rate and disease control rates were also higher with atezolizumab and bevacizumab.

What treatment would you recommend for the patient considering his status at follow-up?

He has a high AFP [level] and progressed on sorafenib. There are a lot of options here: regorafenib [Stivarga], cabozantinib [Cabometyx], ramucirumab [Cyramza], nivolumab [Opdivo], and pembrolizumab [Keytruda]. All of these are options for this patient. In terms of the options that show a survival benefit in a randomized clinical trial, [there is] regorafenib.

The RESORCE trial [NCT01774344] was a randomized trial with patients who progressed on sorafenib but tolerated it and had Child-Pugh A disease. Investigators looked at second-line regorafenib versus [placebo], and OS was the primary end point. This showed a significant improvement in median survival [10.6 months with regorafenib vs 7.8 months with placebo]. Median PFS was also modestly improved, and AEs were manageable.

This is now an FDA-approved drug in the second line.

What other drugs are approved in this setting?

The next approved drug in the second line is cabozantinib.

CELESTIAL [NCT01908426] was a second-line trial in patients with Child-Pugh A disease. Patients with progression on first-line sorafenib were randomized 2:1 to cabozantinib, which is a meta-inhibitor, versus placebo. The primary end point was OS. There was no crossover.

This was another positive trial of a second-line agent. Median OS was improved by about 2 months with cabozantinib, and there was improvement in disease control favoring the cabo-zantinib arm. There were few responses, though, only about a 4% response rate, but there was disease stabilization and improvement in PFS.

Ramucirumab in the second line [is also approved].

 The original REACH trial [NCT01140347] treated all patients with sorafenib progression, and this was a negative trial; however, in the subset of patients who had a high AFP [level], there was a survival benefit.

 This led to the REACH-2 trial [NCT02435433], which enrolled only patients on second-line therapy who had an AFP [level] higher than 400 ng/mL.

How did ramucirumab do in terms of efficacy in the REACH-2 trial?

REACH-2 [results] showed a PFS benefit for ramucirumab over placebo [HR, 0.45; 95% CI, 0.34-0.60; P <.0001] and a modest survival improvement. The pooled data from these trials look at [the overall population and] classification of liver function. There were [survival] benefits as well as PFS improvement. This is another option for a patient with a high AFP [level]. A big plus with ramucirumab is that it’s nontoxic, so this is a drug I would consider in the second line for a patient with a high AFP [level] who is not symptomatic and for whom we may want to give something that is less toxic. Cabozantinib, arguably, is going to have more toxicity. 

Would you consider checkpoint inhibitors such as nivolumab for this patient?

The phase II data for nivolumab in CheckMate 040 [NCT01658878] that led to approval had response rates of about 20% across the board, with response durations that were respect-able, about 8 to 9 months.

There were provocative data for the combination of nivolumab and ipilimumab [Yervoy] in cohort 4 of CheckMate 040. This was more for second-line or refractory disease. This looked at nivolumab and ipilimumab in 3 different combinations followed by nivolumab maintenance.

The regimen that had the best response rate was arm A, with nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg every 3 weeks. There was the suggestion of best OS [for this regimen]. The caveat here is this was a phase II trial with small numbers, so there is a suggestion of some additive benefit for ipilimumab and nivolumab. They did not see a lot of grade 3/4 toxicity, even for the dual-targeted regimens.

Based on these data, the arm A regimen was FDA approved in second- and third-line treatments.

 I always pause when I see drugs approved based on second-line data, [although] this does represent a treatment option for later lines, but nivolumab plus ipilimumab is going to put the patient at risk for more toxicity.

The FDA granted approval for the combination in patients with refractory disease. That being said, however, the phase III trials of checkpoint inhibitors as single agents have been negative. In CheckMate 459 [NCT02576509], untreated patients received nivolumab versus sorafenib. There was no clear survival difference. PFS and OS were not improved. Nivolumab did have a better response rate, but this was a negative trial for first-line nivolumab versus sorafenib.

What other studies looked at treatment for patients with HCC?

The second-line trial for pembrolizumab versus placebo in KEYNOTE-240 [NCT02702401]. These were patients progressing on sorafenib. There was a trend toward better survival for pembro-lizumab, but it was not statistically significant: 13.9 versus 10.6 months for pembrolizumab versus placebo, respectively [HR, 0.781; 95% CI, 0.611-0.998; P = .0238). It did not meet the criteria to declare pembrolizumab better than supportive care, even though there was a trend.

