In Aug 2023 I was diagnosed with GI Junction cancer that had spread to 3 celiac lymph nodes, because of the spread surgery was not an option, dna test of cancer cells showed MSI-High and TMB-High so I have been on 4 rounds on Yervoy every 6 weeks and Opdivo every 2 weeks. In Aug 2024 CT scan with contrast and EGD with biopsy no longer shows any Cancer. I did have adverse event in Jan 2024 and now have Hypothyroidism and Adrenal Insufficiency, I take Prednisone and Levothyroxine daily. Present treatment plan is to continue Opdivo until the two year mark.
Error: At 6:20 I mistakenly said B-cells enter the lymphocytes. It should be lymph nodes, ie, B-cells enter the lymph nodes (not lymphocytes). The T-cells also enter the lymph nodes (not lymphocytes) after matured in the thymus.
- Urothelial carcinoma- In CheckMate 901, nivolumab was added to chemotherapy: With 304 patients randomized to each arm, nivolumab add-on led to a median overall survival of 21.7 months versus 18.9 months with stand-alone gemcitabine/cisplatin, a 22% drop in the risk of mortality (P = .0171). It's the first time that adding immunotherapy to first-line chemotherapy improved survival in metastatic urothelial carcinoma. However, when compared with pembrolizumab + enfortumab vedotin, the overall survival seems to be shorter. www.annalsofoncology.org/article/S0923-7534(23)04271-0/fulltext
New ICI for metastatic cutaneous squamous cell carcinoma: Cosibelimab The US Food and Drug Administration (FDA) has approved the immune checkpoint inhibitor cosibelimab (Unloxcyt; Checkpoint Therapeutics, Inc.) for the treatment of adults with metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) who are not candidates for curative surgery or curative radiation. The programmed death ligand-1 (PD-L1)-blocking antibody is the first and only treatment of its kind approved for advanced CSCC, according to a Checkpoint Therapeutics press release. The FDA approval was based on findings from the multicenter, open-label Study CK-301-101 trial of 109 patients. In that trial, the objective response rate (ORR) was 47% in 78 patients with metastatic CSCC and 48% in 31 patients with locally advanced CSCC. Median duration of response (DOR) in treated patients was not reached in those with metastatic disease and was 17.7 months in those with locally advanced disease, according to the FDA approval notice.
New FDA approval: Pembrolizumab as a neoadjuvant with platinum based chemotherapy and adjuvant therapy KEYNOTE-671 (NCT03425643), a multicenter, randomized, double-blind, placebo-controlled trial in 797 patients with previously untreated and resectable Stage II, IIIA, or IIIB (N2) NSCLC by AJCC 8th edition. Patients were randomized (1:1) to either pembrolizumab or placebo, with platinum-based chemotherapy, every 3 weeks for 4 cycles (neoadjuvant treatment) followed by either continued single-agent pembrolizumab or placebo, every 3 weeks for up to 13 cycles (adjuvant treatment). Chemotherapy details and surgical window are provided in the above drug label link. The major efficacy outcome measures were overall survival (OS) and investigator-assessed event-free survival (EFS). Median OS was not reached in the pembrolizumab arm (95% CI: not estimable [NE], NE) and 52.4 months for those receiving placebo (95% CI: 45.7, NE) (hazard ratio [HR] 0.72 [95% CI: 0.56, 0.93]; p-value=0.0103). Median EFS was not reached in the pembrolizumab arm (95% CI: 34.1 months, NE) and 17 months in the placebo arm (95% CI: 14.3, 22.0) (HR 0.58 [95% CI: 0.46, 0.72]; p-value=
