Immunotherapy Hot Questions and Answers (3): Drugs

10. What PD-1/PD-L1 inhibitors are currently available for lung cancer patients?

There are four PD-1/PD-L1 inhibitors that have been approved by the FDA for lung cancer treatment:

①Pembrolizumab (trade name Keytruda, commonly known as K-drug), made by Merck Sharp & Dohme, is approved by the FDA for first-line and second-line treatment of NSCLC;

② Nivolumab (trade name Opdivo, commonly known as O drug), manufactured by Bristol-Myers Squibb, was approved for second-line treatment of NSCLC; in September 2018, the FDA approved nabumab for the treatment of patients with metastatic small cell lung cancer (SCLC) who are susceptible to platinum-based chemotherapy and at least one other treatment did not work.

③ Atezolizumab (trade name Tecentriq, commonly known as T-drug), manufactured by Roche, is approved for second-line treatment of NSCLC;

④ Durvalumab (trade name Imfinzi, commonly known as the I drug), manufactured by AstraZeneca and approved for second-line treatment of NSCLC.

Among them, Nabumab (Nivolumab) was approved by the State Drug Administration for marketing in China in June 2018 (name: Navulizumab). Pembrolizumab (Pembrolizumab) followed suit, having been approved for marketing in the same year in July (name: pablizumab) for the treatment of advanced malignant melanoma, with related clinical studies for lung cancer underway. The remaining two are not currently available in China.

11. Is there a difference in the efficacy of PD-1 inhibitors and PD-L1 inhibitors?

The PD-1 inhibitors currently approved for NSCLC treatment include Nivolumab (made by Bristol-Myers Squibb) and Pembrolizumab (made by Merck Sharp & Dohme), and PD-L1 inhibitors include Atezolizumab (made by Roche) and Durvalumab (made by AstraZeneca). Because of the difference in manufacturers, there is no “head-to-head” (head-to-head) efficacy data between these drugs.

By mechanism of action, PD-1 inhibitors block PD-1 on lymphocytes, and PD-L1 inhibitors block PD-L1 on the tumor surface. Atezolizumab) and 28.4% (Durvalumab).

So it appears that PD-L1 inhibitors are more effective than PD-1 inhibitors, but these studies were conducted at different times, and the PD-1 inhibitor second-line treatment studies did not screen for enrollment of specific populations (PD-L1 expression-positive), so the reflections are in the total population. After screening by markers, both Pembrolizumab and Nivolumab first-line therapy also had efficiencies between 25% and 30%.

Therefore, there is no significant difference in efficacy between PD-1 inhibitors and PD-L1 inhibitors based on the available data. In terms of adverse effects, they are similar, with a somewhat lower incidence of adverse effects associated with PD-L1 antibodies.

In the future, I look forward to the opportunity for these 4 drugs to play “two-by-two”, and the truth will be revealed as to who is better.

12. What are the characteristics of each of the drugs currently available?

The four PD-1/PD-L1 inhibitors currently approved by the FDA for NSCLC treatment (Nivolumab, Pembrolizumab, Atezolizumab, and Durvalumab) can all be used for second-line treatment of NSCLC, but only Pembrolizumab can be used in tumor tissue PD-L1 expression greater than 50% in patients with advanced NSCLC in first-line treatment.

Below, we compare several aspects of their efficacy, adverse effects, and current prices in approved studies to see how they differ in second-line treatment of NSCLC (table below). pembrolizumab has been filed and is expected to be approved in 2018, and the prices in the table use Hong Kong and US prices.

Drug name

Dose, usage

Efficacy

Adverse reactions

Half-life

Price

Nivolumab

3 mg/kg, 2 week course, intravenous

CheckMate017

OS (overall survival) in patients with advanced squamous carcinoma: 9.2 months; ORR (objective remission rate): 20%.

CheckMate057 study

OS in patients with advanced adenocarcinoma: 12.2 months; ORR: 19%

Lethargy, skin adverse reactions, diarrhea, etc.

26.7 days

Specification: 100 mg/stem, Price: HK$28,000/stem

Pembrolizumab

2 mg/kg, 3 weeks course, intravenous

KEYNOTE-010

OS in patients with advanced NSCLC: 10.4 months; ORR: 18%.

PD-L1> OS in 50% of patients, 14.9 months; ORR: 30%

Lethargy, rash, GI reaction, etc.

26 days

Specification: 100 mg/spot, price: HK$42,000/spot

Atezolizumab

1200 mg, 3 week course, intravenous

POPLAR study:

OS in PD-L1-positive patients with advanced NSCLC: 12.6 months; ORR: 15%.

OAK study: OS in PD-L1-positive patients with advanced NSCLC: 13.8 months; ORR: 18%.

Fatigue, decreased appetite, shortness of breath, cough, nausea, constipation

27 days

Specification: 1200 mg/spot, price: $12,500/month

Durvalumab

10 mg/kg, 2 week course, intravenous

PACIFIC study:

ORR in patients with stage III NSCLC without disease progression after concurrent radiotherapy: 28.4% (OS data not yet mature)

Fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection

17 days

Specification: 120 mg/spot, priced: $15,000/month

The data in the comparison table show how these 4 agents compare in terms of disease remission, prolonged survival, and adverse effects in second-line treatment of NSCLC, as detailed in the analysis in the answer to question 32.