The response rate was higher, 18% versus 4%, with pembrolizumab. The disease control rate was similar overall.



Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in fi rst-line treat-ment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163-1173. doi:10.1016/S0140-6736(18)30207-1

FDA approves lenvatinib for unresectable hepatocellular carcinoma. FDA. August 16, 2018. Accessed February 19, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lenvatinib-unresectable-hepatocellular-carcinoma

Cheng AL, Qin S, Ikeda M, et al. IMbrave150: effi cacy and safety results from a ph III study evaluating atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (Sor) as fi rst treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC). Ann Oncol. 2019;30(suppl 9):ix186-ix187. doi:10.1093/annonc/mdz446.002

Bruix J, Qin S, Merle P, et al; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56-66. doi:10.1016/S0140-6736(16)32453-9. Published correc-tion appears in Lancet. 2017;389(10064):36. doi:10.1016/S0140-6736(16)32615-0

Regorafenib. FDA. April 27, 2017. Accessed April 29, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/regorafenib 

FDA approves cabozantinib for hepatocellular carcinoma. FDA. January 14, 2019. Updated March 12, 2019. Accessed April 29, 2020. https://www.fda.gov/drugs/fda-approves-cabozantinib-hepatocellular-carcinoma

Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54-63. doi:10.1056/NEJMoa1717002

FDA approves ramucirumab for hepatocellular carcinoma. FDA. May 10, 2019. Accessed April 29, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ramucirumab-hepatocellular-carcinoma

Zhu AX, Park JO, Ryoo BY, et al; REACH Trial Investigators. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carci-noma following fi rst-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2015;16(7):859-870. doi:10.1016/S1470-2045(15)00050-9

Zhu AX, Kang YK, Yen CJ, et al; REACH-2 study investigators. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(2):282-296. doi:10.1016/S1470-2045(18)30937-9

FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib. FDA. September 22, 2017. Updated September 25, 2017. Accessed February 18, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-nivolumab-hcc-previously-treated-sorafenib 

El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepato-cellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492-2502. doi:10.1016/S0140-6736(17)31046-2

Yau T, Kang Y-K, Kim T-Y, et al. Nivolumab (NIVO) + ipilimumab (IPI) combina-tion therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040. J Clin Oncol. 2019;37(suppl 15):4012. doi: 10.1200/JCO.2019.37.15_suppl.4012

FDA grants accelerated approval to nivolumab and ipilimumab combination for hepa-tocellular carcinoma. March 10, 2020. Updated March 11, 2020. Accessed April 29, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-nivolumab-and-ipilimumab-combination-hepatocellular-carcinoma

Yau T, Park JW, Finn RS, et al. CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as fi rst-line (1L) treatment in patients (PTS) with advanced hepatocellular carcinoma (AHCC). Ann Oncol. 2019;30(suppl 5):v874-v875. doi: 10.1093/annonc/mdz394.029

Finn RS, Ryoo BY, Merle P, et al; KEYNOTE-240 investigators. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J Clin Oncol. 2020;38(3):193-202. doi:10.1200/JCO.19.01307CBPP_MAY2020.2 copy.indd 51CBPP_MAY2020.2 copy.indd 515/11/20 4:53 PM5/11/20 4:53 PM

Articles

In a Targeted Oncology case-based peer perspectives live discussion, David H. Ilson, MD, PhD, discusses the treatment options for patients with hepatocellular carcinoma

Ilson Explores Treatment Options for Patients With Metastatic HCC

Adding a subcutaneous formulation of daratumumab (Darzalex Faspro) to the triplet regimen cyclophosphamide, bortezomib (Velcade), and dexamethasone (CyBorD) may hold promise for patients with newly diagnosed light chain (AL) amyloidosis who are in urgent need of new treatment options. Data from the phase 3 ANDROMEDA (NCT03201965) trial, which demonstrated the superiority of CyBorD plus subcutaneous daratumumab (Dara-CyBorD) versus CyBorD alone, were presented virtually during the 25th Congress of the European Hematology Association. The experimental combination resulted in deeper and more rapid hematologic responses and led to better clinical outcomes with an acceptable safety profile.