Pembrolizumab + chemotherapy improves 31-month survival over chemotherapy alone in HER2 (-) metastatic gastric or GEJ adenocarcinoma, regardless of PD-L1 (KEYNOTE-859) www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00515-6/fulltext At Median follow up of 31 months, Median OS was 12.9 mo with pembro + chemo vs 11.5 mo with placebo + chemo (HR 0.78, 95% CI 0.70-0.87; P < 0.0001). Median PFS was 6.9 mo vs 5.6 mo (HR 0.76, 95% CI 0.67-0.85; P < 0.0001). Results were generally consistent across subgroups, including those by PD-L1 CPS. ORR was 51.3% vs 42.0% (P = 0.00009). Median DOR was 8.0 mo vs 5.7 mo. Grade 3-5 treatment-related AEs occurred in 59.4% of 785 pts treated with pembro + chemo and 51.1% of 787 treated with placebo + chemo; 1.0% and 2.0%, respectively, died of treatment-related AEs. However, this result is somewhat conflicting when compared with those of KEYNOTE-062: The median overall survival of the patients who had pembrolizumab alone was compared with pembrolizumab + chemotherapy. OS of the group w/ CPS 10 or higher: 17.4 vs 10.8 months. In KEYNOTE-859, median overall survival in the CPS 10 or higher group was 15.7 months. In other words, adding chemotherapy to the pembrolizumab in this group (CPS>10) may not be beneficial but more toxic. Furthermore, the OS of the group w/CPS 1 or higher: pembrolizumab + chemo was not better than chemotherapy alone; and pembrolizumab alone was not inferior to chemotherapy.
Keynote 811 trial update ( ASCO GI Symposium Jan.2024): The trial randomized HER2-positive patients with unresectable advanced gastroesophageal junction adenocarcinoma irrespective of PDL-1 status to pembrolizumab plus trastuzumab and chemotherapy or trastuzumab and chemotherapy alone. Median overall survival in HER2-positive patients with a PD-L1 CPS of 1 or more was 20.0 months vs 15.7 months (hazard ratio [HR], 0.81; 95% CI, 0.67-0.98) compared with 20.0 vs 16.8 months in the overall cohort (HR, 0.84; 95% CI, 0.70-1.01). However, patients with PD-L1 CPS below 1 showed limited benefit from pembrolizumab (HR, 1.41 for overall survival; 95% CI, 0.90-2.20).
-Urothelial Carcinoma- Enfortumab vedotin (Padcev) plus pembrolizumab (Keytruda) is being called the new standard of care for the upfront treatment of locally advanced/metastatic urothelial carcinoma, regardless of PD-L1, Cisplatin-ineligibility, or presence of visceral metastasis. It means that platinum chemotherapy is not the first line, but the second line therapy. www.annalsofoncology.org/article/S0923-7534(23)04270-9/fulltext EV-302/Keynote A39, a phase 3 trial was presented at the 2023 European Society for Medical Oncology annual meeting. The combination soundly beat the current standard of care - platinum-based chemotherapy - with a median overall survival of 31.5 months among 442 subjects versus 16.1 months among 444 randomized to gemcitabine with cisplatin or carboplatin, an unprecedented 53% drop in the risk of mortality (P < .00001).
FDA approval of SQ nivolumab: The US Food and Drug Administration has approved subcutaneous nivolumab and hyaluronidase-nvhy (Opdivo Qvantig) for some of the same indications as intravenous nivolumab (Opdivo). Nivolumab-hyaluronidase is approved to treat adults with renal cell carcinoma, melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, urothelial carcinoma, colorectal cancer, hepatocellular carcinoma, esophageal carcinoma, gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. Nivolumab-hyaluronidase is approved for use as monotherapy and in combination with chemotherapy or cabozantinib but not in combination with intravenous ipilimumab. The approval is supported by results from the CHECKMATE-67T trial. This trial (NCT04810078) included 495 patients with advanced or metastatic clear cell renal cell carcinoma who had received no more than 2 prior systemic therapies. The patients were randomly assigned to receive subcutaneous nivolumab-hyaluronidase (n=248) or intravenous nivolumab (n=247). The predefined acceptance margin for pharmacokinetic endpoints was met. The lower boundary of the 90% confidence interval of geometric mean ratios was not less than 0.8 for both the time-averaged serum concentration of nivolumab over the first 28 days of treatment and the trough serum concentration of nivolumab at steady state. The overall response rate was 24% in the nivolumab-hyaluronidase arm and 18% in the intravenous nivolumab arm. Safety outcomes were generally similar between the arms. The most common adverse events observed were fatigue, musculoskeletal pain, pruritus, rash, and cough. The recommended doses of nivolumab-hyaluronidase vary by indication.