In PD-L1>50% of patients, it appears that the K drug is somewhat more efficacious. However, none of these data are the result of a direct comparison between the two drugs, so they should only be used as a reference. Price wise, Nivolumab and Pembrolizumab are similar, Atezolizumab is almost double the price of the first two, and Durvalumab is more expensive than Atezolizumab.

In addition, in addition to being able to be used for NSCLC treatment, these 4 drugs were also approved for other tumors. A comparison of the major indications for the 4 drugs is shown in the table below.

Drug name

Indications

Nivolumab

Melanoma, NSCLC, metastatic small cell lung cancer, renal cancer, classical Hodgkin’s lymphoma, head and neck squamous carcinoma, uroepithelial carcinoma, metastatic colorectal cancer with MSI-H (high microsatellite instability) and dMMR (defective mismatch gene repair), and hepatocellular carcinoma

Pembrolizumab

Melanoma, NSCLC, head and neck tumors, classical Hodgkin’s lymphoma, uroepithelial carcinoma, solid tumors with MSI-H and dMMR, gastric cancer

Atezolizumab

Urothelial carcinoma, NSCLC

Durvalumab

Uroepithelial carcinoma, NSCLC

13. What is the price of this drug?

Refer to the right column of Table 1 in the previous question.

14. Is this drug available in China? What is the current stage?

Nivolumab was approved for marketing in China in June 2018. pembrolizumab was also launched in July of the same year for the treatment of advanced malignant melanoma, and related clinical studies are ongoing for lung cancer.

Studies of Atezolizumab and Durvalumab enrolling Chinese patients are ongoing and are still some time away from launch.

15. Only K drugs are approved for first-line, so does that mean K drugs are better than O drugs? Should K drugs also be preferred in second line?

O (trade name Opdivo) refers to Nivolumab, manufactured by Bristol-Myers Squibb, which has been approved by the FDA for second-line treatment of advanced NSCLC (squamous and adenocarcinoma). in September 2018, the FDA approved nabumab for the treatment of patients with metastatic small cell lung cancer (SCLC) In September 2018, the FDA approved nabumab for the treatment of patients with metastatic small cell lung cancer (SCLC) who are not responding to platinum-based chemotherapy and at least one other treatment.

K drug (trade name Keytruda) refers to Pembrolizumab, manufactured by Merck Sharp & Dohme and approved by the FDA in advanced NSCLC as first-line therapy for PD-L1 expression above 50% and second-line therapy for PD-L1 expression above 1%.

The K drug was approved by the FDA for first-line treatment of patients with advanced NSCLC because it delivered better survival and higher disease remission rates as first-line treatment in the KEYNOTE024 study. However, this is a comparison of K drugs with chemotherapy, not a direct comparison study of K drugs with O drugs, and does not indicate that K drugs are superior to O drugs.

Both O and K drugs can be used as second-line therapy; are they superior or inferior? At this point, the two drugs have not had a chance to get in the ring for a direct comparison (no head-to-head prospective controlled studies yet), so we can only compare them in terms of several aspects of their efficacy, adverse effects, and current price in approved studies to see what the differences are in second-line therapy (see Table 1 in question 12).

By comparing the data in the table, it is clear that in second-line therapy for NSCLC, there is no significant difference between O and K drugs in terms of disease remission, prolonged survival, and adverse effects. However, in PD-L1>50% of patients, it seems that K drugs are somewhat more effective. However, none of these data are the result of a direct comparison between the two drugs, so they can only be used as a reference. In terms of price, the O drug was slightly cheaper than the K drug, but the difference was minimal.

The CHECKMATE026 study, published at the same time as the KEYNOTE024 study, failed to meet the primary clinical endpoint (PFS) with O in the first line. However, the results of that study may have been related to its failure to screen for appropriate patients, and the investigators’ subsequent analysis found that after switching to screening patients with tumor mutational load (TMB) rather than PD-L1 expression>5%, they were able to better identify a population for which O drug therapy was effective. Thus, the jury is still out on exactly how effective O drugs are in first-line therapy.

16. Can I buy the drug from abroad or Hong Kong and inject it myself?

Neither PD-1/PD-L1 inhibitors are currently approved in China, so some patients have purchased drugs from abroad or Hong Kong. It is important to note that according to the drug instructions, PD-1/PD-L1 inhibitors need to be stored at 2 °C to 8 °C, usually in ice boxes. If not properly stored during transportation after purchase, PD-1/PD-L1 inhibitors may fail.

The dosing of PD-1/PD-L1 inhibitors needs to be calculated based on the user’s body weight and requires intravenous administration by a specially trained nurse. Furthermore, PD-1/PD-L1 inhibitor therapy can lead to serious adverse reactions (interstitial pneumonia, myocarditis, encephalitis, etc.), which are fatal, although not very frequent. If you buy the injections on your own, when an adverse reaction occurs, even a serious one, it can have very serious consequences.

Therefore, patients are not advised to buy the drug for injection from abroad or Hong Kong. Navulizumab and pablizumab have now been approved for marketing in June and July 2018, respectively, and do not need to be purchased overseas. There are also a number of clinical trials underway for other drugs, and patients who need this treatment can access it through their physician’s participation in the trials.