The combination of Dara-CyBorD therapy improved major organ deterioration progression-free survival (MOD-PFS) and resulted in substantially higher organ responses in patients with newly diagnosed AL amyloidosis, according to Efstathios Kastritis, MD, associate professor of clinical therapeutics/medical oncology at the National and Kapodistrian University of Athens in Greece.

Systemic AL amyloidosis is a rare disease characterized by insoluble amyloid fibril deposition in tissues and organs. There is no approved treatment, and about 30% of patients die within the first year of diagnosis. Treatment with the CyBorD combination has improved outcomes, but sustained hematologic response is needed to reverse amyloid-mediated organ dysfunction and improve overall survival.

The primary end point of the phase 3, randomized, open-label, active-controlled study was overall hematologic complete response (CR) rate in the intention-to-treat population. Secondary end points included MOD-PFS, organ response rate, time to hematologic response, survival, and safety.

Results showed that hematologic CR rate was 53% for Dara-CyBorD compared with 18% for CyBorD alone (OR, 5.1; 95% CI, 3.2-8.2; 

 <.0001). The 6-month organ response rate was nearly doubled for patients treated with the addition of subcutaneous daratumumab versus CyBorD alone for both cardiac (42% vs 22%) and kidney (54% vs 27%) responses.

The Dara-CyBorD combination achieved higher rates of overall hematologic response (92% vs 77%) and very good partial response or better (VGPR; 79% vs 49%) (FIGURE).

 Among responders, median time to VGPR or better was 17/60 days for the daratumumab arm compared with 25/85 days for CyBorD alone. MOD-PFS favored DARA-CyBorD-treated patients (HR, 0.58; 95% CI, 0.37-0.93; 

There were 388 patients randomized to either Dara-CyBorD (n = 195) or CyBorD (n = 193). All patients received weekly cyclophosphamide (300 mg/m

 orally or intravenously), bortezomib (1.3 mg/m

 subcutaneously), and dexamethasone (20-40 mg orally or intravenously) for six 28-day cycles. Subcutaneous daratumumab was administered weekly by injection in cycles 1 and 2, every 2 weeks in cycles 3 through 6, and every 4 weeks thereafter for up to 24 cycles.

The efficacy and safety profile of intravenous and subcutaneous daratumumab are well characterized. The agent showed no new safety concerns, according to Kastritis. The rate of discontinuation due to treatment-emergent adverse events (TEAEs) was 4% in both arms.

The most common grade 3/4 TEAEs occurring in more than 5% of patients treated on the daratumumab arm were lymphopenia (13% with Dara-CyBorD vs 10% with CyBorD), pneumonia (8% vs 4%, respectively), diarrhea (6% vs 4%), cardiac failure (congestive; 6% vs 5%), neutropenia (5% vs 3%), syncope (5% vs 6%), and peripheral edema (3% vs 6%). Fourteen patients (7%) experienced systemic administration-related reactions with daratumumab-CyBorD; all were grade 1/2 in severity, and most occurred during the fi rst infusion. A total of 56 deaths occurred in the entire trial, 29 patients treated with Dara-CyBorD and 27 who got CyBorD.

Daratumumab is the first and only subcutaneous CD38-directed antibody approved globally. In May of this year, the FDA approved the subcutaneous formulation alone and in combination for the treatment of adult patients with multiple myeloma.

The manufacturer responsible for producing daratumumab, Janssen Biotechnologies, collaborated with Halozyme Therapeutics to develop the subcutaneous form of the agent. Halozyme’s Enhanze system works to degrade hyaluronan, a polysaccharide found in the extracellular matrix of the subcutaneous tissue, thus allowing large volumes of the drug to be delivered in a single subcutaneous injection.

1. Kastritis E, Palladini G, Minnema MC, et al. Subcutaneous daratumumab + cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in patients with newly diagnosed light chain (AL) amyloidosis: primary results from the phase 3 ANDROMEDA study. Presented at: 25th Congress of the European Hematology Association; June 11-21, 2020. Abstract LB2604. https://bit.ly/32eSmJU

2. FDA approves daratumumab and hyaluronidase-fi hj for multiple myeloma. FDA. May 1, 2020. Accessed July 13, 2020. https://bit.ly/2BYcnKd3

3. Enhanze drug delivery technology. Halozyme. Accessed June 3, 2020. https://bit.ly/3fqTjm2

Clinical Articles

Adding a subcutaneous formulation of daratumumab to the triplet regimen cyclophosphamide, bortezomib, and dexamethasone may hold promise for patients with newly diagnosed light chain amyloidosis who are in urgent need of new treatment options, according to a clinical trial.