The US Food and Drug Administration (FDA) has approved tislelizumab-jsgr (Tevimbra, BeiGene, Ltd.) as second-line monotherapy for certain adult patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC). Specifically, the novel checkpoint inhibitor is approved for patients with ESCC after prior systemic chemotherapy that did not include a programmed death-ligand 1 (PD-L1) inhibitor. Approval was based on findings from the open-label, phase 3 RATIONALE 302 trial showing a statistically significant and clinically meaningful overall survival benefit with tislelizumab vs investigator's choice of chemotherapy. Study participants included 512 adults enrolled at 123 research sites in 11 countries in Europe, Asia, and North America. Patients were randomly assigned to receive intravenous tislelizumab, a humanized immunoglobulin G4 anti-programmed cell death protein 1 monoclonal antibody, at a dose of 200 mg every 3 weeks or investigator's choice of standard chemotherapy with paclitaxel, docetaxel, or irinotecan until disease progression, unacceptable toxicity, or study withdrawal. Median overall survival in the intention-to-treat population, the primary study endpoint, was 8.6 months vs 6.3 months in the chemotherapy arms (hazard ratio [HR], 0.70). The survival benefit was observed across predefined subgroups, including baseline PD-L1 status and region. The new agent was also associated with improved overall response rate (20.4% vs 9.8%) and more durable response (median duration of response of 7.1 vs 4.0 months; HR, 0.42) compared with chemotherapy. The most common adverse reactions for tislelizumab, each occurring in at least 20% of treated patients, included increased glucose and decreased hemoglobin, lymphocytes, sodium, and albumin as well as increased alkaline phosphatase, anemia, fatigue, increased aspartate aminotransferase, musculoskeletal pain, decreased weight, increased alanine aminotransferase, and cough. Fewer patients in the tislelizumab arm experienced grade 3 or greater treatment-emergent adverse events compared with the chemotherapy arm (46% vs 68%, respectively), and fewer patients discontinued tislelizumab vs chemotherapy due to such an event (7% vs 14%).
***New data *** How long patients have to take immunotherapy ? Answer: In the absence of progression, patients in response after 2 years of immunotherapy can safely discontinue treatment and transition to active surveillance. Overall survival (OS) outcomes did not significantly differ between patients with advanced non-small cell lung cancer (NSCLC) who received immunotherapy indefinitely or for a fixed duration. jamanetwork.com/journals/jamaoncology/fullarticle/2805798 Many clinical trials of immunotherapy in patients with NSCLC set a fixed therapy duration of 2 years, but in clinical practice, treatment often extends beyond this point. Extended exposure to immune checkpoint inhibitors can be associated with increased toxicities and a high financial burden.
After ICPi was discontinued for severe irAEs, can the ICPi be resumed after patient recovered? A recent article suggested ‘watchful waiting’ instead of resuming ICPi especially when patient had response because about 40% continued in remission and 23% developed oligometastasis which could be controlled with radiation therapy. www.sciencedirect.com/science/article/pii/S2666364322001655
Thank you for your lectures 😊
Thank you for wonderful lecture. Can you please make a lecture on chemotherapy 2023? Thank you
In Aug 2023 I was diagnosed with GI Junction cancer that had spread to 3 celiac lymph nodes, because of the spread surgery was not an option, dna test of cancer cells showed MSI-High and TMB-High so I have been on 4 rounds on Yervoy every 6 weeks and Opdivo every 2 weeks. In Aug 2024 CT scan with contrast and EGD with biopsy no longer shows any Cancer. I did have adverse event in Jan 2024 and now have Hypothyroidism and Adrenal Insufficiency, I take Prednisone and Levothyroxine daily. Present treatment plan is to continue Opdivo until the two year mark.