Patients With AL Amyloidosis May Benefit From Subcutaneous Daratumumab/CyBorD Combination

 case-based peer perspectives live discussion, David Gerber, MD, a professor of internal medicine and associate director of clinical research at The University of Texas Southwestern Medical Center in Dallas, addressed the role of biomarkers in guiding treatment decisions for patients with non–small cell lung cancer based on a patient scenario. 

: Why do you think they did a biopsy on the patient’s metastases instead of the primary site?

You can tap the pleural effusion to improve symptoms. The challenge of pleural fluid is that it might be harder to do molecular analysis because there may be fewer cells. You may have a bony metastatic site where it’s also hard to do molecular analysis because you have to decalcify the tissue and it’s not as viable.

It may be that biopsying the liver is safer than biopsying a lung lesion. You still have issues of bleeding and pain and infection, but usually you don’t have a risk of pneumothorax. They biopsied the liver lesion and it showed adenocarcinoma, so now we have pathologically proven stage IV adenocarcinoma in a former smoker.

: What kind of molecular testing would you order for this patient?

[I would order] next-generation sequencing [NGS] plus PD-L1 testing.

You don’t get PD-L1 status from a blood test. We get [plasma for molecular biomarkers testing]; we’re looking at DNA. We’re looking at the genes in the cancer, so you can detect a mutation. PD-L1 is a protein on the cancer cell surface.

If you have a patient with stage IV cancer, maybe 0.5% or 0.3% of the DNA in the blood is from the cancer. We [have tests that can] pull that out, so that’s another option.

These tests don’t necessarily [look for] circulating tumor cells; this is just the [circulating tumor] DNA. Circulating tumor cells have a diff erent assay. We’re not sure what to do with that information right now in a lot of cancers. There are some cancers, like breast, prostate, and maybe colon cancer, where it’s prognostic [for] response to therapy.

: Which mutations do you usually test for in these patients?

If we’re sending [tissue for] NGS, [the number of genes] depends on the panel. It might be 22,000 genes through [the] Caris Life Sciences [assay]. At The University of Texas Southwestern, we have a panel that’s CLIA [Clinical Laboratory Improvement Amendments] certified, and it’s 1415 genes. It pairs germline, or the patient’s DNA, with the tumor’s DNA.

In lung cancer, the National Comprehensive Cancer Network [NCCN] recommends, at a minimum, testing for 

mutations.¹ Those are 4 subsets of lung cancer. If you think about nonsquamous, non–small cell lung cancer [NSCLC], what is [the rate of] 

mutations are around 1% of cases. [As you go down the list] they start to get rare; but if you don’t look for it, you don’t find it.

If you have a nonsquamous case, it can’t hurt to look for an 

mutation also because there are TRK inhibitors that are FDA approved regardless of the type of cancer.

 It doesn’t matter anatomically what it is. There are 

mutations in lung cancers. I’m not talking about 

-amplified or HER2-expressing tumors, like you would look for in breast cancer; it’s a different biomarker. [We would] look for a mutation in 

exon 20 that predicts response to HER2 inhibitors.

This patient is a former smoker; does smoking history or other factors affect the patient’s mutation status?

mutations will probably be in less than 5% of those cases. If your patient is a never smoker and you’re looking for 

, depending on the histology and the patient, [it will be about] 60%.

I do have patients who are African American men who smoked a lot and have 

mutations. But there are times where you may go to greater efforts to genotype. In general, the [treatable] mutations are going to be in the patients who have smoked less.

There are a couple of exceptions. I’m not sure that 

mutations are necessarily more common in never smokers or former smokers. 

mutations have long been considered [untreatable] in oncology. It is the second most common mutation in human cancer. The most common mutation in human cancer is 

Why do you never hear about inhibitors of 

They don’t exist. All these other mutations are proto-oncogenes, so when they are mutated, they function more. 

is a tumor suppressor; its job is to prevent cancer. When it’s mutated, it stops doing its job or doesn’t do it as much. You’re not trying to inhibit mutant 

; you’re trying to increase its function. It’s a lot harder to increase the function of a molecule in medicine than it is to inhibit it or slow it down.

What other mutations or issues should physicians keep in mind when testing?

mutations in lung cancer for a long time, and it came down to which MET cases matter. We were looking at 

amplification, such as with FISH [fluorescence in situ hybridization]; we were counting the number of genes or chromosomes. We were looking at 

expression, so that’s the protein [detected by] immunohistochemistry, and those trials were negative. It’s the 

exon 14 mutation [that should be targeted, and this mutation] tends to respond well to MET inhibitors.

When you do a blood test looking for the DNA of cancer, there are times that the test will be negative but the tumor is positive [for a mutation]. Maybe the tumor didn’t shed enough DNA [for the test] to pick it up. There are also cases where there is negative testing in the tissue, and the patient is positive for a mutation with a blood test. Is that a false-positive blood test? It’s not; it could have to do with tumor heterogeneity. When you stick a needle in the tumor, you’re [sequencing] just 1 site, whether it’s a lymph node or a primary or metastatic tumor. That area might not have that particular mutation that you could detect.

Have you had cases where the first and/or second biopsy didn’t have enough tissue and you still needed to get a third biopsy?

I have. This is going back to 2009, when we first learned about 

fusion-positive lung cancer. I had a patient who was a never smoker with lung cancer, and she had been on an EGFR inhibitor, hadn’t had any testing, and hadn’t responded at all [to therapy]. She received some chemotherapy; she was on hospice in a wheelchair, getting supplemental oxygen, and she came for a second opinion.

I told her I had just heard about a new subtype of lung cancer called 

-positive lung cancer, and I thought we should look to see if she had it. Even though just 3% of lung adenocarcinoma is 

 positive, for a never smoker with adenocarcinoma, the chance of having an 

mutation is about 50%. I did a biopsy on her liver and there was insufficient tissue. I asked if we could do 1 more, and it came back 

positive. Our pathologist had never heard of the test, so I had to get them to order it, and it was positive. She went on to live another 5 years. These are hard decisions.

How does PD-L1 factor in when deciding on treatment, and is it considered a biomarker?

If you test for PD-L1, we consider negative as 1% or less expression, ntermediate as 1% to 49%, and high or positive as 50% or greater. PD-L1 is the biomarker that helps us determine the efficacy of immune checkpoint inhibitors that target PD-L1 or PD-1. It is not a perfect biomarker.

mutations if you suspect a patient has them?

We were spoiled in thoracic oncology with biomarkers like 

mutation and I’m giving an EGFR inhibitor, my response rate is over 90% with a third-generation EGFR inhibitor. If I don’t have an 

mutation and I give an EGFR inhibitor, my response rate is below 1%. I can only give an EGFR inhibitor if the biomarker is positive. With greater than 90% versus less than 1%, it’s a clear decision. You know what to do.

What makes mutation biomarkers positive in this setting?

For the most part, when we’re looking for mutations, we tend to take any evidence of a mutation as the tumor being positive [for that aberration]. It tends not to come back measured by cells because we’re looking at the DNA and not a cell surface marker. At the cellular level, that’s difficult to interpret. With 

, when we’re doing FISH testing, there is a cutoff saying it should be that 15% of cells or more have that rearrangement. What do you do if it’s 14%? Is that different from 16%? You can do another test looking for the protein. If that’s there, that’s not to be functionally meaningful—especially when we’re testing the blood—because the denominator of DNA is not cancer DNA, it’s all the DNA in the blood. The total cancer DNA may be 0.5%. We don’t know that, but when you get 0.2% coming back with a mutation, that’s a positive result, and you’re going to act on it.

How would you handle this patient, considering the results by IHC?

The relationship between mutations of a cancer and the likelihood of immunotherapy working is antigenicity. The more mutations the cancer has, the more foreign it appears to

the patient’s immune system and the more likely immunotherapy will work.

[This patient has] 14 mutations per megabase; is that a high level or a low level? It depends on the company and the clinical trial. Bristol Myers Squibb uses 10 mutations per megabase [as a threshold for high expression], and AstraZeneca uses 16 mutations per megabase in their durvalumab [Imfinzi] with or without tremelimumab studies, so it depends. It’s something that’s hard to agree upon.

What are the treatment choices, and which factors influence your recommendations for this patient?