Error:
At 6:20 I mistakenly said B-cells enter the lymphocytes. It should be lymph nodes, ie, B-cells enter the lymph nodes (not lymphocytes).
The T-cells also enter the lymph nodes (not lymphocytes) after matured in the thymus.
Can you please tell if polycythemia can cause dehydration?
- Urothelial carcinoma-
In CheckMate 901, nivolumab was added to chemotherapy: With 304 patients randomized to each arm, nivolumab add-on led to a median overall survival of 21.7 months versus 18.9 months with stand-alone gemcitabine/cisplatin, a 22% drop in the risk of mortality (P = .0171).
It's the first time that adding immunotherapy to first-line chemotherapy improved survival in metastatic urothelial carcinoma.
However, when compared with pembrolizumab + enfortumab vedotin, the overall survival seems to be shorter.
www.annalsofoncology.org/article/S0923-7534(23)04271-0/fulltext
New ICI for metastatic cutaneous squamous cell carcinoma: Cosibelimab
The US Food and Drug Administration (FDA) has approved the immune checkpoint inhibitor cosibelimab (Unloxcyt; Checkpoint Therapeutics, Inc.) for the treatment of adults with metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) who are not candidates for curative surgery or curative radiation.
The programmed death ligand-1 (PD-L1)-blocking antibody is the first and only treatment of its kind approved for advanced CSCC, according to a Checkpoint Therapeutics press release. The FDA approval was based on findings from the multicenter, open-label Study CK-301-101 trial of 109 patients.
In that trial, the objective response rate (ORR) was 47% in 78 patients with metastatic CSCC and 48% in 31 patients with locally advanced CSCC. Median duration of response (DOR) in treated patients was not reached in those with metastatic disease and was 17.7 months in those with locally advanced disease, according to the FDA approval notice.
New FDA approval:
Pembrolizumab as a neoadjuvant with platinum based chemotherapy and adjuvant therapy
KEYNOTE-671 (NCT03425643), a multicenter, randomized, double-blind, placebo-controlled trial in 797 patients with previously untreated and resectable Stage II, IIIA, or IIIB (N2) NSCLC by AJCC 8th edition. Patients were randomized (1:1) to either pembrolizumab or placebo, with platinum-based chemotherapy, every 3 weeks for 4 cycles (neoadjuvant treatment) followed by either continued single-agent pembrolizumab or placebo, every 3 weeks for up to 13 cycles (adjuvant treatment). Chemotherapy details and surgical window are provided in the above drug label link.
The major efficacy outcome measures were overall survival (OS) and investigator-assessed event-free survival (EFS). Median OS was not reached in the pembrolizumab arm (95% CI: not estimable [NE], NE) and 52.4 months for those receiving placebo (95% CI: 45.7, NE) (hazard ratio [HR] 0.72 [95% CI: 0.56, 0.93]; p-value=0.0103). Median EFS was not reached in the pembrolizumab arm (95% CI: 34.1 months, NE) and 17 months in the placebo arm (95% CI: 14.3, 22.0) (HR 0.58 [95% CI: 0.46, 0.72]; p-value=
Pembrolizumab + chemotherapy improves 31-month survival over chemotherapy alone in HER2 (-) metastatic gastric or GEJ adenocarcinoma, regardless of PD-L1
(KEYNOTE-859)
www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00515-6/fulltext
At Median follow up of 31 months,
Median OS was 12.9 mo with pembro + chemo vs 11.5 mo with placebo + chemo (HR 0.78, 95% CI 0.70-0.87; P < 0.0001). Median PFS was 6.9 mo vs 5.6 mo (HR 0.76, 95% CI 0.67-0.85; P < 0.0001). Results were generally consistent across subgroups, including those by PD-L1 CPS. ORR was 51.3% vs 42.0% (P = 0.00009). Median DOR was 8.0 mo vs 5.7 mo. Grade 3-5 treatment-related AEs occurred in 59.4% of 785 pts treated with pembro + chemo and 51.1% of 787 treated with placebo + chemo; 1.0% and 2.0%, respectively, died of treatment-related AEs.