You don’t want to give checkpoint inhibitor monotherapy. You want to give chemotherapy alone [or in a combination]. We have platinum [therapy] plus pemetrexed [Alimta] and pembrolizumab [Keytruda]. We also have platinum- and taxane-based therapy plus atezolizumab [Tecentriq] with or without bevacizumab [Avastin].

There was a time when I could look at the NCCN guidelines and they told me what to do for patients with lung cancer. That is no longer the case, and I’m sad to say they’ve lost some of their usefulness. 

In this case, the patient has NSCLC and PD-L1 expression status of 2%. About 70% of cases fall into that category. About 30% are going to be PD-L1 negative, so I’m talking about the 70% [that are positive].

[The NCCN recommends] platinum chemotherapy, pemetrexed [Alimta], and the immune checkpoint inhibitor pembrolizumab as category 1. [You may also use] the platinum/taxane combination with the antiangiogenic [agent] bevacizumab plus anti–PD-L1 atezolizumab. We also have platinum nanoparticle albumin-bound paclitaxel [Abraxane] as an option. There’s no FDA indication for this, but combination immunotherapy [is also suggested].

Do you feel that there’s a difference between the approved drugs for this setting (pembrolizumab, nivolumab [Opdivo], atezolizumab, and durvalumab) in toxicity or efficacy?

Some are PD-1 versus PD-L1, some are humanized antibody versus fully human antibody, and some are immunoglobin G1 [IgG1] versus IgG4. I’m not sure there is a meaningful difference in efficacy or toxicity between PD-1 and PD-L1. IgG1 versus IgG4 would tell you how [the] complement interacts with the antibody; I don’t think that’s relevant to the mechanism. And a fully humanized versus a human antibody would tell you the likelihood of an infusion reaction.

With a humanized antibody—that’s atezolizumab or pembrolizumab—the chance of an infusion reaction is probably 1% to 2%. With a fully human antibody like durvalumab or nivolumab, the risk of an infusion reaction is less than 1%. The single time in my practice I have changed from one checkpoint inhibitor to another was when a patient had pembrolizumab and they had an infusion reaction; not autoimmune toxicity, not pneumonitis, not nephritis, not colitis—they had an allergic infusion reaction. I said, “I’m going to switch to a fully human antibody.”

What are the design and efficacy of relevant trials in this setting?

The KEYNOTE-042 [NCT02220894] study [involves] patients that had PD-L1 status of less than 1%, and they’re receiving immunotherapy [of pembrolizumab] or chemotherapy.

Looking at the progression-free survival [PFS] of the group whose status is at least 50%, there was the greatest benefit in PFS, with a hazard ratio of 0.81 [95% CI, 0.67-0.99; 

 = .017]. For patients with less than 20% PD-L1 status, there was a hazard ratio of 0.94 [95% CI, 0.80-1.11]; it’s not significant. When you look at patients with PD-L1 expression greater than 1%, that’s also not significant [HR, 1.07; 95% CI, 0.94-1.21]. But it’s never worse than chemotherapy.

What’s interesting to me is that the OS is better with immunotherapy than it is with chemotherapy regardless of the PD-L1 cutoff.

There was an exploratory analysis, and [it showed that] no difference in OS whether you give immunotherapy first or chemotherapy first. We don’t know about chemotherapy plus immunotherapy; that has not been formally asked.

Please discuss the important aspects of the IMpower150 study.

IMpower150 [NCT02366143] was a 3-arm study; patients received chemotherapy plus bevacizumab, an antiangiogenic drug; chemotherapy plus the immune checkpoint inhibitor atezolizumab; or both immunotherapy and antiangiogenic therapy.

I want to point out that this trial suggests that immunotherapy works better if the patient has liver metastases. I don’t know why that was looked at [as a stratification factor]. There is another trial that looks at liver metastases, and those patients did worse. I don’t know why this question is being asked. However, if you ask enough questions, you’ll eventually find something.

The other trials that I [mentioned], which added chemotherapy or immunotherapy to chemotherapy, excluded patients with 

positive. Those patients were [about 13% of the entire cohort] were included in this trial, and they benefited. We didn’t know whether they would benefit from the addition of immunotherapy to platinum [therapy and] pemetrexed; that question hadn’t been asked in that study.

How does the CheckMate 227 [NCT02477826] trial compare to these other therapies?

The investigators enrolled about 1700 patients, so it was a big trial. If a patient was negative for PD-L1 expression, there was a different 3-way randomization than if they were PD-L1 positive. For example, in the PD-L1–positive cases, 1 of the arms is single-agent immunotherapy of nivolumab. That was not offered to the patients with negative PD-L1 expression. The second arm was chemotherapy alone, and the third was combination immunotherapy, with nivolumab and ipilimumab [Yervoy]. In the PD-L1–negative comparison, there was combination immunotherapy, chemotherapy alone, and then chemotherapy plus immunotherapy. The main comparisons were combination immunotherapy versus chemotherapy.

The OS in all patients showed an improvement with combination nivolumab plus ipilimumab versus chemotherapy alone [median OS with nivolumab and ipilimumab, 17.1 months versus 14.9 months with chemotherapy; 

 Looking at the subset of patients who had at least 1% PD-L1 expression, there was a signifi cant improvement in OS. I don’t [know] the hazard ratio, which is always more meaningful to me than the 

 value and get it lower just by having more patients on your trial, regardless of the diff erence in efficacy. 

In the PD-L1–negative cases, combination immune checkpoint inhibitor is better than chemotherapy. The only biomarker we’re looking at is PD-L1; we’re not looking at tumor mutation burden.

What else did the CheckMate 227 trial show about biomarkers?

They looked at both PD-L1 and tumor mutation burden [TMB]. In general, we think of [tumors with] high PD-L1 and high mutation burden as more likely to respond to immunotherapy. How much do these groups overlap? If you look at these groups of patients, are they synonymous with each other? Not at all. The overlap is only about 60%, believe it or not.

For PD-L1–negative cases that are TMB low versus high, it’s almost the same number of patients treated—111 versus 86, respectively—and that’s amazing. For PD-L1–positive tumors, more are TMB low than are high. I think that when it comes to single-agent immunotherapy, PD-L1 is a more meaningful biomarker. But when you add in the CTLA-4 [antibody] and you think about what biomarkers perform with those combinations, I would say TMB performs better than PD-L1.

If you add them together, there was benefit across all these [subgroups]. You’re seeing slightly greater benefit with the higher level of PD-L1. But is this the reason, when you look across all [recommended therapies], that the NCCN [recommends] this as a reasonable option for our patients.

Would you change treatment in this patient? If not, why not?

I’m going to assume that it’s a clinically meaningful change, because [if] it’s a 2-mm diff erence, I may say that’s not [clinically meaningful and doesn’t warrant a change].

Another reason to not change treatment is [the possibility of] pseudoprogression. There are data out there that say that if the patient feels better but [the progression is] worse, then it’s pseudoprogression; but if they don’t feel better and [the progression is] worse, then it’s not pseudoprogression. I don’t make my decisions based on that. At The University of Texas Southwestern, we have published cases of patients who clinically deteriorated and went on hospice, and then 18 months later came back for a visit and their tumor had shrunk, so you can’t rely on clinical status [alone].

The other interesting thing about immunotherapy is this concept of hyperprogression. That’s where not only do you have disease progression but also…the cancer growth rate has at least doubled after starting immunotherapy. I’ve had tiny pleural base disease after starting immunotherapy; the entire hemithorax was gone, and the patient couldn’t move his arm.

People do studies trying to quantitate this and determine how often it happens; it’s thought to happen in about 5% of patients who get chemotherapy—they meet that definition of a doubling of growth—and up to 15% of patients with immunotherapy. I had cases in my practice, before the combination era with chemotherapy, where I was giving them immunotherapy and they progressed; I switched them to chemotherapy, and then they had [a great] chemotherapy response. Is that response to chemotherapy, is that resolution of pseudoprogression, or is it both?

What are the options for second-line therapy, and what data support these approaches?

The ramucirumab [Cyramza] clinical trial data came in an era before immunotherapy [was available] for patients with lung cancer. The idea of a positive clinical trial was different. You can enroll 1300 patients to a clinical trial and [have barely any separation of the] Kaplan-Meier survival curves, but they had so many patients on the trial where the 

The REVEL [NCT01168973] study investigated ramucirumab and docetaxel [versus placebo and docetaxel]. Ramucirumab is an antiangiogenic, antivascular EGFR antibody. This was in patients with NSCLC [of all histologies].