However, this result is somewhat conflicting when compared with those of KEYNOTE-062:
The median overall survival of the patients who had pembrolizumab alone was compared with pembrolizumab + chemotherapy.
OS of the group w/ CPS 10 or higher: 17.4 vs 10.8 months. In KEYNOTE-859, median overall survival in the CPS 10 or higher group was 15.7 months. In other words, adding chemotherapy to the pembrolizumab in this group (CPS>10) may not be beneficial but more toxic.
Furthermore, the OS of the group w/CPS 1 or higher: pembrolizumab + chemo was not better than chemotherapy alone; and pembrolizumab alone was not inferior to chemotherapy.
Keynote 811 trial update ( ASCO GI Symposium Jan.2024):
The trial randomized HER2-positive patients with unresectable advanced gastroesophageal junction adenocarcinoma irrespective of PDL-1 status to pembrolizumab plus trastuzumab and chemotherapy or trastuzumab and chemotherapy alone.
Median overall survival in HER2-positive patients with a PD-L1 CPS of 1 or more was 20.0 months vs 15.7 months (hazard ratio [HR], 0.81; 95% CI, 0.67-0.98) compared with 20.0 vs 16.8 months in the overall cohort (HR, 0.84; 95% CI, 0.70-1.01). However, patients with PD-L1 CPS below 1 showed limited benefit from pembrolizumab (HR, 1.41 for overall survival; 95% CI, 0.90-2.20).
-Urothelial Carcinoma-
Enfortumab vedotin (Padcev) plus pembrolizumab (Keytruda) is being called the new standard of care for the upfront treatment of locally advanced/metastatic urothelial carcinoma, regardless of PD-L1, Cisplatin-ineligibility, or presence of visceral metastasis.
It means that platinum chemotherapy is not the first line, but the second line therapy.
www.annalsofoncology.org/article/S0923-7534(23)04270-9/fulltext
EV-302/Keynote A39, a phase 3 trial was presented at the 2023 European Society for Medical Oncology annual meeting.
The combination soundly beat the current standard of care - platinum-based chemotherapy - with a median overall survival of 31.5 months among 442 subjects versus 16.1 months among 444 randomized to gemcitabine with cisplatin or carboplatin, an unprecedented 53% drop in the risk of mortality (P < .00001).
Is immunotherapy doable in case of Hodgkin lymphoma ?
Yes
Watch my lecture of immunotherapy
FDA approval of SQ nivolumab:
The US Food and Drug Administration has approved subcutaneous nivolumab and hyaluronidase-nvhy (Opdivo Qvantig) for some of the same indications as intravenous nivolumab (Opdivo).
Nivolumab-hyaluronidase is approved to treat adults with renal cell carcinoma, melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, urothelial carcinoma, colorectal cancer, hepatocellular carcinoma, esophageal carcinoma, gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.
Nivolumab-hyaluronidase is approved for use as monotherapy and in combination with chemotherapy or cabozantinib but not in combination with intravenous ipilimumab.
The approval is supported by results from the CHECKMATE-67T trial. This trial (NCT04810078) included 495 patients with advanced or metastatic clear cell renal cell carcinoma who had received no more than 2 prior systemic therapies. The patients were randomly assigned to receive subcutaneous nivolumab-hyaluronidase (n=248) or intravenous nivolumab (n=247).