The investigators looked at whether the patients progressed within the first month of therapy. Within the first month, the OS hazard ratio was 0.40 [95% CI, 0.22-0.73]. That tells me that [if this patient] progressed within the first 4 weeks of getting firstline therapy, [he would respond to ramucirumab].

1. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Non-Small Cell lung Cancer (version 3.2020). Updated February 11, 2020. Accessed April 15, 2020. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf

2. FDA approves entrectinib for NTRK solid tumors and ROS-1 NSCLC. FDA website. FDA. Updated August 16, 2019. Accessed April 15, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-entrectinib-ntrk-solid-tumors-and-ros-1-nsclc

3. Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. 

2019;393(10183):1819-1830. doi: 0.1016/S0140-6736(18)32409-7

4. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for fi rst-line treatment of metastatic nonsquamous NSCLC. 

 2018;378(24):2288-2301. doi:10.1056/NEJMoa1716948

5. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. 

2018;378(22):2093-2104. doi:10.1056/NEJMoa1801946

6. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. 

2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231

7. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, doubleblind, randomised phase 3 trial. 

 2014;384(9944):665-673. doi: 10.1016/S0140-6736(14)60845-X

In a Targeted Oncology case-based peer perspectives live discussion, David Gerber, MD, addresses the role of biomarkers in guiding treatment decisions for patients with non–small cell lung cancer based on a patient scenario.

Gerber Addresses the Role of Mutations and Treatment in NSCLC at Different Stages

Leslie M. Randall, MD, MAS, professor, Department of Obstetrics and Gynecology Division Director, Division of Gynecologic Oncology, Virginia Commonwealth University, discussed the treatment regimens available for an African American patient with ovarian cancer. 

™: Are you choosing oral regimens over intravenous regimens because of coronavirus disease 2019? Are you making changes to therapy schedules and dosages or choosing different agents?

I’ve tried to change to oral [treatment] where I could. We don’t have a lot of options for oral gynecologic oncology. It’s why the data I’ll be talking about are exciting. Mostly in my purely palliative-intent chemotherapy, I’ve definitely de-escalated doses and schedules. I’ve used more growth factor support, trying to keep people out of the hospital for things that can be prevented, like neutropenia and sepsis. So I’ve changed my practice in that way.

What testing would you order for this patient? Do you typically test for 

and somatic mutations? And, if so, how do you test and when?

We have to test for germline mutations, for the benefit of the family and the patient, to understand their breast cancer risks. I think “Do you have to do somatic testing anymore?” is the debate. If you have a patient with a germline 

mutation, you don’t need to somatic test.

I think many of us still believe that we need to test in order to counsel our patients on what the magnitude of benefit would be—maybe to [switch] our patients who are biomarker negative off therapy and onto something else sooner, if we felt like they weren’t receiving benefit from niraparib [Zejula]. If the drug is approved for all-comers, do you have to test? I think you still have to get a germline 

test, but if you’re not going to change your management based on the results of a somatic 

or a homologous recombination deficiency [HRD] test, it’s a great question.

How do you use HRD testing in this patient population?

The Myriad HRD assay accompanied niraparib with the FDA approval [documentation].1 [The manufacturer] had hoped for a companion diagnostic, but they got a complementary diagnostic. It was because the assay was not discriminatory enough to show that the benefit was isolated to the germline in the HRD [population]. There was still a benefit outside that population. Plus, I don’t feel like the [cutoff] point has been sufficiently defined for the Myriad assay.

Leslie M. Randall, MD, MAS, discussed the treatment regimens available for an African American patient with ovarian cancer. 

May 2020 CBPP Spotlight

Ilson Explores Treatment Options for Patients With Metastatic HCC

Patients With AL Amyloidosis May Benefit From Subcutaneous Daratumumab/CyBorD Combination

Gerber Addresses the Role of Mutations and Treatment in NSCLC at Different Stages

Randall Discusses Testing and Treatment Choices for Ovarian Cancer

Matous Evaluates Treatment Strategies for Transplant-Ineligible Multiple Myeloma

Sabari Examines Frontline and Second-Line Treatment Options in NSCLC

Morgans Discusses How to Sequence Therapies in Metastatic CRPC

Vescio Debates Quadruplet Versus Triplet Therapy in Newly Diagnosed Multiple Myeloma