The predefined acceptance margin for pharmacokinetic endpoints was met. The lower boundary of the 90% confidence interval of geometric mean ratios was not less than 0.8 for both the time-averaged serum concentration of nivolumab over the first 28 days of treatment and the trough serum concentration of nivolumab at steady state.
The overall response rate was 24% in the nivolumab-hyaluronidase arm and 18% in the intravenous nivolumab arm.
Safety outcomes were generally similar between the arms. The most common adverse events observed were fatigue, musculoskeletal pain, pruritus, rash, and cough.
The recommended doses of nivolumab-hyaluronidase vary by indication.
The US Food and Drug Administration (FDA) has approved tislelizumab-jsgr (Tevimbra, BeiGene, Ltd.) as second-line monotherapy for certain adult patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC).
Specifically, the novel checkpoint inhibitor is approved for patients with ESCC after prior systemic chemotherapy that did not include a programmed death-ligand 1 (PD-L1) inhibitor.
Approval was based on findings from the open-label, phase 3 RATIONALE 302 trial showing a statistically significant and clinically meaningful overall survival benefit with tislelizumab vs investigator's choice of chemotherapy.
Study participants included 512 adults enrolled at 123 research sites in 11 countries in Europe, Asia, and North America. Patients were randomly assigned to receive intravenous tislelizumab, a humanized immunoglobulin G4 anti-programmed cell death protein 1 monoclonal antibody, at a dose of 200 mg every 3 weeks or investigator's choice of standard chemotherapy with paclitaxel, docetaxel, or irinotecan until disease progression, unacceptable toxicity, or study withdrawal.
Median overall survival in the intention-to-treat population, the primary study endpoint, was 8.6 months vs 6.3 months in the chemotherapy arms (hazard ratio [HR], 0.70). The survival benefit was observed across predefined subgroups, including baseline PD-L1 status and region. The new agent was also associated with improved overall response rate (20.4% vs 9.8%) and more durable response (median duration of response of 7.1 vs 4.0 months; HR, 0.42) compared with chemotherapy.
The most common adverse reactions for tislelizumab, each occurring in at least 20% of treated patients, included increased glucose and decreased hemoglobin, lymphocytes, sodium, and albumin as well as increased alkaline phosphatase, anemia, fatigue, increased aspartate aminotransferase, musculoskeletal pain, decreased weight, increased alanine aminotransferase, and cough.
Fewer patients in the tislelizumab arm experienced grade 3 or greater treatment-emergent adverse events compared with the chemotherapy arm (46% vs 68%, respectively), and fewer patients discontinued tislelizumab vs chemotherapy due to such an event (7% vs 14%).
***New data ***
How long patients have to take immunotherapy ?
Answer:
In the absence of progression, patients in response after 2 years of immunotherapy can safely discontinue treatment and transition to active surveillance.
Overall survival (OS) outcomes did not significantly differ between patients with advanced non-small cell lung cancer (NSCLC) who received immunotherapy indefinitely or for a fixed duration.
jamanetwork.com/journals/jamaoncology/fullarticle/2805798
Many clinical trials of immunotherapy in patients with NSCLC set a fixed therapy duration of 2 years, but in clinical practice, treatment often extends beyond this point. Extended exposure to immune checkpoint inhibitors can be associated with increased toxicities and a high financial burden.
What are the chances for someone with hcc 6.2 centimeter tumor in liver if immunotherapy is done
About 30% of patients with metastatic HCC will respond. If responded, only God knows how long the response continues (usually for a long time)
@@stanleykim1924 thanks and god bless you
After ICPi was discontinued for severe irAEs, can the ICPi be resumed after patient recovered?
A recent article suggested ‘watchful waiting’ instead of resuming ICPi especially when patient had response because about 40% continued in remission and 23% developed oligometastasis which could be controlled with radiation therapy.
www.sciencedirect.com/science/article/pii/S2666364322001655